Phase I/II, Observer-blind, Safety, Reactogenicity and Immunogenicity Study of GSK Biologicals' Respiratory Syncytial Virus (RSV) Vaccine GSK3844766A in Subjects Aged 18-40 or 60-80 Years
Phase: PHASE1
Conditions: Respiratory Syncytial Virus Infections
Sponsor: GlaxoSmithKline

 
 
 
 
 
Protocol Amendment 1 
 
 
Phase I/II, observer-blind, safety, reactogenicity and immunogenicity study of GSK 
Biologicals’ respiratory syncytial virus (RSV) vaccine GSK3844766A in subjects 
aged 18-40 or 60-80 years 
 
 
NCT ID: NCT03814590 
EudraCT Number: 2018-000849-38 
 
 
 
Amendment 1 Final: 13 May 2020 
 
 

CONFIDENTIAL 
208851 (RSV OA=ADJ-002) 
Protocol Amendment 1 Final 
13-MAY-2020 
1 
 
Clinical Study Protocol 
Sponsor: 
GlaxoSmithKline Biologicals SA 
Rue de l’Institut, 89 
1330 Rixensart, Belgium 
Primary Study vaccine 
and number 
GlaxoSmithKline (GSK) Biologicals’ investigational 
respiratory syncytial virus (RSV) vaccine BIO RSV 
OA=ADJ (GSK3844766A): 
• RSVPreF3 recombinant antigen, 30 µg 
• RSVPreF3 recombinant antigen, 30 µg adjuvanted 
with AS01E  
• RSVPreF3 recombinant antigen, 30 µg adjuvanted 
with AS01B  
• RSVPreF3 recombinant antigen, 60 µg  
• RSVPreF3 recombinant antigen, 60 µg adjuvanted 
with AS01E  
• RSVPreF3 recombinant antigen, 60 µg adjuvanted 
with AS01B  
• RSVPreF3 recombinant antigen, 120 µg  
• RSVPreF3 recombinant antigen, 120 µg adjuvanted 
with AS01E 
• RSVPreF3 recombinant antigen, 120 µg adjuvanted 
with AS01B  
Other Study 
vaccine/product 
Control: Saline solution 
eTrack study number 
and Abbreviated Title 
208851 (RSV OA=ADJ-002) 
Investigational New 
Drug (IND) number 
18540 
EudraCT number 
2018-000849-38 
Date of protocol 
Final Version 2: 11 September 2018 
Date of administrative 
change / amendment 
Administrative change 1 Final: 25 July 2019 
Amendment 1 Final: 13 May 2020 
Title 
Phase I/II, observer-blind, safety, reactogenicity and 
immunogenicity study of GSK Biologicals’ respiratory 
syncytial virus (RSV) vaccine GSK3844766A in subjects 
aged 18-40 or 60-80 years.  
208851 | Protocol Amendment 1 19 May 2020 | TMF-1772243 | 1.0

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CONFIDENTIAL 
208851 (RSV OA=ADJ-002) 
Protocol Amendment 1 Final 
13-MAY-2020 
3 
Protocol Amendment 1 Sponsor Signatory Approval 
eTrack study number and 
Abbreviated Title 
208851 (RSV OA=ADJ-002) 
IND number 
18540 
EudraCT number 
2018-000849-38  
Date of protocol amendment 
Amendment 1 Final: 13 May 2020 
Detailed Title  
A Phase I/II, randomized, placebo-controlled, 
observer-blind, multicenter study to evaluate the 
safety, reactogenicity and immunogenicity of GSK 
Biologicals’ investigational respiratory syncytial 
virus (RSV) vaccine (adjuvanted with AS01E or 
AS01B or unadjuvanted) when administered 
intramuscularly according to a 0, 2 month schedule in 
adults aged 18-40 or 60-80 years.  
Sponsor signatory  
Narcisa Mesaros  
Clinical and Epidemiology R&D Project Lead, Older 
Adults project 
 
 
Signature 
 
 
 
Date 
 
 
 
 
 
208851 | Protocol Amendment 1 19 May 2020 | TMF-1772243 | 1.0

CONFIDENTIAL 
208851 (RSV OA=ADJ-002) 
Protocol Amendment 1 Final 
13-MAY-2020 
4 
Protocol Amendment 1 Rationale 
Amendment number: 
Amendment 1, 13 May 2020 
Rationale/background for changes: 
This Protocol Amendment 1 outlines measures that may be applicable during special 
circumstances (e.g., Coronavirus disease 2019 [COVID-19] pandemic). The purpose of 
the amendment is to protect subject’s welfare and safety, and as far as possible ensure 
the potential benefit to the subject and promote data integrity. A new section has been 
added (Section 5.10) to provide guidance on adapting study procedures during special 
circumstances, such as COVID-19 pandemic. 
The measures include the following: 
• 
Instruction for the remaining scheduled visit (Visit 8): Planned study visit can 
proceed, if the study subjects are healthy and allowed to come to the site to have 
the blood sample and safety information collected. If the visit is impacted due to 
the national guidelines and/or site restrictions linked to the special circumstances, 
and it is not possible to collect the biological samples within the interval 
predefined in the protocol (see Table 8), the samples will be encoded as missing 
and encoded as protocol deviation. If the visit is impacted, the safety information 
(as per protocol: SAEs, pIMDs, concomitant medications/vaccinations and 
intercurrent medical conditions) will be collected by site staff via telephone 
contact or other means of virtual contact, and this will not be considered as 
protocol deviation. 
• 
Instruction for collection of home self-swabs in case study participant 
experiences suspected respiratory tract infection (RTI) symptoms: In case the 
investigator determines this is not posing additional risk to the subjects or 
household members, the subjects will be instructed to perform the home self-swab 
and keep it in their freezer (preferred) or refrigerator until recovered, and able to 
bring it to the site. If there is a possibility, a healthy relative can bring the sample 
to the site to be processed. In case investigator judges this is not advisable due to 
the national guidelines and/or site restrictions linked to the special circumstances, 
the self-swab will not be collected and the sample will be encoded as missing. 
Samples that are not collected will be documented as protocol deviations. The 
investigator and/or the site staff will provide these instructions to the subjects 
during the active surveillance contacts carried out every 2 weeks during the RSV 
season period. 
• 
Instructions for assessment visit for suspected respiratory tract infection 
(RTI): Site staff will decide on the management of the cases (either having a 
site/different site location/home visit or by telephone contact) based on COVID-19 
national guidelines and/or site restrictions linked to the special circumstances. If 
the nasal and throat samples cannot be collected at site, the sample will be encoded 
as missing. Samples that are not collected will be documented as protocol 
deviations. Biological samples will not be collected if they cannot be processed in 
a timely manner or appropriately stored until the intended use. 
208851 | Protocol Amendment 1 19 May 2020 | TMF-1772243 | 1.0

CONFIDENTIAL 
208851 (RSV OA=ADJ-002) 
Protocol Amendment 1 Final 
13-MAY-2020 
5 
Additional changes: 
• 
As per the request from the regulatory (Belgian) authorities, clarification has been 
added to the holding rule wording for non-life-threatening SAEs in Section 7.10.4. 
The paragraph has been modified to add clarification that SAEs that are not related 
to study vaccination will not be considered for safety holding rules.  
• 
Blood collection and testing plan for samples arising at the last study visit (Visit 8) 
have been updated, following the formulation selection and based on data 
generated from the first analysis. At the last visit, blood samples will be collected 
for humoral and CMI determination from a subset of subjects (N460; from all 
subjects in part B1 [N100] and subjects who received a selected level of antigen 
dose and Placebo in part B2 [N360]). 
• 
Blinding instructions have been updated to reflect the impact of the change in 
blood collection and testing plan at the last study visit (Visit 8). During the last 
study visit, the blood samples will be collected only from a subset of subjects 
(N460; from all subjects in part B1 and subjects who received a selected level of 
antigen dose and Placebo in part B2). Therefore, the investigators, site and study 
staff will be partially unblinded at group level, but not at the individual level. 
In case there will be an extension study planned, with all or a subset of participants 
included, the investigators may be provided with the list of study subjects eligible 
to participate in such study, before the parent study ends. Therefore, the 
investigators, site and study staff will potentially receive an individual data listings 
for a subset. All subjects in this subset may be unblinded before the study ends. 
• 
Missing cut-off values for some humoral assays have been included. The new 
naming for the competitive ELISA (RSVPreF3 RSB1 specific) has been 
implemented. 
208851 | Protocol Amendment 1 19 May 2020 | TMF-1772243 | 1.0

CONFIDENTIAL 
208851 (RSV OA=ADJ-002) 
Protocol Amendment 1 Final 
13-MAY-2020 
6 
Protocol Amendment 1 Investigator Agreement 
I agree: 
• 
To conduct the study in compliance with this protocol, any future protocol 
amendments or protocol administrative changes, with the terms of the clinical trial 
agreement and with any other study conduct procedures and/or study conduct 
documents provided by GlaxoSmithKline (GSK) Biologicals. 
• 
To assume responsibility for the proper conduct of the study at this site. 
• 
That I am aware of, and will comply with, ‘Good Clinical Practice’ (GCP) and all 
applicable regulatory requirements.  
• 
To ensure that all persons assisting me with the study are adequately informed about 
the GSK Biologicals’ study vaccine and other study-related duties and functions as 
described in the protocol. 
• 
To acquire the reference ranges for laboratory tests performed locally and, if required 
by local regulations, obtain the laboratory’s current certification or Quality 
Assurance procedure manual. 
• 
To ensure that no clinical samples (including serum samples) are retained onsite or 
elsewhere without the approval of GSK Biologicals and the express written informed 
consent of the subject and/or the subject’s legally acceptable representative.  
• 
To perform no other biological assays on the clinical samples except those described 
in the protocol or its amendment(s).  
• 
To co-operate with a representative of GSK Biologicals in the monitoring process of 
the study and in resolution of queries about the data. 
• 
That I have been informed that certain regulatory authorities require the sponsor to 
obtain and supply, as necessary, details about the investigator’s ownership interest in 
the sponsor or the investigational vaccine, and more generally about his/her financial 
ties with the sponsor. GSK Biologicals will use and disclose the information solely 
for the purpose of complying with regulatory requirements. 
Hence I: 
• 
Agree to supply GSK Biologicals with any necessary information regarding 
ownership interest and financial ties (including those of my spouse and dependent 
children). 
• 
Agree to promptly update this information if any relevant changes occur during the 
course of the study and for one year following completion of the study.  
• 
Agree that GSK Biologicals  
• 
may disclose any information it has about such ownership interests and financial ties 
to regulatory authorities. 
• 
Agree to provide GSK Biologicals with an updated Curriculum Vitae and other 
documents required by regulatory agencies for this study. 
208851 | Protocol Amendment 1 19 May 2020 | TMF-1772243 | 1.0

CONFIDENTIAL 
208851 (RSV OA=ADJ-002) 
Protocol Amendment 1 Final 
13-MAY-2020 
7 
eTrack study number and 
Abbreviated Title 
208851 (RSV OA=ADJ-002) 
IND number  
18540 
EudraCT number 
2018-000849-38  
Date of protocol amendment 
Amendment 1 Final: 13 May 2020 
Detailed Title 
A Phase I/II, randomized, placebo-controlled, 
observer-blind, multicenter study to evaluate the 
safety, reactogenicity and immunogenicity of GSK 
Biologicals’ investigational respiratory syncytial 
virus (RSV) vaccine (adjuvanted with AS01E or 
AS01B or unadjuvanted) when administered 
intramuscularly according to a 0, 2 month schedule in 
adults aged 18-40 or 60-80 years.  
Investigator name 
 
 
 
Signature 
 
 
 
Date 
 
 
 
208851 | Protocol Amendment 1 19 May 2020 | TMF-1772243 | 1.0

CONFIDENTIAL 
208851 (RSV OA=ADJ-002) 
Protocol Amendment 1 Final 
13-MAY-2020 
8 
Sponsor Information 
1. Sponsor 
GlaxoSmithKline Biologicals 
2. Sponsor Medical Expert for the Study 
Refer to the local study contact information document. 
3. Sponsor Study Monitor 
Refer to the local study contact information document. 
4. Sponsor Study Contact for Reporting of a Serious Adverse Event 
GSK Biologicals Central Back-up Study Contact for Reporting SAEs: refer to protocol 
Section 7.4.2. 
5. GSK Biologicals’ Central Safety Physician On-Call Contact information for 
Emergency Unblinding 
GSK Biologicals Central Safety Physician and Back-up Phone contact: refer to 
protocol Section 7.8.  
208851 | Protocol Amendment 1 19 May 2020 | TMF-1772243 | 1.0

CONFIDENTIAL 
208851 (RSV OA=ADJ-002) 
Protocol Amendment 1 Final 
13-MAY-2020 
9 
SYNOPSIS 
Detailed Title 
A Phase I/II, randomized, placebo-controlled, observer-blind, 
multicenter study to evaluate the safety, reactogenicity and 
immunogenicity of GSK Biologicals’ investigational 
respiratory syncytial virus (RSV) vaccine (adjuvanted with 
AS01E or AS01B or unadjuvanted) when administered 
intramuscularly according to a 0, 2 month schedule in adults 
aged 18-40 or 60-80 years.  
Indication 
Active immunization in the prevention of moderate-to-severe 
lower respiratory tract disease (LRTD) caused by respiratory 
syncytial virus (RSV) in adults aged 60 years or above.  
Rationale for the 
study and study 
design 
Rationale for the study 
Despite the significant medical need in older adults, there is 
currently no prophylactic vaccine approved for the prevention 
of LRTD caused by RSV. 
GlaxoSmithKline (GSK) Biologicals is developing a new 
investigational RSV vaccine against moderate to severe RSV-
associated (subtypes A and B) disease in adults aged 60 years 
or above. 
Rationale for the study design 
This study will evaluate 9 investigational RSV vaccine 
formulations, with different concentrations of pre-fusion 
conformation antigen RSVPreF3 (30, 60 or 120 µg), either 
unadjuvanted or adjuvanted with AS01E or AS01B when 
administered intramuscularly according to a 2-dose schedule 
at 0, 2 months in older adults (60-80 years). The main purpose 
will be to evaluate the safety, reactogenicity and 
immunogenicity of the vaccine candidates and select a 
formulation for further development of the RSV vaccine, 
based on those results. In terms of immunogenicity, the 
selection of the vaccine formulation will rely primarily on the 
levels of RSV-A neutralizing antibody titers and CD4+ T-
cells response. Further assessment of immune responses, 
including the RSVPreF3 IgG antibody, might additionally 
guide the vaccine candidate selection.  
As this dose ranging study will include the target population 
of older adults aged 60-80 years, it has been designed as a 
Phase I/II study. 
208851 | Protocol Amendment 1 19 May 2020 | TMF-1772243 | 1.0

CONFIDENTIAL 
208851 (RSV OA=ADJ-002) 
Protocol Amendment 1 Final 
13-MAY-2020 
10 
 
• 
Vaccine antigen and adjuvant selection: The antigen 
which will be used in the investigational RSV vaccine is 
an engineered version of the RSV fusion (F) surface 
glycoprotein, stabilized in the pre-fusion conformation, 
resulting in the “RSVPreF3” pre-fusion molecule. The F 
protein has been selected because it is a major surface 
antigen of the RSV virus that is well conserved among 
RSV-A and RSV-B subtypes.  
In addition to boosting pre-existing neutralizing 
antibodies, another important element for the RSV 
candidate vaccine in older adults might be to boost or 
elicit RSV-specific T-cell responses. The use of an 
adjuvant may enable induction of CD4+ T-cells in 
addition to antibodies, leading to a stronger and persistent 
protection. Amongst the current GSK portfolio of 
adjuvants, AS01 has the potential to induce the targeted 
immune profile as it has been shown to improve antibody 
and T-cell response in older adults.  
• 
Dose regimen: It is proposed to evaluate a 2-dose 
vaccination regimen with an interval of 2 months 
between doses.  
• 
Staggered design and safety monitoring: As the 
RSVPreF3 antigen has not been administered to humans 
yet, this study will first evaluate the safety of 3 different 
dosages of RSVPreF3 (30, 60 and 120 g, unadjuvanted) 
in healthy men and women aged 18-40 years in Part A 
(~12 subjects/group) before proceeding with vaccination 
of the target population in Part B (~100 subjects/group). 
To ensure the safety of the study participants, Part B will 
follow a staggered enrolment with 2 steps. For each part, 
study holding rules have been defined. 
After the first and second vaccine dose in Part A, safety 
evaluations will be performed by an Independent Data 
Monitoring Committee (IDMC). Only upon favorable 
outcome of the first IDMC evaluation, the vaccination in 
Part B of the study will be initiated. In this part, the safety 
and immunogenicity of 9 investigational RSV vaccine 
formulations (adjuvanted and unadjuvanted) will be 
evaluated in older adults aged 60-80 years. IDMC safety 
evaluations will be performed after each study 
vaccination step.  
208851 | Protocol Amendment 1 19 May 2020 | TMF-1772243 | 1.0

CONFIDENTIAL 
208851 (RSV OA=ADJ-002) 
Protocol Amendment 1 Final 
13-MAY-2020 
11 
 
• 
Study blinding: Given the difference in reconstitution 
and visual appearance of the investigational RSV 
vaccine, double blinding is not possible and the study will 
be conducted in an observer-blind manner for the 
vaccination phases (up to one month post-Dose 2) of both 
study parts.  
A statistical analysis will be performed on data from 
vaccinated subjects up to one month post-Dose 2. Given 
that summary results may unblind some specific subjects, 
the persistence phase of Part B (Epoch 003) will be 
considered as single-blind, with subjects remaining 
blinded up to study end. The investigators will not be 
provided with the individual data listings or with the 
randomization listings until the end of study analysis. 
During the last study visit, blood samples will be 
collected only from a subset of subjects (N460, all 
subjects in part B1 and subjects who received a selected 
level of antigen dose and Placebo in part B2). 
Therefore, the investigators, site and study staff will be 
partially unblinded at group level, but not at the 
individual level.  
In case there will be an extension study planned, with 
all or a subset of participants included, the investigators 
may be provided with the list of study subjects eligible to 
participate in such study, before the parent study ends. 
Therefore, the investigators, site and study staff will 
potentially receive an individual data listings for a 
subset. All subjects in this subset may be unblinded 
before the study ends. (Amended, 13 May 2020) 
Rationale for the use of placebo 
As there is currently no licensed RSV vaccine available, a 
placebo group (receiving saline solution) will be used as 
control for the safety, reactogenicity and immunogenicity 
assessments in both study parts. 
Objectives 
Primary 
For Part A and Part B 
• To evaluate the safety and reactogenicity of 2 doses of the 
investigational RSV vaccine administered IM according to 
a 0, 2 month schedule, up to one month after the last dose 
(Day 91, Visit 6).  
208851 | Protocol Amendment 1 19 May 2020 | TMF-1772243 | 1.0

CONFIDENTIAL 
208851 (RSV OA=ADJ-002) 
Protocol Amendment 1 Final 
13-MAY-2020 
12 
 
Secondary 
For Part A and Part B 
• To characterize the humoral immune responses (including 
dose-response) in relation to the investigational RSV 
vaccine formulations administered IM according to a 0, 2 
month schedule, up to one month after the last dose (Day 
91, Visit 6).  
• To characterize the cell-mediated immune responses in 
relation to the investigational RSV vaccine formulations 
administered IM according to a 0, 2 month schedule, up to 
one month after the last dose (Day 91, Visit 6).   
 
For Part B 
• To evaluate the safety and reactogenicity of 2 doses of the 
investigational RSV vaccines administered IM according 
to a 0, 2 month schedule, up to the end of follow-up 
(Month 14, Visit 8). 
• To evaluate the occurrence of RSV-associated respiratory 
tract infections (RTI) during the RSV season in 
nasal/throat swab samples collected during the assessment 
visit for potential RSV-RTI.  
Tertiary 
For Part A and Part B 
• To further characterize the cell-mediated immune 
responses to investigational RSV vaccine formulations.  
For Part B 
• 
To further characterize immune responses to 
investigational RSV vaccine formulations.  
• 
To characterize persistence of immune responses to the 
investigational RSV vaccine formulations at Month 8 
(Visit 7) and Month 14 (Visit 8).  
• 
To further evaluate the occurrence of RSV-associated 
RTI (including co-infections with other respiratory 
viruses) during the RSV seasons in nasal/throat swab 
samples collected during the assessment visit for potential 
RSV-RTI.  
• 
To evaluate the occurrence of RSV-associated RTI during 
the RSV season using self-collected nasal swabs.  
208851 | Protocol Amendment 1 19 May 2020 | TMF-1772243 | 1.0

CONFIDENTIAL 
208851 (RSV OA=ADJ-002) 
Protocol Amendment 1 Final 
13-MAY-2020 
13 
Study design 
• 
Experimental design: Phase I/II, observer-blind, 
randomized, controlled, multi-country study with 2 parts 
(i.e., Part A in young adults aged 18-40 years with 
4 parallel groups and Part B in older adults aged 60-80 
years with 10 parallel groups). 
• 
Duration of the study:  
Approximately 3 months per subject in Part A: 
− 
Epoch 001: Screening Visit (Day -30 to -3) 
− 
Epoch 002: Primary (vaccination phase) starting at 
Visit 1 (Day 1) and ending at Visit 6 (Day 91) 
 
Approximately 14 months per subject in Part B: 
− 
Epoch 001: Screening Visit (Day -30 to -3) 
− 
Epoch 002: Primary (vaccination phase) starting at 
Visit 1 (Day 1) and ending at Visit 6 (Day 91)  
− 
Epoch 003: Follow-up (persistence phase) starting 
after Visit 6 (Day 91) and ending at Visit 8 (Month 
14) 
• 
Primary completion Date: last visit of the vaccination 
phase in Part B (Visit 6 [Day 91]). 
• 
End of Study: Last testing results released of samples 
collected up to Visit 8 in Part B (Month 14) (for assays 
related to primary and secondary endpoints only). 
• 
Treatment allocation: Subjects will be randomized 
using a centralised randomization system on internet 
(SBIR) on Day 1.  
In Part A, the aim is to enrol approximately 48 subjects 
aged 18-40 years. The randomization algorithm will use a 
minimisation procedure accounting for center and gender. 
In Part B, the aim is to enrol approximately 700 subjects 
aged 60-69 years and approximately 300 subjects aged 
70-80 years. The randomization algorithm will use a 
minimisation procedure accounting for age, center and 
gender in each step. 
• 
Study groups: For the investigational RSV vaccine in 
Part A and Step 1 in Part B, the RSVPreF3 high-dose 
formulation containing 120 g RSVPreF3 will be used 
for all groups. For Step 2 in Part B, the RSVPreF3 low-
dose and mid-dose formulations will be used for the 
groups receiving 30 g and 60 g of RSVPreF3, 
respectively. As subjects enrolled in Step 1 and 2 of Part 
B will thus receive different vaccine formulations for the 
low-and mid-dose groups, separate study groups have 
been identified (referred to as B1 and B2).  
208851 | Protocol Amendment 1 19 May 2020 | TMF-1772243 | 1.0

CONFIDENTIAL 
208851 (RSV OA=ADJ-002) 
Protocol Amendment 1 Final 
13-MAY-2020 
14 
Synopsis Table 1 
Study groups and epochs foreseen in the study 
Study groups 
Number of subjects 
Age (Min/Max) 
Epochs 
Epoch 001 
Epoch 002 
Epoch 003 
Part A 
30-PLAIN_A  
12  
18 - 40 years  
x  
x  
 
60-PLAIN_A  
12  
18 - 40 years  
x  
x  
 
120-PLAIN_A  
12  
18 - 40 years  
x  
x  
 
Placebo_A  
12  
18 - 40 years  
x  
x  
 
Part B - Step 1 
30-PLAIN_B1  
10  
60 - 80 years  
x  
x  
x  
30-AS01E_B1  
10  
60 - 80 years  
x  
x  
x  
30-AS01B_B1  
10  
60 -80 years  
x  
x  
x  
60-PLAIN_B1  
10  
60 - 80 years  
x  
x  
x  
60-AS01E_B1  
10  
60 - 80 years  
x  
x  
x  
60-AS01B_B1  
10  
60 - 80 years  
x  
x  
x  
120-PLAIN_B1  
10  
60 - 80 years  
x  
x  
x  
120-AS01E_B1  
10  
60 - 80 years  
x  
x  
x  
120-AS01B_B1  
10  
60 - 80 years  
x  
x  
x  
Placebo_B1  
10  
60 - 80 years  
x  
x  
x  
Part B - Step 2 
30-PLAIN_B2  
90  
60 - 80 years  
x  
x  
x 
30-AS01E_B2  
90  
60 - 80 years 
x  
x  
x  
30-AS01B_B2  
90  
60 - 80 years 
x  
x  
x  
60-PLAIN_B2  
90  
60 - 80 years 
x  
x  
x  
60-AS01E_B2  
90  
60 - 80 years 
x  
x  
x  
60-AS01B_B2  
90  
60 - 80 years 
x  
x  
x  
120-PLAIN_B2  
90  
60 - 80 years 
x  
x  
x  
120-AS01E_B2  
90  
60 - 80 years 
x  
x  
x  
120-AS01B_B2  
90  
60 - 80 years 
x  
x  
x  
Placebo_B2  
90  
60 - 80 years 
x  
x  
x  
Synopsis Table 2 
Study groups and treatment foreseen in Part A 
Treatment name 
Vaccine/Product 
name  
Study Groups 
30-PLAIN_A  
60-PLAIN_A  120-PLAIN_A  
Placebo_A  
30 µg RSVPreF3 plain 
RSVPreF3 high dose  
x  
 
 
 
NaCl 
x  
60 µg RSVPreF3 plain  
RSVPreF3 high dose  
 
x  
 
 
NaCl 
x  
120 µg RSVPreF3 
plain  
RSVPreF3 high dose  
 
 
x  
 
NaCl 
x  
Placebo 
NaCl 
 
 
 
x  
 
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Synopsis Table 3 
Study groups and treatment foreseen in Part B - Step 1 
Treatment name 
Vaccine/ 
Product name 
Study Groups 
30-
PLAIN_B1  
30-
AS01E_B1  
30-
AS01B_B1  
60-
PLAIN_B1  
60-
AS01E_B1  
60-
AS01B_B1  
120-
PLAIN_B1  
120-
AS01E_B1 
120-
AS01B_B1  Placebo_B1  
30 µg RSVPreF3 
plain 
RSVPreF3 high 
dose  
x  
 
 
 
 
 
 
 
 
 
NaCl 
x  
30 µg 
RSVPreF3/AS01E 
RSVPreF3 high 
dose  
 
x  
 
 
 
 
 
 
 
 
AS01E 
x  
30 µg 
RSVPreF3/AS01B  
RSVPreF3 high 
dose  
 
 
x  
 
 
 
 
 
 
 
AS01B 
x  
60 µg RSVPreF3 
plain  
RSVPreF3 high 
dose  
 
 
 
x  
 
 
 
 
 
 
NaCl 
x  
60 µg 
RSVPreF3/AS01E  
RSVPreF3 high 
dose  
 
 
 
 
x  
 
 
 
 
 
AS01E 
x  
60 µg 
RSVPreF3/AS01B  
RSVPreF3 high 
dose  
 
 
 
 
 
x  
 
 
 
 
AS01B 
x  
120 µg 
RSVPreF3 plain  
RSVPreF3 high 
dose  
 
 
 
 
 
 
x  
 
 
 
NaCl 
x  
120 µg 
RSVPreF3/AS01E  
RSVPreF3 high 
dose  
 
 
 
 
 
 
 
x  
 
 
AS01E 
x  
120 µg 
RSVPreF3/AS01B  
RSVPreF3 high 
dose  
 
 
 
 
 
 
 
 
x  
 
AS01B 
x  
Placebo 
NaCl 
 
 
 
 
 
 
 
 
 
x  
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Synopsis Table 4 
Study groups and treatment foreseen in Part B - Step 2 
Treatment name 
Vaccine/ 
Product name 
Study Groups 
30-
PLAIN_B2 
30-
AS01E_B2 
30-
AS01B_B2 
60-
PLAIN_B2 
60-
AS01E_B2 
60-
AS01B_B2 
120-
PLAIN_B2 
120-
AS01E_B2  
120-
AS01B_B2 
Placebo_B2 
30 µg RSVPreF3 
plain 
RSVPreF3 low 
dose  
x  
 
 
 
 
 
 
 
 
 
NaCl 
x  
30 µg 
RSVPreF3/AS01E 
RSVPreF3 low 
dose  
 
x  
 
 
 
 
 
 
 
 
AS01E 
x  
30 µg 
RSVPreF3/AS01B  
RSVPreF3 low 
dose  
 
 
x  
 
 
 
 
 
 
 
AS01B 
x  
60 µg RSVPreF3 
plain  
RSVPreF3 mid 
dose  
 
 
 
x  
 
 
 
 
 
 
NaCl  
x  
60 µg 
RSVPreF3/AS01E  
RSVPreF3 mid 
dose  
 
 
 
 
x  
 
 
 
 
 
AS01E  
x  
60 µg 
RSVPreF3/AS01B  
RSVPreF3 mid 
dose  
 
 
 
 
 
x  
 
 
 
 
AS01B  
x  
120 µg 
RSVPreF3 plain  
RSVPreF3 high 
dose  
 
 
 
 
 
 
x  
 
 
 
NaCl  
x  
120 µg 
RSVPreF3/AS01E  
RSVPreF3 high 
dose  
 
 
 
 
 
 
 
x  
 
 
AS01E  
x  
120 µg 
RSVPreF3/AS01B  
RSVPreF3 high 
dose  
 
 
 
 
 
 
 
 
x  
 
AS01B  
x  
Placebo 
NaCl  
 
 
 
 
 
 
 
 
 
x  
 
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• 
Control: placebo control. 
• 
Vaccination schedules: Two vaccine doses administered 
intramuscularly at Day 1 and Day 61. 
• 
Blinding: observer-blind. 
Synopsis Table 5 
Blinding of study epochs 
Study Epochs 
Blinding 
Epoch 001  
N/A  
Epoch 002 
observer-blind  
Epoch 003  
single-blind  
N/A: Not applicable 
 
• 
RTI surveillance in Part B: Active and passive 
surveillance will only be carried out during RSV seasons 
(approximately from October to March) throughout the 
entire Part B of the study: 
• 
Sampling schedule: 
In Part A: 
− 
At Screening (Pre-Day 1), a blood sample for 
eligibility assessment will be drawn from all subjects.  
− 
At Day 1 (Visit 1), a blood sample for 
cytomegalovirus (CMV) status determination will be 
drawn from all subjects. 
− 
Blood samples for safety assessment 
(hematology/biochemistry) will be drawn from all 
subjects on Days 1, 8, 61 and 68 (Visits 1, 2, 4 and 5).  
− 
Blood samples for humoral immunogenicity and 
cell-mediated immunity (CMI) testing will be drawn 
from all subjects at Days 1, 31, 61 and 91 (Visits 1, 3, 
4 and 6).  
In Part B: 
− 
At Screening (Pre-Day 1), a blood sample for 
eligibility assessment will be drawn from all subjects.  
− 
At Day 1 (Visit 1), a blood sample for CMV status 
determination will be drawn from all subjects. 
− 
Blood samples for safety assessment 
(hematology/biochemistry) will be drawn from all 
subjects and on Days 1, 8, 61 and 68 (Visits 1, 2, 4 
and 5).  
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− 
Blood samples for humoral immunogenicity and 
CMI testing will be drawn from all subjects at Days 
1, 31, 61, 91 and Month 8, and from a subset at 
Month 14 (Visits 1, 3, 4, 6, 7 and 8). (Amended, 13 
May 2020) 
− 
Nasal/throat swabs: In case of RTI symptoms during 
the RSV season (approximately from October to 
March), the study participants will be asked to collect 
a nasal swab at home and contact the 
investigator/study staff to schedule an assessment 
visit for collection of an additional nasal swab and a 
throat swab by qualified staff from the study team. 
• 
Type of study: self-contained. 
• 
Data collection: eCRF. Solicited symptoms will be 
collected using an electronic subject Diary (eDiary). 
Unsolicited symptoms will be collected using a paper 
subject Diary. 
• 
Safety monitoring: The study will be conducted in 2 parts 
with oversight by an IDMC. The investigator is not 
permitted to start vaccinating the subjects in the next step 
in each part until the Sponsor communicates the favorable 
outcome of the respective safety evaluations by the IDMC. 
Part A: Approximately 48 young adults aged 18-40 years 
will be enrolled and vaccinated with the first dose. If the 
IDMC evaluation is favorable, the Part A study 
participants will be vaccinated with the second dose and 
the vaccination in Part B of the study will be initiated. 
Part B: This part will be conducted in a 2-step staggered 
design to ensure maximum safety of the participating 
subjects. In Step 1, 100 subjects will be enrolled and 
vaccinated. Safety evaluations based on unblinded data 
from those 100 subjects will be performed by the IDMC to 
allow the start of Step 2. In Step 2, the remaining study 
participants (N900) will be enrolled and vaccinated.  
In total, 6 IDMC meetings for safety evaluation are 
foreseen in the vaccination phase of the study (Epoch 
002), i.e., 2 meetings in Part A and 4 meetings in Part B. 
During the persistence phase of Part B (Epoch 003), 
2 IDMC meetings will be planned with an interval of 
approximately 6 months.  
If any safety concern is identified by the investigator or 
the sponsor, ad-hoc safety evaluations by the IDMC may 
be performed. 
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Number of subjects 
A total of approximately 1048 participants are planned to be 
enrolled in this study, of whom 48 in Part A and 1000 in 
Part B. 
Endpoints 
Primary 
For Part A and Part B: 
• 
Occurrence of AEs from first vaccination up to 30 days 
after the second vaccination (Day 91): 
− 
Occurrence of each solicited local and general AE 
during a 7-day follow-up period (i.e., on the day of 
vaccination and 6 subsequent days) after each 
vaccination. 
− 
Occurrence of any unsolicited AE during a 30-day 
follow up period (i.e., on the day of vaccination and 
29 subsequent days) after each vaccination.  
− 
Occurrence of any hematological (erythrocytes, WBC 
and differential count, platelets count and hemoglobin 
level) and biochemical (ALT, AST, creatinine, BUN 
and uric acid) laboratory abnormalities at Days 1, 8, 
61 and 68. 
− 
Occurrence of all Grade 3 non-serious AEs (solicited 
and unsolicited) during the 30-day follow-up period 
after each vaccination. 
− 
Occurrence of SAEs from Dose 1 up to 30 days after 
the second vaccine dose (Day 91).  
For Part B only: 
− 
Occurrence of pIMDs from Dose 1 up to 30 days after 
the second vaccine dose (Day 91). 
Secondary 
For Part A and Part B: 
• 
Humoral immune response with respect to components of 
the investigational vaccine at pre-vaccination (Day 1), 30 
days post-Dose 1 (Day 31), on the day of second 
vaccination (Day 61) and 30 days post-Dose 2 (Day 91):  
− 
Neutralizing antibody titers against RSV serotype A. 
− 
RSVPreF3-specific IgG antibody concentrations.  
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• 
Cell-mediated immune response profile with respect to 
components of the investigational vaccine at pre-
vaccination (Day 1), 30 days post-Dose 1 (Day 31), pre-
Dose 2 (Day 61) and 30 days post-Dose 2 (Day 91):  
− 
Frequency of RSVPreF3-specific CD4+ T-cells 
identified as expressing at least 2 markers among IL-
2, CD40L, TNF-, IFN- in vitro. 
For Part B only: 
• 
Occurrence of RSV-associated RTI (as measured by qRT-
PCR in nasal/throat swab samples collected during the 
assessment visit for potential RSV-RTI) during the RSV 
seasons, up to the end of follow-up. 
• 
Occurrence of SAEs from Dose 1 up to the end of 
follow-up.  
• 
Occurrence of pIMDs from Dose 1 up to the end of 
follow-up.  
(Amended, 13 May 
2020) 
 
Tertiary 
For Part A and Part B: 
• 
Cell-mediated immune response profile with respect to 
components of the investigational vaccine at pre-
vaccination (Day 1), 30 days post-Dose 1 (Day 31), pre-
Dose 2 (Day 61) and 30 days post-Dose 2 (Day 91): 
− 
Frequency of RSVPreF3-specific CD4+ and/or CD8+ 
T-cells identified as expressing one or any 
combination of immune marker(s) in vitro.  
For Part B only: 
• 
Humoral immune response with respect to components of 
the investigational vaccine at pre-vaccination (Day 1) and 
30 days post-Dose 2 (Day 91): 
− 
Neutralizing antibody titers against RSV serotype B 
in all subjects.  
− 
RSVPreF3 RSB1 specific antibody concentrations in 
a subset of subjects who received the selected vaccine 
formulation or placebo.  
 
• 
Cell-mediated immune response profile with respect to 
components of the investigational vaccine at pre-
vaccination (Day 1), 30 days post-Dose 1 (Day 31) and 30 
days post-Dose 2 (Day 91):  
− 
Frequency of RSVPreF3-specific memory B-cells in a 
subset of subjects who received the selected level of 
antigen dose (3 RSV vaccine formulations) or 
placebo. 
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• 
Persistence of the humoral immune response with respect 
to components of the investigational vaccine at Months 8 
and 14: 
− 
Neutralizing antibody titers against RSV serotype A. 
− 
RSVPreF3-specific IgG antibody concentrations.  
• 
Persistence of the cell-mediated immune response profile 
with respect to components of the investigational vaccine: 
− 
Frequency of RSVPreF3-specific CD4+ and/or CD8+ 
T-cells identified as expressing one or any 
combination of immune marker(s) in vitro, in all 
subjects (Month 8) and in a subset of subjects who 
received the selected level of antigen dose (3 RSV 
vaccine formulations) or placebo (Month 14). 
− 
Frequency of RSVPreF3-specific CD4+ T-cells 
identified as expressing at least 2 markers among IL-
2, CD40L, TNF-, IFN- in vitro, in all subjects 
(Month 8) and in a subset of subjects who received 
the selected level of antigen dose (3 RSV vaccine 
formulations) or placebo (Month 14). 
− 
Frequency of RSVPreF3-specific memory B-cells at 
Month 14 in a subset of subjects who received the 
selected level of antigen dose (3 RSV vaccine 
formulations) or placebo. 
• 
Any further exploratory immunology to detect RSV-
related immune responses, such as but not limited to:  
− 
Antibodies against specific protein F epitopes.  
− 
Potential new immunological markers for protection.  
− 
Cross-reactive neutralizing antibody titers against 
hMPV.  
• 
Occurrence of RSV-associated RTI, including co-
infections with other respiratory viruses (as measured by 
multiplex PCR in self-collected nasal swab samples and 
nasal/throat swab samples collected during the assessment 
visit for potential RSV-RTI) during the RSV seasons.  
• 
Occurrence of RSV-associated RTI as measured by qRT-
PCR in self-collected nasal swab samples during the RSV 
seasons, up to the end of follow-up. 
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TABLE OF CONTENTS 
PAGE 
SPONSOR INFORMATION ............................................................................................ 8 
SYNOPSIS ...................................................................................................................... 9 
LIST OF ABBREVIATIONS ........................................................................................... 31 
GLOSSARY OF TERMS ............................................................................................... 34 
TRADEMARKS ............................................................................................................. 38 
1. 
INTRODUCTION .................................................................................................... 39 
1.1. 
Background ................................................................................................ 39 
1.2. 
Rationale for the study and study design .................................................... 39 
1.2.1. 
Rationale for the study ................................................................. 39 
1.2.2. 
Rationale for the study design ...................................................... 40 
1.2.2.1. 
Vaccine antigen and adjuvant selection ...................... 40 
1.2.2.2. 
Dose regimen ............................................................. 41 
1.2.2.3. 
Staggered design and safety monitoring ..................... 42 
1.2.2.4. 
Study blinding ............................................................. 42 
1.2.2.5. 
Rationale for the use of placebo ................................. 43 
1.3. 
Benefit : Risk Assessment .......................................................................... 43 
1.3.1. 
Risk Assessment ......................................................................... 44 
1.3.2. 
Benefit Assessment ..................................................................... 45 
1.3.3. 
Overall Benefit : Risk Conclusion ................................................. 45 
2. 
OBJECTIVES ......................................................................................................... 45 
2.1. 
Primary objective ........................................................................................ 45 
2.2. 
Secondary objectives .................................................................................. 45 
2.3. 
Tertiary objectives ....................................................................................... 46 
3. 
STUDY DESIGN OVERVIEW ................................................................................ 47 
4. 
STUDY COHORT ................................................................................................... 56 
4.1. 
Number of subjects/centers ........................................................................ 56 
4.2. 
Inclusion criteria for enrolment .................................................................... 57 
4.3. 
Exclusion criteria for enrolment ................................................................... 58 
5. 
CONDUCT OF THE STUDY .................................................................................. 60 
5.1. 
Regulatory and ethical considerations, including the informed 
consent process.......................................................................................... 60 
5.2. 
Subject identification and randomization ..................................................... 61 
5.2.1. 
Subject identification .................................................................... 61 
5.2.2. 
Randomization of treatment ......................................................... 61 
5.2.2.1. 
Randomization of supplies .......................................... 61 
5.2.2.2. 
Treatment allocation to the subject ............................. 62 
5.2.2.2.1. 
Study group and treatment 
number allocation ................................... 62 
5.2.2.2.2. 
Treatment number allocation for 
subsequent doses .................................. 63 
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5.3. 
Method of blinding ...................................................................................... 63 
5.4. 
General study aspects ................................................................................ 64 
5.5. 
Outline of study procedures ........................................................................ 65 
5.6. 
Detailed description of study procedures applicable for both study 
parts ........................................................................................................... 70 
5.6.1. 
Informed consent ......................................................................... 70 
5.6.2. 
Screening procedures to check subject eligibility ......................... 70 
5.6.2.1. 
Check inclusion and exclusion criteria ........................ 70 
5.6.2.2. 
Collect demographic data, medical history, 
vaccination history and perform physical 
examination ................................................................ 71 
5.6.2.3. 
Blood sampling for eligibility assessment .................... 71 
5.6.2.4. 
Screening conclusion ................................................. 71 
5.6.3. 
Procedures during the vaccination phases (Parts A and B) 
and/or persistence phase (Part B)................................................ 71 
5.6.3.1. 
Check inclusion and exclusion criteria ........................ 71 
5.6.3.2. 
Collect demographic data ........................................... 71 
5.6.3.3. 
Medical history ........................................................... 72 
5.6.3.4. 
Vaccination history ..................................................... 72 
5.6.3.5. 
Physical examination .................................................. 72 
5.6.3.6. 
Check contraindications to vaccination ....................... 72 
5.6.3.7. 
Assess pre-vaccination body temperature .................. 72 
5.6.3.8. 
Study group and treatment number allocation ............ 73 
5.6.3.9. 
Study vaccine administration ...................................... 73 
5.6.3.10. Sampling .................................................................... 73 
5.6.3.11. Blood sampling for safety or immune response 
assessments .............................................................. 73 
5.6.3.12. Check and record concomitant 
medication/vaccination and intercurrent 
medical conditions ...................................................... 74 
5.6.3.13. Distribution of eDiary devices ..................................... 74 
5.6.3.14. Distribution of paper diary cards ................................. 75 
5.6.3.15. Recording of AEs and SAEs ....................................... 75 
5.6.3.16. Study conclusion ........................................................ 75 
5.7. 
Detailed description of study procedures applicable for Part A only ............ 75 
5.7.1. 
Pregnancy test ............................................................................. 75 
5.7.2. 
Recording of pregnancies ............................................................ 76 
5.8. 
Detailed description of study procedures applicable for Part B only ............ 76 
5.8.1. 
Surveillance for RSV-RTI and nasal/throat swab sampling .......... 76 
5.8.2. 
Recording of potential immune-mediated diseases 
(pIMDs) ........................................................................................ 77 
5.9. 
Biological sample handling and analysis ..................................................... 77 
5.9.1. 
Use of specified study materials .................................................. 78 
5.9.2. 
Biological samples ....................................................................... 79 
5.9.3. 
Laboratory assays ....................................................................... 80 
5.9.4. 
Biological samples evaluation ...................................................... 83 
5.9.4.1. 
Immunological read-outs (Amended, 13 May 
2020) .......................................................................... 83 
5.9.4.2. 
Haematology/Blood Chemistry and CMV 
serology ...................................................................... 86 
5.9.4.3. 
Molecular biology ....................................................... 87 
5.9.5. 
Immunological correlates of protection ......................................... 87 
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5.10. 
Study procedures during special circumstances (Amended, 13 May 
2020) .......................................................................................................... 87 
6. 
STUDY VACCINE AND ADMINISTRATION ........................................................... 88 
6.1. 
Description of study vaccine ....................................................................... 88 
6.2. 
Storage and handling of study vaccine ....................................................... 91 
6.3. 
Dosage and administration of study vaccine ............................................... 92 
6.4. 
Replacement of unusable vaccine doses .................................................... 92 
6.5. 
Contraindications to subsequent vaccination .............................................. 93 
6.6. 
Concomitant medications/products and concomitant vaccinations .............. 94 
6.6.1. 
Recording of concomitant medications/products and 
concomitant vaccinations ............................................................. 94 
6.6.2. 
Concomitant medications/products/vaccines that may lead 
to the elimination of a subject from per-protocol analyses ............ 95 
6.7. 
Intercurrent medical conditions that may lead to elimination of a 
subject from per-protocol analyses ............................................................. 95 
7. 
SAFETY ................................................................................................................. 96 
7.1. 
Safety definitions ........................................................................................ 96 
7.1.1. 
Definition of an adverse event ...................................................... 96 
7.1.2. 
Definition of a serious adverse event ........................................... 97 
7.1.3. 
Solicited adverse events .............................................................. 98 
7.1.3.1. 
Solicited local (injection-site) adverse events .............. 98 
7.1.3.2. 
Solicited general adverse events ................................ 98 
7.1.4. 
Clinical laboratory parameters and other abnormal 
assessments qualifying as adverse events or serious 
adverse events ............................................................................ 99 
7.1.5. 
Adverse events of specific interest (Potential immune-
mediated diseases) ...................................................................... 99 
7.2. 
Events or outcomes not qualifying as adverse events or serious 
adverse events ......................................................................................... 102 
7.2.1. 
Pregnancy in Part A ................................................................... 102 
7.3. 
Detecting and recording adverse events, serious adverse events 
and pregnancies ....................................................................................... 103 
7.3.1. 
Time period for detecting and recording adverse events, 
serious adverse events and pregnancies ................................... 103 
7.3.2. 
Post-Study adverse events and serious adverse events ............ 106 
7.3.3. 
Evaluation of adverse events and serious adverse events ......... 107 
7.3.3.1. 
Active questioning to detect adverse events 
and serious adverse events ...................................... 107 
7.3.3.2. 
Assessment of adverse events ................................. 107 
7.3.3.2.1. 
Assessment of intensity ........................ 107 
7.3.3.2.2. 
Assessment of causality ....................... 109 
7.3.3.3. 
Assessment of outcomes.......................................... 110 
7.3.3.4. 
Medically attended visits ........................................... 110 
7.4. 
Reporting of serious adverse events, pregnancies, and other events ....... 110 
7.4.1. 
Prompt reporting of serious adverse events, pregnancies, 
and other events to GSK Biologicals .......................................... 110 
7.4.2. 
Contact information for reporting serious adverse events, 
pregnancies and pIMDs ............................................................. 111 
7.4.3. 
Completion and transmission of SAE reports to GSK 
Biologicals ................................................................................. 111 
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7.4.3.1. 
Back-up system in case the electronic 
reporting system does not work ................................ 112 
7.4.4. 
Completion and transmission of pregnancy reports to GSK 
Biologicals ................................................................................. 112 
7.4.5. 
Reporting of pIMDs to GSK Biologicals ...................................... 112 
7.4.6. 
Updating of SAE, pregnancy, and pIMD information after 
removal of write access to the subject’s eCRF ........................... 113 
7.4.7. 
Regulatory reporting requirements for serious adverse 
events ........................................................................................ 113 
7.5. 
Follow-up of adverse events, serious adverse events, and 
pregnancies .............................................................................................. 113 
7.5.1. 
Follow-up of adverse events and serious adverse events .......... 113 
7.5.1.1. 
Follow-up during the study ........................................ 113 
7.5.1.2. 
Follow-up after the subject is discharged from 
the study ................................................................... 114 
7.5.2. 
Follow-up of pregnancies ........................................................... 114 
7.6. 
Treatment of adverse events .................................................................... 114 
7.7. 
Unblinding ................................................................................................. 114 
7.8. 
Emergency unblinding .............................................................................. 115 
7.9. 
Subject card .............................................................................................. 116 
7.10. 
Holding rules and safety monitoring .......................................................... 116 
7.10.1. 
Part A ........................................................................................ 117 
7.10.2. 
Part B ........................................................................................ 117 
7.10.2.1. Part B - Step 1 .......................................................... 117 
7.10.2.2. Part B - Step 2 .......................................................... 118 
7.10.2.3. Additional safety monitoring in Part B ....................... 118 
7.10.3. 
Safety evaluation by the IDMC ................................................... 120 
7.10.3.1. Outcome of the IDMC safety evaluation ................... 120 
7.10.3.2. Process of suspension of vaccination and/ or 
study modification ..................................................... 120 
7.10.4. 
Study holding rules for the vaccination phase ............................ 121 
7.10.5. 
Risk assessment ........................................................................ 124 
7.10.5.1. Part A ....................................................................... 124 
7.10.5.2. Part B ....................................................................... 125 
8. 
RTI SURVEILLANCE DURING PART B OF THE STUDY .................................... 127 
8.1. 
Active surveillance .................................................................................... 127 
8.2. 
Passive surveillance ................................................................................. 128 
8.3. 
Assessment Visit for potential RSV-RTI .................................................... 128 
9. 
SUBJECT COMPLETION AND WITHDRAWAL ................................................... 130 
9.1. 
Subject completion ................................................................................... 130 
9.2. 
Subject withdrawal .................................................................................... 130 
9.2.1. 
Subject withdrawal from the study ............................................. 130 
9.2.2. 
Subject withdrawal from study vaccine ...................................... 131 
9.3. 
Screen and baseline failures ..................................................................... 131 
10. STATISTICAL METHODS .................................................................................... 132 
10.1. 
Primary endpoints ..................................................................................... 132 
10.2. 
Secondary endpoints ................................................................................ 132 
10.3. 
Tertiary endpoints ..................................................................................... 133 
10.4. 
Determination of sample size .................................................................... 134 
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10.5. 
Cohorts for Analyses ................................................................................ 136 
10.5.1. 
Exposed Set .............................................................................. 136 
10.5.2. 
Per-protocol Set for analysis of immunogenicity......................... 136 
10.6. 
Derived and transformed data ................................................................... 137 
10.7. 
Analysis of demographics ......................................................................... 138 
10.8. 
Analysis of safety ...................................................................................... 138 
10.9. 
Analysis of immunogenicity ....................................................................... 139 
10.9.1. 
Within groups evaluation - humoral immune response ............... 140 
10.9.2. 
Within groups evaluation - Cell-mediated immune 
response .................................................................................... 140 
10.9.3. 
Between groups evaluation (Part B only) ................................... 141 
10.10. Analysis of RTI for Part B .......................................................................... 142 
10.11. Interpretation of analyses .......................................................................... 142 
10.12. Conduct of analyses ................................................................................. 142 
10.12.1. Sequence of analyses................................................................ 143 
10.12.2. Statistical considerations for interim analyses ............................ 144 
11. ADMINISTRATIVE MATTERS ............................................................................. 144 
11.1. 
electronic Case Report Form instructions ................................................. 144 
11.2. 
Study Monitoring by GSK Biologicals ........................................................ 145 
11.3. 
Record retention ....................................................................................... 145 
11.4. 
Quality assurance ..................................................................................... 146 
11.5. 
Posting of information on publicly available clinical trial registers and 
publication policy ...................................................................................... 146 
11.6. 
Provision of study results to investigators ................................................. 147 
11.7. 
Data Sharing ............................................................................................. 147 
12. REFERENCES ..................................................................................................... 148 
13. APPENDICES ...................................................................................................... 151 
 
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LIST OF TABLES 
PAGE 
Table 1 
Study groups and epochs foreseen in the study ..................................... 50 
Table 2 
Study groups and treatment foreseen in Part A ...................................... 51 
Table 3 
Study groups and treatment foreseen in Part B - Step 1 ......................... 52 
Table 4 
Study groups and treatment foreseen in Part B - Step 2 ......................... 53 
Table 5 
Blinding of study epochs ........................................................................ 54 
Table 6 
List of study procedures for Part A ......................................................... 65 
Table 7 
List of study procedures for Part B ......................................................... 67 
Table 8 
Intervals between study visits ................................................................. 70 
Table 9 
Biological samples ................................................................................. 79 
Table 10 
Humoral Immunity (Antibody determination) (Amended, 13 May 
2020) ...................................................................................................... 80 
Table 11 
Cell-mediated Immunity (CMI) ................................................................ 81 
Table 12 
Hematology/biochemistry ....................................................................... 81 
Table 13 
Molecular Biology (PCR tests) ................................................................ 82 
Table 14 
Immunological read-outs in Part A ......................................................... 84 
Table 15 
Immunological read-outs in Part B (Amended, 13 May 2020) ................. 85 
Table 16 
Hematology and biochemistry read-outs and CMV serology 
testing .................................................................................................... 86 
Table 17 
Molecular biology tests on nasal/throat swab specimen for Part B ......... 87 
Table 18 
Study vaccine for Part A and Part B - Step 1 .......................................... 89 
Table 19 
Study vaccine for Part B - Step 2 ........................................................... 90 
Table 20 
Dosage and administration ..................................................................... 92 
Table 21 
Solicited local adverse events ................................................................ 98 
Table 22 
Solicited general adverse events ............................................................ 98 
Table 23 
List of potential immune-mediated diseases ......................................... 100 
Table 24 
Reporting periods for collecting safety information in Part A ................. 105 
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Table 25 
Reporting periods for collecting safety information in Part B ................. 106 
Table 26 
Intensity scales for solicited symptoms in adults................................... 108 
Table 27 
Timeframes for submitting serious adverse event, pregnancy and 
other events reports to GSK Biologicals ............................................... 111 
Table 28 
Contact information for emergency unblinding ..................................... 115 
Table 29 
Study holding rules for Part A and Part B Step 1 (Dose 1 and 
Dose 2) ................................................................................................ 122 
Table 30 
Study holding rules for Part B (Steps 1 and 2 pooled) .......................... 123 
Table 31 
Factorial design .................................................................................... 135 
Table 32 
Effect of second vaccination: Power and fold increase with a 
sample size of 270 subjects per pooled group ...................................... 135 
Table 33 
Effect of adjuvant: Power and fold increase with a sample size of 
270 subjects per pooled group ............................................................. 135 
Table 34 
Antigen dose-response: Power and fold increase with a sample 
size of 90 subjects per group................................................................ 136 
Table 35 
GSK Biologicals’ laboratories ............................................................... 155 
Table 36 
Outsourced laboratories ....................................................................... 155 
Table 37 
FDA toxicity grading scales for hematology/ biochemistry 
parameters evaluated in the current study RSV OA=ADJ-002 ............. 158 
 
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LIST OF FIGURES 
PAGE 
Figure 1 
Overview of IDMC safety evaluations in each study part and 
staggered enrolment in Part B .............................................................. 119 
Figure 2 
Evaluations based on 12 subjects - Risk assessment curves for 
Part A ................................................................................................... 124 
Figure 3 
Evaluations based on 10 subjects - Risk assessment curve for 
one formulation based on the proposed safety holding rules for 
Part B - Step 1 ..................................................................................... 125 
Figure 4 
Evaluations based on 8 subjects - Risk assessment curve for 
one formulation based on the proposed safety holding rules for 
Part B - Step 1 ..................................................................................... 126 
Figure 5 
Risk assessment curve for the Part B study population for one 
formulation based on the proposed safety holding rules (25%) ............ 127 
 
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LIST OF APPENDICES 
PAGE 
APPENDIX A LABORATORY ASSAYS ..................................................................... 151 
APPENDIX B CLINICAL LABORATORIES ................................................................ 155 
APPENDIX C FDA GUIDANCE FOR INDUSTRY: TOXICITY GRADING 
SCALE FOR HEALTHY ADULT AND ADOLESCENT 
VOLUNTEERS ENROLLED IN PREVENTIVE VACCINE 
CLINICAL TRIALS (SEPTEMBER 2007) ............................................. 156 
APPENDIX D COMMUNICATION FLOW IN CASE HOLDING RULES ARE 
MET ..................................................................................................... 160 
APPENDIX E AMENDMENTS AND ADMINISTRATIVE CHANGES TO THE 
PROTOCOL ......................................................................................... 161 
 
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LIST OF ABBREVIATIONS 
AE: 
Adverse Event 
ALT: 
Alanine Aminotransferase 
ANCOVA: 
Analysis of Covariance 
ANOVA: 
Analysis of Variance 
AS01B: 
MPL, QS-21, liposome based Adjuvant System (50 μg MPL and 
50 μg QS-21) 
AS01E: 
MPL, QS-21, liposome based Adjuvant System (25 μg MPL and 
25 μg QS-21) 
AST: 
Aspartate Aminotransferase 
BUN: 
Blood Urea Nitrogen 
CD40L: 
Cluster of Differentiation 40 Ligand 
CDC: 
Centers for Disease Control 
CI: 
Confidence Interval 
CLS: 
Clinical Laboratory Sciences 
CMI: 
Cell-Mediated Immunity 
CMV: 
Cytomegalovirus 
COPD: 
Chronic Obstructive Pulmonary Disease 
COVID-19 
Coronavirus Disease 2019 (Amended, 13 May 2020) 
eCRF: 
electronic Case Report Form 
EDD: 
Estimated Date of Delivery 
eDiary: 
electronic Diary 
EGA: 
Estimated Gestational Age 
ELISA: 
Enzyme-Linked Immunosorbent Assay 
EoS: 
End of Study 
ES: 
Exposed Set 
eTDF: 
Electronic Temperature excursion Decision Form 
FDA: 
Food and Drug Administration, United States of America 
GCP: 
Good Clinical Practice 
gE: 
glycoprotein E 
GM: 
Geometric Mean 
GMC: 
Geometric Mean Concentration 
GMT: 
Geometric Mean Titer 
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GSK: 
GlaxoSmithKline 
HIV: 
Human Immunodeficiency Virus 
hMPV: 
Human Metapneumovirus 
HRP: 
Horseradish Peroxidase 
HZ/su: 
Herpes Zoster subunit vaccine 
ICF: 
Informed Consent Form 
ICH: 
International Conference on Harmonisation 
ICS: 
Intracellular Cytokine Staining 
IDMC: 
Independent Data Monitoring Committee 
IEC: 
Independent Ethics Committee 
IFN-: 
Interferon Gamma 
IgG: 
Immunoglobulin G 
IL: 
Interleukin 
IM: 
Intramuscular(ly) 
IMP: 
Investigational Medicinal Product 
IND: 
Investigational New Drug 
IRB: 
Institutional Review Board 
LML: 
Local Medical Lead  
LMP: 
Last Menstrual Period 
LOC: 
Local Operating Company 
LRTD: 
Lower Respiratory Tract Disease 
LSLV: 
Last Subject Last Visit 
MACDP: 
Metropolitan Atlanta Congenital Defects Program 
MedDRA: 
Medical Dictionary for Regulatory Activities 
PBMC: 
Peripheral Blood Mononuclear Cells 
PCR: 
Polymerase Chain Reaction 
pIMD: 
Potential Immune-Mediated Disease 
PPS: 
Per Protocol Set 
PT: 
Preferred Term 
Q: 
Quartile 
qRT-PCR: 
Quantitative Reverse Transcription Polymerase Chain Reaction 
QS-21: 
Quillaja saponaria Molina, fraction 21 (Licensed by GSK from 
Antigenics Inc, a wholly owned subsidiary of Agenus Inc., a 
Delaware, USA corporation) 
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RNA: 
Ribonucleic Acid 
RSV: 
Respiratory Syncytial Virus 
RTI: 
Respiratory Tract Infection 
SAE: 
Serious Adverse Event 
SAP: 
Statistical Analysis Plan 
SBIR: 
Randomization System on Internet 
SDV: 
Source Document Verification 
SPM: 
Study Procedures Manual 
TNF-: 
Tumor Necrosis Factor Alpha 
US: 
United States 
WBC: 
White Blood Cells 
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GLOSSARY OF TERMS 
Adequate contraception: 
(Amended, 13 May 2020) 
Adequate contraception is defined as a contraceptive 
method with failure rate of less than 1% per year when 
used consistently and correctly and when applicable, in 
accordance with the product label for example:  
• 
Abstinence from penile-vaginal intercourse, when 
this is their preferred and usual lifestyle; 
• 
Combined estrogen and progesterone oral 
contraceptives; 
• 
Injectable progestogen; 
• 
Implants of etonogestrel or levonorgestrel; 
• 
Contraceptive vaginal ring; 
• 
Percutaneous contraceptive patches; 
• 
Intrauterine device or intrauterine system; 
• 
Male partner sterilisation prior to the female 
subject’s entry into the study, and this male is the 
sole partner for that subject; 
The information on the male sterility can come from 
the site personnel’s review of the subject’s medical 
records; or interview with the subject on her medical 
history. 
Adequate contraception does not apply to subjects of 
child bearing potential with same sex partners, or for 
subjects who are and will continue to be abstinent from 
penile-vaginal intercourse on a long term and persistent 
basis, when this is their preferred and usual lifestyle. 
Adverse event: 
Any untoward medical occurrence in a patient or clinical 
investigation subject, temporally associated with the use 
of a medicinal product, whether or not considered related 
to the medicinal product.  
An adverse event (AE) can therefore be any unfavourable 
and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of a medicinal product. 
For marketed medicinal products, this also includes 
failure to produce expected benefits (i.e. lack of efficacy), 
abuse or misuse. 
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Blinding: 
A procedure in which one or more parties to the trial are 
kept unaware of the treatment assignment in order to 
reduce the risk of biased study outcomes. The level of 
blinding is maintained throughout the conduct of the trial, 
and only when the data are cleaned to an acceptable level 
of quality will appropriate personnel be unblinded or 
when required in case of a serious adverse event. In a 
single-blind study, the investigator and/or his staff are 
aware of the treatment assignment but the subject is not. 
In an observer-blind study, the subject and the site and 
sponsor personnel involved in the clinical evaluation of 
the subjects are blinded while other study personnel may 
be aware of the treatment assignment (see Section 5.3 for 
details on observer-blinded studies).  
Designate: 
A person who helps the subject with performing some of 
the study procedures if the subject has difficulties to 
perform them alone (such as completion of the eDiary, 
receiving phone calls and planning of the study visits), 
e.g. a relative of the subject, a field worker who is linked 
to this study. Designates are appointed by the subject for 
help with the study procedures solely and cannot make 
decisions on behalf of the subject. 
Eligible: 
Qualified for enrolment into the study based upon strict 
adherence to inclusion/exclusion criteria. 
End of Study  
(Synonym of End of Trial) 
For studies without collection of human biologicals 
samples or imaging data EoS is the Last Subject Last 
Visit (LSLV).  
For studies with collection of Human Biologicals 
Samples or imaging data, EoS is defined as the date of the 
last testing/reading released of the Human Biological 
Samples or imaging data, related to primary and 
secondary endpoints. EoS must be achieved no later than 
8 months after LSLV. 
Epoch: 
An epoch is a set of consecutive timepoints or a single 
timepoint from a single protocol. Epochs are defined to 
support a main purpose which is either to draw 
conclusions on subject participation or to draw a 
complete conclusion to define or precise the targeted 
label of the product. Supporting means that data collected 
at the timepoints included in an epoch must be sufficient 
to fulfil the purpose of the epoch. 
Typical examples of epochs are screening, primary 
vaccinations, boosters, yearly immunogenicity follow-
ups, and surveillance periods for efficacy or safety. 
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eTrack: 
GSK’s tracking tool for clinical trials. 
Evaluable: 
Meeting all eligibility criteria, complying with the 
procedures defined in the protocol, and, therefore, 
included in the per-protocol analysis (see Sections 6.6.2 
and 10.5 for details on criteria for evaluability). 
Immunological correlate 
of protection: 
The defined immune response above which there is a high 
likelihood of protection in the absence of any host factors 
that might increase susceptibility to the infectious agent. 
Intercurrent medical 
condition: 
A condition that has the capability of altering the immune 
response to the study vaccine or is confirmed to have an 
alteration of the subject’s initial immune status. 
Investigational vaccine: 
(Synonym of 
Investigational Medicinal 
Product) 
A pharmaceutical form of an active ingredient being 
tested in a clinical trial, including a product with a 
marketing authorisation when used in a way different 
from the approved form, or when used for an unapproved 
indication, or when used to gain further information about 
an approved use.  
Potential Immune-
Mediated Disease: 
Potential immune-mediated diseases (pIMDs) are a subset 
of AEs that include autoimmune diseases and other 
inflammatory and/or neurologic disorders of interest 
which may or may not have an autoimmune aetiology. 
Primary completion date: 
The date that the final subject was examined or received 
an intervention for the purpose of final collection of data 
for all primary outcomes, whether the clinical trial was 
concluded according to the pre-specified protocol or was 
terminated. 
Protocol amendment: 
The International Conference on Harmonisation (ICH) 
defines a protocol amendment as: ‘A written description 
of a change(s) to or formal clarification of a protocol.’ 
GSK Biologicals further details this to include a change 
to an approved protocol that affects the safety of subjects, 
scope of the investigation, study design, or scientific 
integrity of the study. 
Protocol administrative 
change: 
A protocol administrative change addresses changes to 
only logistical or administrative aspects of the study.  
Randomization: 
Process of random attribution of treatment to subjects in 
order to reduce bias of selection. 
Self-contained study: 
Study with objectives not linked to the data of another 
study. 
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Site Monitor: 
An individual assigned by the sponsor who is responsible 
for assuring proper conduct of clinical studies at one or 
more investigational sites. 
Solicited adverse event: 
AEs to be recorded as endpoints in the clinical study. The 
presence/occurrence/intensity of these events is actively 
solicited from the subject or an observer during a 
specified post-vaccination follow-up period. 
Study vaccine/product: 
Any investigational vaccine/product being tested and/or 
any authorized use of a vaccine/ product /placebo as a 
reference or administered concomitantly, in a clinical trial 
that evaluates the use of an investigational 
vaccine/product. 
Sub-cohort: 
A group of subjects for whom specific study procedures 
are planned as compared to other subjects or a group of 
subjects who share a common characteristic (e.g. ages, 
vaccination schedule,…) at the time of enrolment. 
Subject: 
Term used throughout the protocol to denote an 
individual who has been contacted in order to participate 
or participates in the clinical study, either as a recipient of 
the vaccines or as a control. 
Subject number: 
A unique number identifying a subject, assigned to each 
subject consenting to participate in the study. 
Treatment: 
Term used throughout the clinical study to denote a set of 
investigational product(s) or marketed product(s) or 
placebo intended to be administered to a subject. 
Treatment number: 
A number identifying a treatment to a subject, according 
to treatment allocation. 
Unsolicited adverse event: 
Any AE reported in addition to those solicited during the 
clinical study. Also any ‘solicited’ symptom with onset 
outside the specified period of follow-up for solicited 
symptoms will be reported as an unsolicited adverse 
event. 
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TRADEMARKS 
The following trademarks are used in the present protocol. 
Note: In the body of the protocol (including the synopsis), the names of the 
vaccines/products and/or medications will be written without the superscript symbol ™ 
or ® and in italics. 
Trademarks of the GlaxoSmithKline 
group of companies 
 
Generic description 
Cervarix 
 
Human Papillomavirus vaccine Types 16 
and 18 (Recombinant, AS04 adjuvanted) 
Shingrix 
 
Zoster vaccine (Recombinant, adjuvanted) 
 
Trademarks not owned by the 
GlaxoSmithKline group of companies 
 
Generic description 
Allplex Respiratory Panel (Seegene) 
 
A multiplex one-step real-time RT-PCR 
assay to detect and identify 16 viruses, 7 
bacteria and 3 Flu A subtypes 
Fluad (Seqirus Inc.) 
 
Influenza virus vaccine (Surface antigen, 
inactivated, adjuvanted with MF59) 
MF59 adjuvant (Novartis) 
 
Oil-in-water emulsion of squalene oil 
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1. 
INTRODUCTION 
1.1. 
Background 
Respiratory syncytial virus (RSV) is a ribonucleic acid (RNA) virus of which 
2 antigenically distinct subgroups exist, referred to as RSV-A and RSV-B [Borchers, 
2013]. RSV is a highly contagious human pathogen that causes respiratory tract 
infections (RTI) in people of all ages. In temperate climates throughout the world, RSV 
predictably causes fall-winter epidemics whereas viral activity is more endemic in (sub) 
tropical regions and outbreaks are less temporally focused. 
According to the Centers for Disease Control and Prevention (CDC) website [CDC, 
2017], RSV leads to 177 000 hospitalizations and 14 000 deaths on average each year 
among adults older than 65 years in the United States (US). As the global population 
ages, the morbidity and mortality of respiratory infections appear to be steadily 
increasing. In the US, the burden of the disease has been shown to be significant and data 
indicate that RSV is comparable to influenza (in an influenza vaccinated population) in 
terms of number of infections, hospitalization and deaths. Based on epidemiological data 
collected prospectively in 2008-2010 in 14 countries worldwide (including North 
America, Europe and East Asia), the average percentage of documented RSV infection in 
older adults ( 65 years) with influenza-like illness is 7.4%, with values between 0% and 
17.1% across countries [Falsey, 2014]. 
Previous infection with RSV does not prevent subsequent infections. Therefore, 
reinfection with RSV occurs throughout an individual’s lifetime and is common in all age 
groups [Simoes, 1999; Krilov, 2011]. Generally, these re-infections go undiagnosed 
because they usually manifest as common acute upper RTIs. However, in more 
vulnerable individuals (e.g. immunocompromized subjects or older adults), re-infections 
can also lead to severe disease [Graham, 2011]. 
1.2. 
Rationale for the study and study design 
1.2.1. 
Rationale for the study 
Despite the significant medical need, there is currently no prophylactic vaccine approved 
for the prevention of lower respiratory tract disease (LRTD) caused by RSV. Several 
attempts have been made to develop an RSV vaccine but to date all have been 
unsuccessful. In the 1960’s, a formalin-inactivated RSV vaccine not only failed to show 
protection, but it promoted more frequent and more severe clinical symptoms of LRTD 
after RSV natural infection in vaccinated children. In 2015, Novavax announced results 
of their Phase II Proof of Concept clinical trial showing the first ever demonstration of 
efficacy following the administration of an active RSV vaccine in older adults over 60 
years of age. However, in September 2016, Novavax announced the vaccine candidate 
had failed the primary and secondary efficacy endpoints in its pivotal Phase III study. 
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GlaxoSmithKline (GSK) Biologicals is developing a new investigational RSV vaccine 
against moderate to severe RSV-associated (subtypes A and B) disease in adults aged 
60 years or above. 
Please refer to the current Investigator Brochure for information regarding the pre-
clinical studies of the investigational RSV older adult vaccine formulations. 
1.2.2. 
Rationale for the study design 
This study will evaluate 9 investigational RSV vaccine formulations, with different 
concentrations of pre-fusion conformation antigen RSVPreF3 (30, 60 or 120 µg), either 
unadjuvanted or adjuvanted with AS01E or AS01B when administered intramuscularly 
according to a 2-dose schedule at 0, 2 months in older adults (60-80 years). The main 
purpose will be to evaluate the safety, reactogenicity and immunogenicity of the vaccine 
candidates and select a formulation for further development of the RSV vaccine. In terms 
of immunogenicity, the selection of the vaccine formulation will rely primarily on the 
levels of RSV-A neutralizing antibody titers and CD4+ T-cells response. Further 
assessment of immune responses, including the RSVPreF3 immunoglobulin G (IgG) 
antibody, might additionally guide the vaccine candidate selection.  
As the RSVPreF3 antigen has not been administered to humans yet, the study will first 
evaluate the safety of 3 different dosages of RSVPreF3 (30, 60 and 120 g) in healthy 
men and women aged 18-40 years according to a 2-dose regimen. As many safety data 
have already been generated with the AS01E and AS01B adjuvants in other GSK vaccine 
programs (Zoster and Malaria), the antigen and adjuvant dose ranging will be evaluated 
directly in the target population of older adults aged 60-80 years.  
Hence, the study will follow a staggered design with the following 2 parts: 
• 
Part A, including 48 healthy adults aged 18-40 years receiving either placebo or one 
of 3 unadjuvanted investigational RSV vaccines containing 30, 60 or 120 µg 
RSVPreF3 (~12 subjects/group). 
• 
Part B, including 1000 older adults aged 60-80 years receiving either placebo or one 
of 9 investigational RSV vaccines containing 30, 60 or 120 µg RSVPreF3 
unadjuvanted or adjuvanted with AS01E or AS01B (~100 subjects/group, enrolled in 
Steps 1 and 2 in a staggered manner). 
As this dose ranging study will include the target population of older adults aged 60-80 
years, it has been designed as a Phase I/II study. 
1.2.2.1. 
Vaccine antigen and adjuvant selection 
The antigen which will be used in the investigational RSV vaccine is an engineered 
version of the RSV fusion (F) surface glycoprotein, stabilized in the pre-fusion 
conformation, resulting in the “RSVPreF3” pre-fusion molecule. The F protein has been 
selected because it is a major surface antigen of the RSV virus that is well conserved 
among RSV-A and RSV-B subtypes. It was shown that most of the RSV neutralizing 
activity present in serum from previously infected individuals is directed to the pre-fusion 
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conformation of RSV F protein [Ngwuta, 2015]. In addition, antibodies specific for the 
RSV F pre-fusion conformation are typically more potent than those common to the post- 
and pre-fusion forms [Kwakkenbos, 2010]. Finally, an RSV F antigen in the prefusion 
conformation elicited higher levels of neutralizing antibodies than those observed with an 
RSV F protein in the post-fusion conformation [McLellan, 2013; Steff, 2017].  
In addition to boosting pre-existing neutralizing antibodies, another important element for 
the RSV candidate vaccine in older adults might be to boost or elicit RSV-specific T-cell 
responses. The use of an adjuvant may enable induction of CD4+ T-cells in addition to 
antibodies, leading to a stronger and persistent protection. Amongst the current GSK 
portfolio of adjuvants, AS01 has the potential to induce the targeted immune profile as it 
has been shown to improve antibody and T-cell response in older adults [Chlibek, 2013; 
Chlibek, 2014; Chlibek, 2016; Schwarz, 2018]. Based on the available evidence, AS01 
would be expected to boost the CD4+ T-cell as well as B-cell memory responses. 
The AS01E and AS01B adjuvants have been evaluated in several GSK candidate vaccines. 
As of 30 June 2017, over 35 000 participants have been vaccinated with at least one dose 
of an AS01-containing vaccine in completed clinical trials. The population vaccinated 
with an AS01-adjuvanted vaccine consists in over 12 700 infants and toddlers 
participating in Malaria trials and over 22 500 adults and older adults mainly coming 
from Zoster trials. Clinical data from the efficacy trials of the Herpes Zoster subunit 
vaccine (HZ/su) in adults aged 50 years or above and adults aged 70 years or above have 
demonstrated the added value of AS01-based adjuvants for older adults. HZ/su 
(glycoprotein E [gE]/AS01B) is able to induce strong and persistent gE-specific antibody 
and CD4+ T-cell responses up to 9 years in a population known for diminished immune 
response (immune-senescence) [Chlibek, 2016; Pauksens, 2017]. The HZ/su (gE/AS01B) 
vaccine is currently licensed in several countries, including the United States, Canada, the 
European Union, Japan and Australia.  
1.2.2.2. 
Dose regimen 
It is proposed to evaluate a 2-dose vaccination regimen with an interval of 2 months 
between doses. This is supported by available data from several clinical studies in GSK’s 
Herpes Zoster and chronic obstructive pulmonary disease (COPD) vaccine development 
programs conducted with an adjuvanted protein in older adults. 
In the Phase II study ZOSTER-003 (Herpes Zoster vaccine program), conducted in older 
adults aged 60 years and above, a statistically significant higher cellular immune 
response (based on frequency of gE-specific CD4+ T-cells) and humoral immune 
response was observed in all groups who received 2 doses of the adjuvanted gE 
(gE/AS01B) vaccine (at 3 different gE dosage levels tested) compared to a single dose of 
the highest concentration of gE/AS01B tested [Chlibek, 2014]. Descriptive data for 
persistence over 3 years further support this observation, as the median gE-specific CD4+ 
T-cell frequencies and anti-gE antibody concentrations remained higher in the 2-dose 
group as compared to the 1-dose group [Chlibek, 2014]. 
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Similarly, in the Phase I study NTHI-003 (COPD vaccine development program) in older 
adults aged 50 to 70 years, a second dose of any of the adjuvanted non-typeable 
Haemophilus influenzae protein vaccine formulations administered 2 months following 
the first dose, induced higher antibody concentrations and cellular immune response 
(based on the frequency of antigen-specific CD4+ T-cells) as compared to one dose 
[Leroux-Roels, 2016]. 
1.2.2.3. 
Staggered design and safety monitoring 
As the RSVPreF3 antigen has not been administered to humans yet, this study will first 
evaluate the safety of 3 different dosages of RSVPreF3 (30, 60 and 120 g, 
unadjuvanted) in healthy adults aged 18-40 years in Part A (~12 subjects/group) before 
proceeding with vaccination of the target population of older adults aged 60-80 years in 
Part B (~100 subjects/group). For each part, study holding rules have been defined. 
After the first and second vaccine dose in Part A, safety evaluations will be performed by 
an Independent Data Monitoring Committee (IDMC) based on data collected up to 30 
and 7 days post-vaccination, respectively, based on all subjects (~12 group). Only upon 
favorable outcome of the first IDMC evaluation, the vaccination in Part B of the study 
will be initiated. In this part, the safety and immunogenicity of 9 investigational RSV 
vaccine formulations (adjuvanted and unadjuvanted) will be evaluated in older adults 
aged 60-80 years. To ensure the safety of the study participants, Part B will follow a 
staggered enrolment with 2 steps. The IDMC evaluations will be based on data after each 
study vaccine administration in the first 100 study participants enrolled in Step 1 (i.e., the 
first 10 study participants per group). In addition, holding rules for the whole population 
will be applied. 
Holding rules for Phase I studies will be applied. The IDMC may recommend to stop 
vaccination in all groups or only in a specific study group while proceeding with 
vaccination in the other groups.  
For more detailed information on the staggered design, study holding rules and safety 
monitoring, refer to Sections 7.10 and 7.10.5 for details). 
1.2.2.4. 
Study blinding 
Given the difference in reconstitution and visual appearance of the investigational RSV 
vaccines, double blinding is not possible and the study will be conducted in an observer- 
blind manner for the vaccination phases (up to one month post-Dose 2) of both study 
parts.  
A statistical analysis will be performed when primary and secondary endpoint data from 
vaccinated subjects up to one month post-Dose 2 in both study parts will be available. 
Given that summary results may unblind some specific subjects, the persistence phase of 
Part B (Epoch 003, see Section 3) will be considered as single-blind, with subjects 
remaining blinded up to study end. The investigators will not be provided with the 
individual data listings or with the randomization listings until study end (Visit 8 
[Month 14]).  
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During the last study visit, blood samples will be collected only from a subset of 
subjects (N460, all subjects in part B1 and subjects who received a selected level of 
antigen dose and Placebo in part B2). Therefore, the investigators, site and study staff 
will be partially unblinded at group level, but not at the individual level.  
In case there will be an extension study planned, with all or a subset of participants 
included, the investigators may be provided with the list of study subjects eligible to 
participate in such study, before the parent study ends. Therefore, the investigators, site 
and study staff will potentially receive an individual data listings for a subset. All 
subjects in this subset may be unblinded before the study ends. (Amended, 13 May 
2020) 
Please refer to the glossary of terms for the definition of observer-blind and single-blind. 
1.2.2.5. 
Rationale for the use of placebo 
As there is currently no licensed RSV vaccine available, a placebo group (receiving 
saline solution) will be used as control for the safety, reactogenicity and immunogenicity 
assessments in both study parts.  
1.3. 
Benefit : Risk Assessment 
In total, approximately 936 subjects in this study will be exposed to the investigational 
RSV vaccine, whereas approximately 112 subjects will receive placebo. 
The following section outlines the risk assessment and mitigation strategy for this study 
protocol: 
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1.3.1. 
Risk Assessment 
Risks, Contraindications 
and Warnings 
Data/Rationale for Risk  
Mitigation Strategy 
All Study Vaccines 
Hypersensitivity including 
allergic reaction such as 
anaphylaxis 
Acute allergic reactions such as a 
rare case of anaphylactic event 
may occur with any vaccine 
administration. These are serious, 
but rare occurrences estimated in 
the range of 1 to 10 cases per 
million of vaccinations, depending 
on the vaccine studied 
[Ruggerberg, 2007]. 
Anaphylaxis following vaccine administration 
is a contraindication to vaccination. The 
onset of vaccine-related allergic symptoms is 
typically quite prompt. In order to treat 
subjects with a serious allergic reaction to 
vaccination, all subjects will need to remain 
under observation (i.e. visibly followed; no 
specific procedure) at the vaccination center 
for at least 60 minutes after vaccination. 
Syncope 
Syncope (fainting) can occur 
following or even before any 
vaccination as a psychogenic 
response to the needle injection.  
All subjects will remain under observation at 
the vaccination center for at least 60 minutes 
after vaccination. 
Intramuscular (IM) injection 
Intramuscular vaccination 
commonly precipitates a transient 
and self-limiting local 
inflammatory reaction. This may 
typically include pain at injection 
site, redness, and swelling. 
All subjects will remain under observation at 
the vaccination center for at least 60 minutes 
after vaccination. 
Solicited local adverse events (AE) will be 
collected and reviewed up to Day 8. 
RSVPreF3 
Due to the lack of experience 
in human subjects to date, 
there is currently not enough 
information available to 
identify the risks of AEs 
related to the administration of 
the RSVPreF3 investigational 
vaccine. 
 
Any untoward symptoms experienced by the 
subject after receiving the vaccine should be 
reported to the investigator. 
The study will be conducted in a staggered 
manner with safety evaluations by an IDMC. 
Holding rules that have been established will 
be applied. 
Adjuvant Systems 
Potential immune-mediated 
diseases (pIMDs) are a 
theoretical concern with 
adjuvanted vaccines.  
There are no safety findings 
suggesting a causal link between 
pIMDs and AS01-containing 
vaccines [Stassijns, 2016]. 
During the informed consent process, the 
subjects enrolling in Part B will be informed 
of this potential risk and the need to attend 
the clinic if they are unwell. pIMD is an AE of 
specific interest and will be collected up to 12 
months after administration of the last dose 
of study vaccine (see Section 7.1.5). The 
occurrence of pIMD cases will be described. 
Study Procedures – Blood sampling 
Pain and bruising 
Pain or bruising at the site where 
blood is drawn.  
A topical analgesic may be applied to the site 
where blood will be taken. 
Syncope 
Syncope (fainting) can occur 
following or even before any 
blood draw as a psychogenic 
response to the needle injection. 
Subject Monitoring (Section 7.10) 
All subjects will remain under observation at 
the clinical center for at least 60 minutes 
after vaccination. 
Nerve Injury 
There is a possibility that in the 
process of collecting blood a 
nerve may be injured. 
Procedure to be performed by qualified 
personnel. 
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1.3.2. 
Benefit Assessment 
The subjects receiving investigational RSV vaccine may not directly benefit from this 
vaccination because vaccine efficacy has not been assessed yet and it is hence not known 
whether the investigational RSV vaccine is effective in protecting against RSV infection. 
An indirect benefit is that the information obtained in this study will aid the development 
of an RSV vaccine, which is intended to prevent LRTD associated with RSV infection in 
older adults. 
Another benefit for all study participants may include gaining of information about their 
general health status through the medical evaluations/assessments associated with this 
study (i.e., physical examination, blood testing [hematology and biochemistry data]). 
1.3.3. 
Overall Benefit : Risk Conclusion 
The investigational RSV vaccine is currently in an early stage of clinical development. 
Taking into account the measures to minimise the risk to subjects participating in this 
study, the potential risks are justified by the potential benefits linked to the development 
of this RSV vaccine. 
2. 
OBJECTIVES 
2.1. 
Primary objective 
For Part A and Part B: 
• 
To evaluate the safety and reactogenicity of 2 doses of the investigational RSV 
vaccine administered IM according to a 0, 2 month schedule, up to one month after 
the last dose (Day 91, Visit 6).  
Refer to Section 10.1 for the definition of the primary endpoints. 
2.2. 
Secondary objectives 
For Part A and Part B: 
• 
To characterize the humoral immune responses (including dose-response) in relation 
to the investigational RSV vaccine formulations administered IM according to a 0, 2 
month schedule, up to one month after the last dose (Day 91, Visit 6). 
• 
To characterize the cell-mediated immune responses in relation to the investigational 
RSV vaccine formulations administered IM according to a 0, 2 month schedule, up 
to one month after the last dose (Day 91, Visit 6). 
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For Part B: 
• 
To evaluate the safety and reactogenicity of 2 doses of the investigational RSV 
vaccines administered IM according to a 0, 2 month schedule, up to the end of 
follow-up (Month 14, Visit 8).  
• 
To evaluate the occurrence of RSV-associated respiratory tract infections (RTI) 
during the RSV season in nasal/throat swab samples collected during the assessment 
visit for potential RSV-RTI. 
Refer to Section 10.2 for the definition of the secondary endpoints. 
2.3. 
Tertiary objectives 
For Part A and Part B: 
• 
To further characterize the cell-mediated immune responses to investigational RSV 
vaccine formulations.  
For Part B: 
• 
To further characterize immune responses to investigational RSV vaccine 
formulations.  
• 
To characterize persistence of immune responses to the investigational RSV vaccine 
formulations at Month 8 (Visit 7) and Month 14 (Visit 8).  
• 
To further evaluate the occurrence of RSV-associated RTI (including co-infections 
with other respiratory viruses) during the RSV seasons in nasal/throat swab samples 
collected during the assessment visit for potential RSV-RTI.  
• 
To evaluate the occurrence of RSV-associated RTI during the RSV season using 
self-collected nasal swabs. 
Refer to Section 10.3 for the definition of the tertiary endpoints. 
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3. 
STUDY DESIGN OVERVIEW 
 
BS S: Blood sample for safety (hematology/biochemistry) 
BS H: Blood sample for humoral immune responses 
BS C: Blood sample for cell-mediated immune responses (for CD4+/CD8+ and/or memory B-cell testing) 
FU: Follow-up; PCR: Polymerase Chain Reaction 
* Visit 1 should take place no longer than 30 days after the Screening Visit. In case Visit 1 occurs more than 30 days 
after the Screening Visit, a re-screening visit should be scheduled before Visit 1 during which blood sample collection 
for safety laboratory assessment must be repeated (maximum one re-screening per subject is allowed). Only 
laboratory results from the re-screening visit, if it occurs, will be taken into consideration and recorded in the eCRF. 
Medical history, physical examination and review of inclusion/exclusion criteria must be repeated if a re-screening visit 
occurs. The subject can only be randomized once the investigator receives the results and confirms the eligibility 
criteria. 
** In Part A, a first IDMC evaluation of safety data up to Day 31 based on all subjects (12 per group or at least 8 per 
group in case of slow recruitment, see Section 7.10.5) will be performed before proceeding with administration of 
Dose 2 in Part A and Dose 1 in Part B. A second IDMC evaluation will be performed based on safety data up to Day 68 
for all subjects. Refer to Section 7.10 for details on the staggered design and safety evaluations. 
*** In Part B, a third and fourth IDMC evaluation of safety data up to Day 8 and Day 68, respectively, for the first 
enrolled and vaccinated subjects (10 per group or at least 8 per group in case of slow recruitment, see Section 
7.10.5) will be performed. Additional IDMC evaluations will happen during the conduct of the study (see Section 7.10 
for details on the staggered enrolment and safety evaluations). 
PART B
60-80 year-old subjects (N1000)
PART A
18-40 year-old subjects (N48)
Randomization
(1:1:1:1)
3 RSV vaccine study groups (N12 per group)
Placebo group (N12)
Visit 4
(Day 61)
BS S
BS H
Visit 2
(Day 8)
BS S 
Visit 3
(Day 31)
BS H
Visit 6
(Day 91)
BS H
Dose 2
Visit 5
(Day 68)
BS S 
Favorable outcome of Safety Evaluations** 
End of FU Part A
Analysis 1£
BS H
Dose 1
Visit 1
(Day 1)
Safety Evaluation **
Safety Evaluation **
Randomization
(1:1:1:1:1:1:1:1:1:1)
9 RSV vaccine study groups (N100 per group)
Placebo group (N100)
Visit 8
(Month 14)
BS H
Study conclusion
Final analysis
Analysis 1£
Analysis 2 £
Vaccination phase
Persistence phase
Epoch 002
Epoch 003
Visit 1
(Day 1)
Visit 4
(Day 61)
BS S
BS H
Dose 2
Visit 2
(Day 8)
BS S 
Visit 3
(Day 31)
BS H
BS C
Visit 5
(Day 68)
BS S 
Visit 6
(Day 91)
BS H
BS C
Visit 7
(Month 8)
BS H
BS C
BS S 
Screening Visit
(Pre-Day 1)*
Surveillance for RTI during RSV season with nasal/throat swab collection 
to assess potential RSV infection by PCR †
Screening
Epoch 001
: Vaccination
BS H
Dose 1
BS C 
Safety Evaluation ***
Safety Evaluation ***
BS C
BS S 
Screening Visit
(Pre-Day 1)*
Vaccination phase
Epoch 002
Screening
Epoch 001
BS C
BS C
BS C
BS C
BS C
BS S 
BS S 
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† In case of RTI symptoms during the RSV seasons (approximately from October to March), the subject will be asked 
to collect a nasal swab at home and contact the investigator/study staff to schedule an assessment visit for collection 
of an additional nasal swab and a throat swab at the site. The assessment visit should take place as soon as possible 
after the start of symptoms (ideally within 48 hours, but no later than 7 days; see Section 8). 
£ Analysis 1 will be performed on all data collected up to Day 91 for at least primary and secondary endpoints based 
on both study parts (except for cell-mediated immune response at pre-Dose 2 [Day 61] in Part A and Part B and the 
occurrence of RSV RTI in Part B). Analysis 2 will be performed when all safety data up to Month 8 (Visit 7) are 
available. The analyses will be based on data as clean as possible (refer to Section 10.12.1 for details on sequence of 
analyses). 
Protocol waivers or exemptions are not allowed unless necessary for the management of 
immediate safety concerns. Therefore, adherence to the study design requirements, 
including those specified in the outline of study procedures (Section 5.5), are essential 
and required for study conduct. Refer to Section 5.10 for study procedures to be 
considered during special circumstances (Amended, 13 May 2020). 
• 
Experimental design: Phase I/II, observer-blind, randomized, controlled, multi-
country study with 2 parts (i.e., Part A in young adults aged 18-40 years with 
4 parallel groups and Part B in older adults aged 60-80 years with 10 parallel 
groups).  
• 
Duration of the study:  
Approximately 3 months per subject in Part A: 
− Epoch 001: Screening Visit (Day -30 to -3)  
− Epoch 002: Primary (vaccination phase) starting at Visit 1 (Day 1) and ending at 
Visit 6 (Day 91) 
Approximately 14 months per subject in Part B: 
− Epoch 001: Screening Visit (Day -30 to -3) 
− Epoch 002: Primary (vaccination phase) starting at Visit 1 (Day 1) and ending at 
Visit 6 (Day 91)  
− Epoch 003: Follow-up (persistence phase) starting after Visit 6 (Day 91) and 
ending at Visit 8 (Month 14) 
• 
Primary Completion Date (PCD): last visit of the vaccination phase in Part B 
(Visit 6 [Day 91]).  
Refer to glossary of terms for the definition of PCD. 
• 
End of Study (EoS): Last testing results released of samples collected up to Visit 8 
in Part B (Month 14) (for assays related to primary and secondary endpoints only). 
Refer to glossary of terms for the definition of EoS. 
• 
Treatment allocation: Subjects will be randomized using a centralised 
randomization system on internet (SBIR) on Day 1.  
In Part A, the aim is to enrol approximately 48 subjects (12 per group) aged 18-40 
years. The randomization algorithm will use a minimisation procedure accounting 
for center and gender. 
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In Part B, the aim is to enrol approximately 700 subjects (70 per group) aged 60-69 
years and approximately 300 subjects (30 per group) aged 70-80 years. The 
randomization algorithm will use a minimisation procedure accounting for age, 
center and gender in each step. 
• 
Study groups: 
For the investigational RSV vaccines in Part A and Step 1 in Part B, the RSVPreF3 
high-dose formulation containing 120 g RSVPreF3 will be used to prepare the 
vaccines for all dose groups (i.e., 30 g, 60 g and 120 g dose groups, see Table 2 
and Table 3). For Step 2 in Part B, the RSVPreF3 low-dose and mid-dose 
formulations (containing 30 g and 60 g RSVPreF3, respectively) will be used for 
the groups receiving 30 g and 60 g of RSVPreF3, respectively, and the RSVPreF3 
high-dose formulation will be used for the 120 g dose groups (see Table 4). As the 
reconstitution methods for the vaccines administered to subjects enrolled in Step 1 
and 2 of Part B will be different, separate study groups have been identified (referred 
to as B1 and B2). Throughout this document, the combined groups for Steps 1 and 2 
are mentioned when referring to the number of groups in Part B (10 groups).  
In Part A: 
− 
Group 30-PLAIN_A: subjects receiving 2 doses of unadjuvanted 
investigational RSV vaccine containing 30 g RSVPreF3. 
− 
Group 60-PLAIN_A: subjects receiving 2 doses of unadjuvanted 
investigational RSV vaccine containing 60 g RSVPreF3. 
− 
Group 120-PLAIN_A: subjects receiving 2 doses of unadjuvanted 
investigational RSV vaccine containing 120 g RSVPreF3. 
− 
Group Placebo_A: subjects receiving 2 doses of placebo as control. 
In Part B (Steps 1 and 2): 
− 
Groups 30-PLAIN_B1 and 30-PLAIN_B2: subjects receiving 2 doses of 
unadjuvanted investigational RSV vaccine containing 30 g RSVPreF3. 
− 
Groups 30-AS01E_B1 and 30-AS01E_B2: subjects receiving 2 doses of the 
investigational RSV vaccine containing 30 g RSVPreF3 adjuvanted with 
AS01E. 
− 
Groups 30-AS01B_B1 and 30-AS01B_B2: subjects receiving 2 doses of the 
investigational RSV vaccine containing 30 g RSVPreF3 adjuvanted with 
AS01B. 
− 
Groups 60-PLAIN_B1 and 60-PLAIN_B2: subjects receiving 2 doses of 
unadjuvanted investigational RSV vaccine containing 60 g RSVPreF3. 
− 
Groups 60-AS01E_B1 and 60-AS01E_B2: subjects receiving 2 doses of the 
investigational RSV vaccine containing 60 g RSVPreF3 adjuvanted with 
AS01E. 
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− 
Groups 60-AS01B_B1 and 60-AS01B_B2: subjects receiving 2 doses of the 
investigational RSV vaccine containing 60 g RSVPreF3 adjuvanted with 
AS01B. 
− 
Groups 120-PLAIN_B1 and 120-PLAIN_B2: subjects receiving 2 doses of 
unadjuvanted investigational RSV vaccine containing 120 g RSVPreF3. 
− 
Groups 120-AS01E_B1 and 120-AS01E_B2: subjects receiving 2 doses of the 
investigational RSV vaccine containing 120 g RSVPreF3 adjuvanted with 
AS01E (Amended, 13 May 2020). 
− 
Groups 120-AS01B_B1 and 120-AS01B_B2: subjects receiving 2 doses of the 
investigational RSV vaccine containing 120 g RSVPreF3 adjuvanted with 
AS01B. 
− 
Groups Placebo_B1 and Placebo_B2: subjects receiving 2 doses of placebo as 
control. 
Table 1 
Study groups and epochs foreseen in the study 
Study groups 
Number of subjects 
Age (Min/Max) 
Epochs 
Epoch 001 
Epoch 002 
Epoch 003 
Part A 
30-PLAIN_A 
12 
18 - 40 years 
x 
x 
 
60-PLAIN_A 
12 
18 - 40 years 
x 
x 
 
120-PLAIN_A 
12 
18 - 40 years 
x 
x 
 
Placebo_A 
12 
18 - 40 years 
x 
x 
 
Part B - Step 1 
30-PLAIN_B1  
10  
60 - 80 years  
x  
x  
x  
30-AS01E_B1  
10  
60 - 80 years  
x  
x  
x  
30-AS01B_B1  
10  
60 -80 years  
x  
x  
x  
60-PLAIN_B1  
10  
60 - 80 years  
x  
x  
x  
60-AS01E_B1  
10  
60 - 80 years  
x  
x  
x  
60-AS01B_B1  
10  
60 - 80 years  
x  
x  
x  
120-PLAIN_B1  
10  
60 - 80 years  
x  
x  
x  
120-AS01E_B1  
10  
60 - 80 years  
x  
x  
x  
120-AS01B_B1  
10  
60 - 80 years  
x  
x  
x  
Placebo_B1  
10  
60 - 80 years  
x  
x  
x  
Part B - Step 2 
30-PLAIN_B2  
90  
60 - 80 years  
x  
x  
x 
30-AS01E_B2  
90  
60 - 80 years 
x  
x  
x  
30-AS01B_B2  
90  
60 - 80 years 
x  
x  
x  
60-PLAIN_B2  
90  
60 - 80 years 
x  
x  
x  
60-AS01E_B2  
90  
60 - 80 years 
x  
x  
x  
60-AS01B_B2  
90  
60 - 80 years 
x  
x  
x  
120-PLAIN_B2  
90  
60 - 80 years 
x  
x  
x  
120-AS01E_B2  
90  
60 - 80 years 
x  
x  
x  
120-AS01B_B2  
90  
60 - 80 years 
x  
x  
x  
Placebo_B2  
90  
60 - 80 years 
x  
x  
x  
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Table 2 
Study groups and treatment foreseen in Part A 
Treatment name 
Vaccine/Product 
name  
Study Groups 
30-PLAIN_A  
60-PLAIN_A  120-PLAIN_A  
Placebo_A  
30 µg RSVPreF3 plain 
RSVPreF3 high dose  
x  
 
 
 
NaCl  
x  
60 µg RSVPreF3 plain  
RSVPreF3 high dose  
 
x  
 
 
NaCl  
x  
120 µg RSVPreF3 
plain  
RSVPreF3 high dose  
 
 
x  
 
NaCl  
x  
Placebo 
NaCl  
 
 
 
x  
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Table 3 
Study groups and treatment foreseen in Part B - Step 1  
Treatment name 
Vaccine/ 
Product name 
Study Groups 
30-
PLAIN_B1  
30-
AS01E_B1  
30-
AS01B_B1  
60-
PLAIN_B1  
60-
AS01E_B1  
60-
AS01B_B1  
120-
PLAIN_B1  
120-
AS01E_B1 
120-
AS01B_B1  Placebo_B1  
30 µg RSVPreF3 
plain 
RSVPreF3 high 
dose  
x  
 
 
 
 
 
 
 
 
 
NaCl 
x  
30 µg 
RSVPreF3/AS01E 
RSVPreF3 high 
dose  
 
x  
 
 
 
 
 
 
 
 
AS01E  
x  
30 µg 
RSVPreF3/AS01B  
RSVPreF3 high 
dose  
 
 
x  
 
 
 
 
 
 
 
AS01B  
x  
60 µg RSVPreF3 
plain  
RSVPreF3 high 
dose  
 
 
 
x  
 
 
 
 
 
 
NaCl  
x  
60 µg 
RSVPreF3/AS01E  
RSVPreF3 high 
dose  
 
 
 
 
x  
 
 
 
 
 
AS01E  
x  
60 µg 
RSVPreF3/AS01B  
RSVPreF3 high 
dose  
 
 
 
 
 
x  
 
 
 
 
AS01B  
x  
120 µg 
RSVPreF3 plain  
RSVPreF3 high 
dose  
 
 
 
 
 
 
x  
 
 
 
NaCl  
x  
120 µg 
RSVPreF3/AS01E  
RSVPreF3 high 
dose  
 
 
 
 
 
 
 
x  
 
 
AS01E  
x  
120 µg 
RSVPreF3/AS01B  
RSVPreF3 high 
dose  
 
 
 
 
 
 
 
 
x  
 
AS01B  
x  
Placebo 
NaCl  
 
 
 
 
 
 
 
 
 
x  
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Table 4 
Study groups and treatment foreseen in Part B - Step 2  
Treatment name 
Vaccine/ 
Product name 
Study Groups 
30-
PLAIN_B2 
30-
AS01E_B2 
30-
AS01B_B2 
60-
PLAIN_B2 
60-
AS01E_B2 
60-
AS01B_B2 
120-
PLAIN_B2 
120-
AS01E_B2  
120-
AS01B_B2 
Placebo_B2 
30 µg RSVPreF3 
plain 
RSVPreF3 low 
dose  
x  
 
 
 
 
 
 
 
 
 
NaCl 
x  
30 µg 
RSVPreF3/AS01E 
RSVPreF3 low 
dose  
 
x  
 
 
 
 
 
 
 
 
AS01E  
x  
30 µg 
RSVPreF3/AS01B  
RSVPreF3 low 
dose  
 
 
x  
 
 
 
 
 
 
 
AS01B  
x  
60 µg RSVPreF3 
plain  
RSVPreF3 mid 
dose  
 
 
 
x  
 
 
 
 
 
 
NaCl  
x  
60 µg 
RSVPreF3/AS01E  
RSVPreF3 mid 
dose  
 
 
 
 
x  
 
 
 
 
 
AS01E  
x  
60 µg 
RSVPreF3/AS01B  
RSVPreF3 mid 
dose  
 
 
 
 
 
x  
 
 
 
 
AS01B  
x  
120 µg 
RSVPreF3 plain  
RSVPreF3 high 
dose  
 
 
 
 
 
 
x  
 
 
 
NaCl  
x  
120 µg 
RSVPreF3/AS01E  
RSVPreF3 high 
dose  
 
 
 
 
 
 
 
x  
 
 
AS01E  
x  
120 µg 
RSVPreF3/AS01B  
RSVPreF3 high 
dose  
 
 
 
 
 
 
 
 
x  
 
AS01B  
x  
Placebo 
NaCl  
 
 
 
 
 
 
 
 
 
x  
 
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• 
Control: placebo. 
• 
Vaccination schedule: Two vaccine doses administered intramuscularly at Day 1 
and Day 61. 
• 
Blinding: observer-blind. 
The vaccination phases of each study part (Epoch 002) will be observer-blind. A first 
statistical analysis will be performed on data available up to one month post-Dose 2 
(Visit 6, Day 91) (see section 10.12.1 for details on the sequence of analyses). Given 
that summary safety results may unblind some specific subjects, the persistence 
phase of Part B (Epoch 003) will be considered as single-blind with subjects 
remaining blinded up to study end (Visit 8 [Month 14]). The investigators will not be 
provided with the individual data listings or with the randomization listings until the 
end of study analysis. 
During the last study visit, blood samples will be collected only from a subset of 
subjects (N460, all subjects in part B1 and subjects who received a selected level 
of antigen dose and Placebo in part B2). Therefore, the investigators, site and 
study staff will be partially unblinded at group level, but not at the individual level.  
In case there will be an extension study planned, with all or a subset of 
participants included, the investigators may be provided with the list of study 
subjects eligible to participate in such study, before the parent study ends. 
Therefore, the investigators, site and study staff will potentially receive an 
individual data listings for a subset. All subjects in this subset may be unblinded 
before the study ends. (Amended, 13 May 2020) 
Table 5 
Blinding of study epochs 
Study Epochs 
Blinding 
Epoch 001  
N/A  
Epoch 002 
observer-blind  
Epoch 003  
single-blind  
N/A: Not applicable 
• 
RTI surveillance in Part B: Active and passive surveillance will only be carried out 
during RSV seasons (approximately from October to March) throughout the entire 
Part B of the study: 
− 
Active surveillance: study participants will be contacted by the 
investigator/study staff every 2 weeks to identify if they experience an RTI. 
− 
Passive surveillance: study participants are instructed to contact the 
investigator/study staff as soon as they experience an RTI. 
At the beginning of RSV seasons, study participants will be reminded of the start of 
the RTI surveillance. 
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• 
Sampling schedule: 
In Part A: 
− 
At Screening (Pre-Day 1), a blood sample for eligibility assessment will be 
drawn from all subjects. In case Visit 1 occurs more than 30 days after the 
Screening visit, a re-screening visit should be scheduled before Visit 1 during 
which blood sample collection must be repeated (maximum one re-screening per 
subject is allowed). Medical history, physical examination and review of 
inclusion/exclusion criteria must be repeated if a re-screening visit occurs. Only 
data from the re-screening visit, if it occurs, will be taken into consideration and 
recorded in the electronic Case Report Form (eCRF). The subject can however 
only be randomized once the investigator receives the safety assessment results 
and confirms the eligibility criteria. 
− 
At Day 1 (Visit 1), a blood sample for cytomegalovirus (CMV) status 
determination will be drawn from all subjects. 
− 
Blood samples for safety assessment (hematology/biochemistry) will be drawn 
from all subjects on Days 1, 8, 61 and 68 (Visits 1, 2, 4 and 5).  
− 
Blood samples for humoral immunogenicity and cell-mediated immunity 
(CMI) testing will be drawn from all subjects at Days 1, 31, 61 and 91 (Visits 1, 
3, 4 and 6).  
In Part B: 
− 
At Screening (Pre-Day 1), a blood sample for eligibility assessment will be 
drawn from all subjects. In case Visit 1 occurs more than 30 days after the 
Screening visit, a re-screening visit should be scheduled before Visit 1 during 
which blood sample collection must be repeated (maximum one re-screening per 
subject is allowed). Medical history, physical examination and review of 
inclusion/exclusion criteria must be repeated if a re-screening visit occurs. Only 
data from the re-screening visit, if it occurs, will be taken into consideration and 
recorded in the eCRF. The subject can however only be randomized once the 
investigator receives the safety assessment results and confirms the eligibility 
criteria. 
− 
At Day 1 (Visit 1), a blood sample for CMV status determination will be drawn 
from all subjects. 
− 
Blood samples for safety assessment (hematology/biochemistry) will be drawn 
from all subjects and on Days 1, 8, 61 and 68 (Visits 1, 2, 4 and 5).  
− 
Blood samples for humoral immunogenicity and CMI testing will be drawn 
from all subjects at Days 1, 31, 61, 91, Month 8 and from a subset at Month 14 
(Visits 1, 3, 4, 6, 7 and 8). (Amended, 13 May 2020) 
− 
Nasal/throat swabs: In case of RTI symptoms during the RSV season 
(approximately from October to March), the study participants will be asked to 
collect a nasal swab at home and contact the investigator/study staff to schedule 
an assessment visit for collection of an additional nasal swab and a throat swab 
by qualified staff from the study team. The assessment visit should take place as 
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soon as possible after the start of symptoms (ideally within 48 hours, but no later 
than 7 days; refer to Section 8 for further details). 
• 
Type of study: self-contained. 
• 
Data collection: eCRF. Solicited symptoms will be collected using an electronic 
subject Diary (eDiary). Unsolicited symptoms will be collected using a paper subject 
Diary. 
• 
Safety monitoring: The study will be conducted in 2 parts with oversight by an 
IDMC. The investigator is not permitted to start vaccinating the subjects in the next 
step in each part until the Sponsor communicates the favorable outcome of the 
respective safety evaluations by the IDMC. 
− 
Part A: Approximately 48 young adults aged 18-40 years will be enrolled and 
vaccinated with the first dose. If the IDMC evaluation on data up to 30 days post 
Dose 1 is favorable, the Part A study participants will be vaccinated with the 
second dose and the vaccination in Part B of the study will be initiated. 
− 
Part B: This part will be conducted in a 2-step staggered design to ensure 
maximum safety of the participating subjects. In Step 1, approximately 
100 subjects will be enrolled and vaccinated. Safety evaluations based on 
unblinded data from those first 100 subjects will be performed by the IDMC to 
allow the start of Step 2. In Step 2, the remaining study participants (N900) 
will be enrolled and vaccinated. 
In total, 6 IDMC meetings for safety evaluation are foreseen in the vaccination phase 
of the study (Epoch 002), i.e., 2 meetings in Part A and 4 meetings in Part B. 
During the persistence phase of Part B (Epoch 003), 2 IDMC meetings will be 
planned with an interval of approximately 6 months.  
If any safety concern is identified by the investigator or the sponsor, ad-hoc safety 
evaluations by the IDMC may be performed. 
Interval for vaccination between study participants:  
Study participants enrolled in Part A and Step 1 of Part B should be vaccinated with 
an interval of at least 60 minutes between participants to allow efficient suspension 
of vaccination in case of any safety concern. This applies to first and second study 
vaccine doses. This safety measure is not applicable for study participants enrolled in 
Step 2 of Part B. 
Refer to Section 7.10 for details on the safety monitoring and holding rules. 
4. 
STUDY COHORT 
4.1. 
Number of subjects/centers 
This will be a multicenter study planned to be conducted in multiple countries. A total of 
approximately 1048 participants are planned to be enrolled in this study, of whom 48 
(approximately 12 in each group) in Part A and 1000 (approximately 100 in each group) 
in Part B. Refer to Section 10.4 for a detailed description of the criteria used in the 
estimation of sample size. 
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In the Part A, there will be 4 study groups, consisting of 3 groups receiving an 
investigational RSV vaccine formulation and one placebo group. The target is to enrol 
approximately 48 eligible participants (12/group). Minimisation per gender and center 
will provide a good balance between the groups within each factor. 
In the Part B, there will be 10 study groups, consisting of 9 groups receiving an 
investigational RSV vaccine formulation and one placebo group. The target is to enrol 
approximately 100 eligible participants in Step 1 (10/group) and approximately 
900 eligible participants in Step 2 (90/group). Approximately 700 participants (70 per 
group) aged 60-69 years and approximately 300 participants (30 per group) aged 
70-80 years will be enrolled. Minimisation per age, gender and center will provide a good 
balance between the groups within each factor in each step.  
Overview of the recruitment plan 
The study is planned to be conducted at sites in multiple countries.  
In case a country would fall behind in subject recruitment (in a specific age group or 
overall), a redistribution of the enrolment target per country may be made to allow the 
other participating country(ies) to enrol additional participants in an effort to ensure full 
and timely enrolment of the overall targeted number of participants specified in this 
protocol. For more detailed information on the staggered enrolment, refer to Section 7.10. 
The recruitment rate will be monitored and transfer of supplies will be tracked using 
SBIR. Monitoring visits frequency will be adapted to the pace of enrolment.  
Vaccine doses will be distributed to each study site respecting the randomization block 
size.  
Prior to Visit 1 (Day 1) in both study parts, a Screening Visit will be scheduled to screen 
potential study participants for eligibility. The purpose of the screening is to collect 
informed consent, check eligibility for study participation and collect a blood sample for 
eligibility evaluation. 
4.2. 
Inclusion criteria for enrolment 
Deviations from inclusion criteria are not allowed because they can potentially jeopardize 
the scientific integrity, regulatory acceptability of the study or subject safety. Therefore, 
adherence to the criteria as specified in the protocol is essential. 
All subjects must satisfy ALL the following criteria at study entry: 
• 
Subjects who, in the opinion of the investigator, can and will comply with the 
requirements of the protocol (e.g. completion of the eDiaries, return for follow-up 
visits).  
• 
Written informed consent obtained from the subject prior to performing any study 
specific procedure.  
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Specific inclusion criteria for Part A: 
• 
A male or female between, and including, 18 and 40 years of age at the time of the 
first vaccination. 
Specific inclusion criteria for Part B: 
• 
A male or female between, and including, 60 and 80 years of age at the time of the 
first vaccination.  
• 
Subjects with residence status allowing free mixing with general community or in an 
assisted-living facility that provides minimal assistance, such that the subject is 
primarily responsible for self-care and activities of daily living, may be enrolled.  
4.3. 
Exclusion criteria for enrolment 
Deviations from exclusion criteria are not allowed because they can potentially 
jeopardize the scientific integrity regulatory acceptability of the study, or subject safety. 
Therefore, adherence to the criteria as specified in the protocol is essential. 
The following criteria should be checked for all subjects at the time of study entry. 
If ANY exclusion criterion applies, the subject must not be included in the study: 
• 
Use of any investigational or non-registered product (drug or vaccine) other than the 
study vaccine during the period starting 30 days before the first dose of study 
vaccine (Day -29 to Day 1), or planned use during the study period.  
• 
Any medical condition that in the judgment of the investigator would make IM 
injection unsafe.  
• 
Chronic administration (defined as more than 14 consecutive days in total) of 
immunosuppressants or other immune-modifying drugs during the period starting 
6 months prior to the first vaccine dose. For corticosteroids, this will mean 
prednisone ( 20 mg/day, or equivalent). Inhaled and topical steroids are allowed.  
• 
Administration of long-acting immune-modifying drugs or planned administration at 
any time during the study period (e.g. infliximab).  
• 
Planned administration/administration of a vaccine not foreseen by the study 
protocol in the period starting 30 days before the first dose and ending 30 days after 
the last dose of study vaccine administration, with the exception of inactivated and 
subunit influenza vaccines which can be administered up to 14 days before or from 
30 days after each study vaccination.  
• 
Concurrently participating in another clinical study, at any time during the study 
period, in which the subject has been or will be exposed to an investigational or a 
non-investigational vaccine/product (pharmaceutical product or device).  
• 
Any confirmed or suspected immunosuppressive or immunodeficient condition, 
based on medical history and physical examination (no laboratory testing required).  
• 
History of any reaction or hypersensitivity likely to be exacerbated by any 
component of the vaccine.  
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• 
Hypersensitivity to latex.  
• 
Serious or unstable chronic illness. Patients with chronic stable conditions with or 
without specific treatment, such as diabetes, hypertension or cardiac disease, are 
allowed to participate in this study.  
• 
Any other condition (e.g. chronic obstructive pulmonary disease or severe 
respiratory condition) that, in the opinion of the investigator, might interfere with the 
evaluations required by the study.  
• 
History of any neurological disorders or seizures.  
• 
Acute disease and/or fever at the time of enrolment.  
− 
Fever is defined as temperature  38.0°C / 100.4°F. The preferred location for 
measuring temperature in this study will be the oral cavity. 
− 
Subjects with a minor illness (such as mild diarrhoea, mild upper respiratory 
infection) without fever may be enrolled at the discretion of the investigator.  
For subjects with acute disease and/or fever at the time of enrolment/vaccination, 
Visit 1 may be re-scheduled within the allowed time-window. 
• 
Acute or chronic, clinically significant pulmonary, cardiovascular, hepatic or renal 
functional abnormality, as determined by the investigator based on medical history, 
physical examination or laboratory screening tests.  
• 
Hepatomegaly, right upper quadrant abdominal pain or tenderness.  
• 
Administration of immunoglobulins and/or any blood products during the period 
starting 3 months before the first dose of study vaccine or planned administration 
during the study period.  
• 
History of chronic alcohol consumption and/or drug abuse as deemed by the 
investigator to render the potential subject unable/unlikely to provide accurate safety 
reports.  
• 
Significant underlying illness that in the opinion of the investigator would be 
expected to prevent completion of the study (e.g., life-threatening disease likely to 
limit survival to less than 2 years).  
• 
Previous vaccination with an RSV vaccine.  
• 
Lymphoproliferative disorder and malignancy within 5 years.  
• 
Body mass index > 40 kg/m².  
• 
Planned move to a location that will prohibit participating in the trial until study end. 
• 
At screening: Hematology parameters (complete blood cell count [red blood cells, 
white blood cells], white blood cells differential count [lymphocytes, neutrophils and 
eosinophils], platelets count or hemoglobin level) and/or biochemistry parameters 
(creatinine, blood urea nitrogen or liver enzymes [alanine aminotransferase [ALT] or 
aspartate aminotransferase [AST]]) outside the normal laboratory ranges, unless the 
laboratory abnormalities are considered not clinically significant by the investigator. 
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Specific exclusion criteria for Part A: 
• 
Pregnant or lactating female. 
• 
Female subjects of childbearing potential, except if the subject: 
− 
has practiced adequate contraception for 30 days prior to vaccination, and 
− 
has a negative pregnancy test on the day of vaccination, and 
− 
has agreed to continue adequate contraception during the entire treatment period 
and for 2 months after completion of the vaccination series. 
Refer to glossary of terms for the definition of adequate contraception. 
Specific exclusion criteria for Part B: 
• 
Known previous administration of a vaccine containing MPL, QS-21 and/or MF59 
(e.g. GSK Biologicals’ vaccine against human papillomavirus infection marketed as 
Cervarix, GSK Biologicals’ Herpes Zoster vaccine marketed as Shingrix, an 
adjuvanted recombinant varicella zoster virus envelope gE subunit vaccine [HZ/su], 
or MF59 adjuvanted influenza vaccines [e.g. Fluad]). 
• 
Planned administration of GSK Biologicals’ Herpes Zoster vaccine marketed as 
Shingrix or an adjuvanted recombinant varicella zoster virus envelope gE subunit 
vaccine [HZ/su] within 180 days after the second dose of the study vaccine. 
• 
Bedridden subjects.  
5. 
CONDUCT OF THE STUDY 
5.1. 
Regulatory and ethical considerations, including the 
informed consent process 
The study will be conducted in accordance with all applicable regulatory requirements. 
The study will be conducted in accordance with the ICH Guideline for GCP, all 
applicable subject privacy requirements and the guiding principles of the Declaration of 
Helsinki.  
GSK will obtain favourable opinion/approval to conduct the study from the appropriate 
regulatory agency, in accordance with applicable regulatory requirements, prior to a site 
initiating the study in that country. 
Conduct of the study includes, but is not limited to, the following: 
• 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) review and 
favourable opinion/approval of study protocol and any subsequent amendments. 
• 
Subject informed consent.  
• 
Investigator reporting requirements as stated in the protocol. 
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GSK will provide full details of the above procedures to the investigator, either verbally, 
in writing, or both. 
Freely given and written or witnessed/ thumb printed informed consent must be obtained 
from each subject prior to participation in the study.  
GSK Biologicals will prepare a model Informed Consent Form (ICF) which will embody 
the ICH GCP and GSK Biologicals required elements. While it is strongly recommended 
that this model ICF is to be followed as closely as possible, the informed consent 
requirements given in this document are not intended to pre-empt any local regulations 
which require additional information to be disclosed for informed consent to be legally 
effective. Clinical judgement, local regulations and requirements should guide the final 
structure and content of the local version of the ICF.  
The investigator has the final responsibility for the final presentation of the ICF, 
respecting the mandatory requirements of local regulations. The ICF generated by the 
investigator with the assistance of the sponsor’s representative must be acceptable to 
GSK Biologicals and be approved (along with the protocol, and any other necessary 
documentation) by the IRB/IEC. 
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 and safety must be applied. For the duration of such special 
circumstances, additional measures may be implemented for enrolled participants. 
Refer to Section 5.10 for further details. (Amended, 13 May 2020). 
5.2. 
Subject identification and randomization 
5.2.1. 
Subject identification 
Subject identification numbers will be assigned sequentially to the subjects who have 
consented to participate in the study, according to the range of subject identification 
numbers allocated to each study center. 
5.2.2. 
Randomization of treatment 
5.2.2.1. 
Randomization of supplies 
The randomization of supplies within blocks will be performed at GSK Biologicals, using 
MATerial EXcellence (MATEX), a program developed for use in Statistical Analysis 
System (SAS®) (Cary, NC, USA) by GSK Biologicals. Entire blocks will be shipped to 
the study centers /warehouse(s). 
To allow GSK Biologicals to take advantage of greater rates of recruitment than 
anticipated at individual centers in this multicenter study and to thus reduce the overall 
study recruitment period, an over-randomization of supplies will be prepared. 
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5.2.2.2. 
Treatment allocation to the subject 
The treatment numbers will be allocated by dose. 
5.2.2.2.1. Study group and treatment number allocation 
The target will be to enrol approximately 1048 eligible subjects who will be randomly 
assigned to the study groups in each study part as follows: 
• 
In Part A, the target is to enrol approximately 48 eligible participants who will be 
randomly assigned to 4 study groups in a (1:1:1:1) ratio (approximately 12 subjects 
in each group).  
• 
In Part B, the target is to enrol: 
− 
Approximately 100 eligible participants in Step 1 who will be randomly 
assigned to 10 study groups in a (1:1:1:1:1:1:1:1:1:1) ratio (approximately 
10 subjects in each group); 
− 
Approximately 900 eligible participants in Step 2 who will be randomly 
assigned to 10 study groups in a (1:1:1:1:1:1:1:1:1:1) ratio (approximately 
90 subjects in each group).  
The aim is to enrol approximately 700 participants (70 per group) aged 60-69 years 
and approximately 300 participants (30 per group) aged 70-80 years. 
Allocation of the subject to a study group at the investigator site will be performed using 
a randomization system on internet (SBIR). The study part (Part A, Part B Step 1, Part B 
Step 2) will be used as stratification factor. For Part A, the randomization algorithm will 
use a minimisation procedure accounting for center and gender. For Part B, the 
randomization algorithm will use a minimisation procedure accounting for age, center 
and gender within each step (Step 1 and Step 2). Minimisation factors will have equal 
weight in the minimisation algorithm. 
After obtaining the signed and dated ICF from the subject and having checked the 
eligibility of the subject, the site staff in charge of the vaccine administration will access 
SBIR. Upon providing the subject identification number, the randomization system will 
determine the study group and will provide the treatment number to be used for the first 
dose. 
The number of each administered treatment must be recorded in the eCRF on the Vaccine 
Administration screen. 
When SBIR is not available, please refer to the SBIR user guide or the Study Procedures 
Manual (SPM) for specific instructions. 
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5.2.2.2.2. Treatment number allocation for subsequent doses  
For each dose subsequent to the first dose, the study staff in charge of the vaccine 
administration will access SBIR, provide the subject identification number, and the 
system will provide a treatment number consistent with the allocated study group. 
The number of each administered treatment must be recorded in the eCRF on the Vaccine 
Administration screen. 
5.3. 
Method of blinding 
During the vaccination phases of each study part (Epoch 002), data will be collected in an 
observer-blind manner. During the last study visit, blood samples will be collected only 
from a subset of subjects (N460, all subjects in part B1 and subjects who received a 
selected level of antigen dose and Placebo in part B2). Therefore, the investigators, site 
and study staff will be partially unblinded at group level, but not at the individual level.  
In case there will be an extension study planned, with all or a subset of participants 
included, the investigators may be provided with the list of study subjects eligible to 
participate in such study, before the parent study ends. Therefore, the investigators, site 
and study staff will potentially receive an individual data listings for a subset. All 
subjects in this subset may be unblinded before the study ends. (Amended, 13 May 
2020) 
 By observer-blind, it is meant that during the course of the study, the vaccine recipient 
and those responsible for the evaluation of any study endpoint (e.g. safety and 
reactogenicity) will all be unaware of which vaccine was administered. To do so, vaccine 
preparation and administration will be done by authorised medical personnel who will not 
participate in any of the study clinical evaluation assays. 
A first statistical analysis will be performed on primary and secondary endpoint data 
available up to one month post-Dose 2 (Visit 6, Day 91) (see Section 10.12.1 for details 
on the sequence of analyses). Given that summary safety results may unblind some 
specific subjects (e.g. an adverse event [AE] occurring only in a single group), anyone 
having access to this first analysis could become unblinded regarding that specific case. 
Therefore, the persistence phase of Part B (Epoch 003) will be considered as single-blind 
with subjects remaining blinded up to study end (Visit 8 [Month 14]). The investigators 
will not be provided with the individual data listings or with the randomization listings 
until the end of study analysis.  
The laboratory in charge of the laboratory testing will be blinded to the treatment, and 
codes will be used to link the subject and study (without any link to the treatment 
attributed to the subject) to each sample. 
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5.4. 
General study aspects 
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the accompanying SPM. The SPM provides the investigator and the site 
personnel with administrative and detailed technical information that does not impact the 
safety of the subjects. 
The study will be conducted in 2 parts, i.e., Part A in young adults aged 18-40 years and 
Part B in older adults aged 60-80 years. Part B of the study will be conducted in a 2-step 
staggered design to ensure maximum safety of the participating subjects. 
Study participants enrolled in Part A and Step 1 of Part B should be vaccinated with an 
interval of at least 60 minutes between participants to allow efficient suspension of 
vaccination in case of any safety concern. This applies to first and second study vaccine 
doses. This safety measure is not applicable for study participants enrolled in Step 2 of 
Part B. 
All participants in each part and enrolment step will be closely observed for a minimum 
of 60 minutes after each vaccination.  
Refer to Section 7.10 for information about the study holding rules, safety monitoring 
and safety evaluation by the IDMC. 
 
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5.5. 
Outline of study procedures 
Table 6 
List of study procedures for Part A 
Epoch 
Screening 
(Epoch 001) 
Vaccination phase 
(Epoch 002) 
Type of contact 
screening 
visit 1  
visit 1  
visit 2  
visit 3  
visit 4  
visit 5  
visit 6  
Time points 
Day 1  
Day 8  
Day 31  
Day 61  
Day 68  
Day 91  
Sampling time points 
Pre-Day 1  
Pre-Vacc  
PI D8  
PI D31  
PI D61  
PII D68  
PII D91  
Informed consent  
●  
 
 
 
 
 
 
Check inclusion/exclusion criteria  
●  
O  
 
 
 
 
 
Collect demographic data  
O  
●  
 
 
 
 
 
Medical history  
O  
●  
 
 
 
 
 
Vaccination history 2  
O  
●  
 
 
 
 
 
Physical examination /Vital signs  
O  
●  
O 3 
O 3 
O 3 
O 3 
O 3 
Check contraindications to vaccination  
 
O  
 
 
O  
 
 
Pre-vaccination body temperature  
 
●  
 
 
●  
 
 
Pregnancy test  4 
●  
●  
 
 
●  
 
●  
Vaccine 
Study group and treatment number allocation  
 
O  
 
 
 
 
 
Treatment number allocation for subsequent doses  
 
 
 
 
O  
 
 
Vaccine administration  
 
●  
 
 
●  
 
 
Recording of administered treatment number  
 
●  
 
 
●  
 
 
Laboratory assays  
Blood sampling for antibody determination (~20 mL)  
 
●  
 
●  
●  
 
●  
Blood sampling for CMI response (~25 mL) 
 
●  
 
●  
●  
 
●  
Blood sampling for hematology and biochemistry analysis (~5.5 mL)  
● 1  
●  
●  
 
●  
●  
 
Blood sampling for CMV status determination (~3.5 mL)  
 
●  
 
 
 
 
 
Safety assessments 
Record any concomitant medications/vaccinations (as defined in Section 6.6) 
 
●  
●  
●  
●  
●  
●  
Record any intercurrent medical conditions 
 
●  
●  
●  
●  
●  
●  
Distribute and instruct subject on the use of eDiary devices for solicited AEs 
 
O  
 
 
O  
 
 
Return of eDiary devices  
 
 
 
 
 
 
O  
Distribution of paper diary cards for unsolicited AEs  
 
O 
 
 
O 
 
 
Return of paper diary cards 
 
 
O  
O  
 
O  
O  
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Epoch 
Screening 
(Epoch 001) 
Vaccination phase 
(Epoch 002) 
Type of contact 
screening 
visit 1  
visit 1  
visit 2  
visit 3  
visit 4  
visit 5  
visit 6  
Time points 
Day 1  
Day 8  
Day 31  
Day 61  
Day 68  
Day 91  
Sampling time points 
Pre-Day 1  
Pre-Vacc  
PI D8  
PI D31  
PI D61  
PII D68  
PII D91  
Recording of unsolicited AEs within 30 days post-vaccination (Days 1-30) 
 
●  
●  
●   
●  
●   
●  
Recording of SAEs  
 
●  
●  
●  
●  
●  
●  
Recording of SAEs related to study participation, or to a concurrent GSK 
medication/vaccine  
●  
●  
●  
●  
●  
●  
●  
Recording of pregnancy and pregnancy outcomes  
O  
●  
●  
●  
●  
●  
●  
Recording of AEs/SAEs leading to withdrawal from the study  
 
●  
●  
●  
●  
●  
●  
Screening conclusion  
●   
 
 
 
 
 
 
End of follow-up for Part A  
 
 
 
 
 
 
●  
Pre-Vacc: pre-vaccination; PI: Post-Dose 1; PII: Post-Dose 2; PI DX: Post-Dose 1 Study Day X; PII DX: Post-Dose 2 Study Day X; D: Day 
● is used to indicate a study procedure that requires documentation in the individual eCRF or on web-portal. 
○ is used to indicate a study procedure that does not require documentation in the individual eCRF or on web-portal. 
1 In case Visit 1 occurs more than 30 days after the Screening visit, a re-screening visit should be scheduled before Visit 1 during which blood sample collection for safety laboratory 
assessment must be repeated (maximum one re-screening per subject is allowed). Medical history, physical examination and review of inclusion/exclusion criteria must be repeated if a 
re-screening visit occurs. Only data from the re-screening visit, if it occurs, will be taken into consideration and recorded in the eCRF. The subject can only be randomized once the 
investigator receives the results and confirms the eligibility criteria. 
2  Any vaccination administered up to 5 years before administration of the first dose of study vaccine should be recorded in the eCRF. 
3 If deemed necessary by the investigator  
4 Only for women of childbearing potential. The results must be obtained and be confirmed negative before vaccination. A serum pregnancy test instead of a urine pregnancy test 
should only be considered if required by local or ethics committee regulations.  
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Table 7 
List of study procedures for Part B 
Epoch 
Screening 
(Epoch 001) 
Vaccination phase 
(Epoch 002) 
Persistence phase 
(Epoch 003) 
RTI surveillance 
Type of contact 
screening 
visit 1 
visit 1  
visit 2  
visit 3  
visit 4  
visit 5  
visit 6  
visit 7  
visit 8  
Regular 
contact for 
RTI 
surveillance  
Assessment 
visit for 
potential 
RSV-RTI   
Time points 
Day 1  
Day 8  
Day 31  
Day 61  
Day 68  
Day 91  
Month 8  Month 14  
Sampling time points 
Pre-Day 1 Pre-Vacc 
PI D8 
PI D31 
PI D61 
PII D68 
PII D91 
PII M8 
PII M14 
Informed consent 
● 
 
 
 
 
 
 
 
 
 
 
Check inclusion/exclusion criteria 
● 
O  
 
 
 
 
 
 
 
 
 
Collect demographic data 
O 
●  
 
 
 
 
 
 
 
 
 
Medical history 
O  
● 
 
 
 
 
 
 
 
 
 
Vaccination history 2 
O 
●  
 
 
 
 
 
 
 
 
 
Physical examination /Vital signs 
O  
●  
O 3 
O 3 
O 3 
O 3 
O 3 
O 3 
O 3 
 
● 
Check contraindications to vaccination 
 
O 
 
 
O 
 
 
 
 
 
 
Pre-vaccination body temperature 
 
● 
 
 
● 
 
 
 
 
 
 
Vaccine 
Study group and treatment number allocation 
 
O  
 
 
 
 
 
 
 
 
 
Treatment number allocation for subsequent 
doses 
 
 
 
 
O 
 
 
 
 
 
 
Vaccine administration 
 
● 
 
 
● 
 
 
 
 
 
 
Recording of administered treatment number 
 
● 
 
 
● 
 
 
 
 
 
 
Laboratory assays 
Blood sampling for antibody determination 
(~20 mL) 
 
● 
 
● 
● 
 
● 
● 
●4 
 
 
Blood sampling for CMI response (~25 mL) 
 
● 
 
● 
● 
 
● 
● 
●4 
 
 
Blood sampling for hematology and 
biochemistry analysis (~5.5 mL) 
● 1 
●  
● 
 
● 
● 
 
 
 
 
 
Blood sampling for CMV status determination 
(~3.5 mL)  
 
●  
 
 
 
 
 
 
 
 
 
RTI surveillance 
Instruct/remind subjects of RTI surveillance 
during RSV seasons  
 
 
 
 
 
 
 
 
 
●  
 
Distribution of material for nasal swab 
collection at home (including instructions) 
 
O  
 
 
 
 
 
 
 
 
 
Recording of nasal swab collection at home  
 
 
 
 
 
 
 
 
 
 
●  
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Epoch 
Screening 
(Epoch 001) 
Vaccination phase 
(Epoch 002) 
Persistence phase 
(Epoch 003) 
RTI surveillance 
Type of contact 
screening 
visit 1 
visit 1  
visit 2  
visit 3  
visit 4  
visit 5  
visit 6  
visit 7  
visit 8  
Regular 
contact for 
RTI 
surveillance  
Assessment 
visit for 
potential 
RSV-RTI   
Time points 
Day 1  
Day 8  
Day 31  
Day 61  
Day 68  
Day 91  
Month 8  Month 14  
Sampling time points 
Pre-Day 1 Pre-Vacc 
PI D8 
PI D31 
PI D61 
PII D68 
PII D91 
PII M8 
PII M14 
Nasal/throat swab sampling 
 
 
 
 
 
 
 
 
 
 
● 
Documentation of symptoms and signs of RTI  
 
 
 
 
 
 
 
 
 
 
● 
Safety assessments 
Record any concomitant 
medications/vaccinations (as defined in 
Section 6.6) 
 
● 
● 
● 
● 
● 
● 
● 
● 
 
● 
Record any intercurrent medical conditions  
 
● 
● 
● 
● 
● 
● 
● 
● 
 
●  
Distribute and instruct subject on the use of 
eDiary devices for solicited AEs 
 
O  
 
 
O  
 
 
 
 
 
 
Return of eDiary devices  
 
 
 
 
 
 
O  
 
 
 
 
Distribution of paper diary cards for 
unsolicited AEs  
 
O 
 
 
O 
 
 
 
 
 
 
Return of paper diary cards 
 
 
O  
O  
 
O  
O  
 
 
 
 
Recording of unsolicited AEs within 30 days 
post-vaccination (Days 1-30)  
 
● 
● 
●   
● 
●   
● 
 
 
 
 
Recording of SAEs and pIMDs  
 
● 
● 
● 
● 
● 
● 
● 
● 
 
● 
Recording of SAEs related to study 
participation, or to a concurrent GSK 
medication/vaccine 
● 
● 
● 
● 
● 
● 
● 
● 
● 
 
● 
Recording of AEs/SAEs leading to withdrawal 
from the study  
 
● 
● 
● 
● 
● 
● 
● 
● 
 
●  
Screening conclusion 
● 
 
 
 
 
 
 
 
 
 
 
Study conclusion 
 
 
 
 
 
 
 
 
● 
 
 
Note: The double-line borders following Day 91 and Month 8 indicate the analyses which will be performed on all data (i.e., data that are as clean as possible) obtained up to these time 
points. 
Pre-Vacc: pre-vaccination; PI: Post-Dose 1; PII: Post-Dose 2; PI DX: Post-Dose 1 Study Day X; PII DX: Post-Dose 2 Study Day X; PII MX: Post-Dose 2 Study Month X; D: Day; M: 
Month 
● is used to indicate a study procedure that requires documentation in the individual eCRF or on web-portal. 
○ is used to indicate a study procedure that does not require documentation in the individual eCRF or on web-portal. 
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1 In case Visit 1 occurs more than 30 days after the Screening visit, a re-screening visit should be scheduled before Visit 1 during which blood sample collection for safety laboratory 
assessment must be repeated (maximum one re-screening per subject is allowed). Medical history, physical examination and review of inclusion/exclusion criteria must be repeated if a 
re-screening visit occurs. Only data from the re-screening visit, if it occurs, will be taken into consideration and recorded in the eCRF. The subject can only be randomized once the 
investigator receives the results and confirms the eligibility criteria.  
2  Any vaccination administered up to 5 years before administration of the first dose of study vaccine should be recorded in the eCRF.  
3 If deemed necessary by the investigator  
4 At Visit 8, blood samples for antibody and CMI determination will be collected from all subjects in part B1; and from a subset of subjects in part B2, who received a 
selected level of antigen dose and Placebo. 
Refer to Section 5.10 for changes to study procedures to be considered during special circumstances (Amended, 13 May 2020). 
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Time intervals between visits related to study procedures performed on subjects 
participating in the study are presented in Table 8. 
Table 8 
Intervals between study visits  
Interval 
Optimal length of interval 
Allowed interval 
Part A 
screening visit → visit 1 
3 - 30 days* 
visit 1 → visit 2 
7 days  
7 - 10 days  
visit 1 → visit 3  
30 days  
30 - 37 days  
visit 1 → visit 4  
60 days  
55 - 80 days  
visit 4 → visit 5  
7 days  
7 - 10 days  
visit 4 → visit 6  
30 days  
30 - 37 days  
Part B 
screening visit → visit 1 
3 - 30 days* 
visit 1 → visit 2 
7 days  
7 - 10 days  
visit 1 → visit 3  
30 days 
30 - 37 days 
visit 1 → visit 4  
60 days 
55 - 75 days 
visit 4 → visit 5  
7 days 
7 - 10 days 
visit 4 → visit 6  
30 days 
30 - 37 days 
visit 4 → visit 7  
180 days  
170 - 190 days  
visit 4 → visit 8  
365 days  
350 - 395 days  
Grey shading indicates visit intervals that will be used to determine a subject’s evaluability for the Per Protocol analysis 
(see Section 10.5.2). 
* Visit 1 should take place no longer than 30 days after the Screening Visit. In case Visit 1 occurs more than 30 days 
after the Screening visit, a re-screening visit should be scheduled before Visit 1 during which blood sample collection 
for safety laboratory assessment must be repeated (maximum one re-screening per subject is allowed). Only 
laboratory results from the re-screening visit, if it occurs, will be taken into consideration and recorded in the eCRF. 
Medical history, physical examination and review of inclusion/exclusion criteria must be repeated if a re-screening visit 
occurs. The subject can only be randomized once the investigator receives the results and confirms the eligibility 
criteria. 
5.6. 
Detailed description of study procedures applicable for both 
study parts 
5.6.1. 
Informed consent 
The signed/witnessed/thumb printed informed consent of the subject must be obtained 
before study participation. In addition, the signed informed consent of the designate must 
be obtained, in case a designate is assigned by the subject. Refer to Section 5.1 for the 
requirements on how to obtain informed consent. 
5.6.2. 
Screening procedures to check subject eligibility 
5.6.2.1. 
Check inclusion and exclusion criteria 
At the Screening Visit, the investigator will confirm strict adherence to all 
inclusion/exclusion criteria to ensure subjects are qualified for enrolment into the study, 
as described in Sections 4.2 and 4.3.  
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5.6.2.2. 
Collect demographic data, medical history, vaccination history and 
perform physical examination 
The investigator will obtain the following information at the Screening Visit to confirm 
subject eligibility before enrolment: demographic data (such as age, gender, race and 
ethnicity), medical history and vaccination history. The investigator will also perform a 
physical examination of the subject, including assessment of oral body temperature and 
resting vital signs: systolic/diastolic blood pressure, pulse oximetry, heart rate and 
respiratory rate after at least 10 minutes of rest. 
Treatment of any abnormality observed during physical examination has to be performed 
according to local medical practice outside this study or by referral to an appropriate 
health care provider. 
These procedures at the Screening Visit do not need to be recorded into the eCRF. 
5.6.2.3. 
Blood sampling for eligibility assessment 
At the Screening Visit, a blood sample for eligibility assessment will be drawn from all 
subjects.  
In case Visit 1 occurs more than 30 days after the Screening visit, a re-screening visit 
should be scheduled before Visit 1 during which blood sample collection must be 
repeated (maximum one re-screening per subject is allowed). Medical history, physical 
examination and review of inclusion/exclusion criteria must be repeated if a re-screening 
visit occurs. Only data from the re-screening visit, if it occurs, will be taken into 
consideration and recorded in the eCRF. The subject can however only be randomized 
once the investigator receives the safety assessment results and confirms the eligibility 
criteria. 
5.6.2.4. 
Screening conclusion 
Complete the Screening Conclusion screen in the eCRF, including the reason for 
screening failure, if applicable. 
5.6.3. 
Procedures during the vaccination phases (Parts A and B) and/or 
persistence phase (Part B) 
5.6.3.1. 
Check inclusion and exclusion criteria 
Before randomization, the investigator should confirm strict adherence to all 
inclusion/exclusion criteria to ensure subjects are still qualified as described in Sections 
4.2 and 4.3. This does not need to be recorded in the subject’s eCRF. 
5.6.3.2. 
Collect demographic data 
Record demographic data such as age, gender, race and ethnicity in the subject’s eCRF. 
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5.6.3.3. 
Medical history 
Obtain the subject’s medical history by interview and/or review the subject’s medical 
records. Any pre-existing conditions or signs and/or symptoms present in a subject prior 
to the first study vaccination should be recorded in the eCRF. 
5.6.3.4. 
Vaccination history 
Obtain the subject’s vaccination history by interview and/or review the subject’s 
vaccination records prior to the first study vaccination. Any vaccination administered up 
to 5 years before administration of the first dose of study vaccine should be recorded in 
the eCRF. 
5.6.3.5. 
Physical examination 
Perform a physical examination of the subject, including assessment of resting vital 
signs: systolic/diastolic blood pressure, pulse oximetry, heart rate and respiratory rate 
after at least 10 minutes of rest.  
Physical examination at each study visit subsequent to the first vaccination visit will be 
performed only if the subject indicates during questioning that there might be some 
underlying pathology(ies) or if deemed necessary by the investigator. 
If the investigator determines that the subject’s health on the day of vaccination 
temporarily precludes vaccination, the visit will be rescheduled. 
Treatment of any abnormality observed during physical examination has to be performed 
according to local medical practice outside this study or by referral to an appropriate 
health care provider. 
In addition, during the assessment visit for potential RSV-RTI, the investigator/study 
staff will evaluate the clinical signs and symptoms of the RTI and measure the subject’s 
resting vital signs (systolic/diastolic blood pressure, pulse oximetry, heart rate, 
respiratory rate after at least 10 minutes of rest) and temperature (refer to Section 8.3 for 
the list of symptoms to be recorded). 
5.6.3.6. 
Check contraindications to vaccination 
Contraindications to vaccination must be checked at the beginning of each vaccination 
visit. Refer to Sections 6.5 for more details.  
5.6.3.7. 
Assess pre-vaccination body temperature 
The body temperature of each subjects needs to be measured prior to any study vaccine 
administration. The preferred location for measuring temperature in this study will be the 
oral cavity. If the subject has fever (fever is defined as temperature  38.0°C/100.4°F 
regardless the location of measurement) on the day of vaccination, the vaccination visit 
will be rescheduled within the allowed interval for this visit (see Table 8). 
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5.6.3.8. 
Study group and treatment number allocation 
Study group and treatment number allocation will be performed as described in Section 
5.2.2. The number of each administered treatment must be recorded in the eCRF. 
5.6.3.9. 
Study vaccine administration 
• 
After completing all prerequisite procedures prior to vaccination, one dose of study 
vaccine will be administered IM in the deltoid of the non-dominant arm (refer to 
Section 6.3 for detailed description of the vaccine administration procedure). If the 
investigator or delegate determines that the subject’s health on the day of 
administration temporarily precludes vaccine administration, the visit will be 
rescheduled within the allowed interval for this visit (refer to Table 8). 
• 
Study participants enrolled in Part A and Step 1 of Part B should be vaccinated with 
an interval of at least 60 minutes between participants to allow efficient suspension 
of vaccination in case of any safety concern. This applies to first and second study 
vaccine doses. This safety measure is not applicable for study participants enrolled in 
Step 2 of Part B. 
All subjects in each part and enrolment step will be observed closely for at least 60 
minutes following the administration of the vaccine, with appropriate medical treatment 
readily available in case of anaphylaxis. 
5.6.3.10. 
Sampling 
Refer to the Module on Biospecimen Management in the SPM for detailed instructions 
for the collection, handling and processing of the samples. 
5.6.3.11. 
Blood sampling for safety or immune response assessments  
Blood samples will be taken during certain study visits as specified in Section 5.5 List of 
Study Procedures. Refer to the SPM for more details. 
• 
A total volume of approximately 5.5 mL of blood should be drawn from all subjects 
for hematology and biochemistry analysis at each pre-defined time point. At Visit 1, 
an additional volume of approximately 3.5 mL should be drawn from all subjects for 
cytomegalovirus (CMV) status testing. After centrifugation, serum samples should 
be kept at room temperature (20 to 25°C/68 to 77°F) until shipment.  
• 
A volume of approximately 20 mL of whole blood (to provide 6.6 mL of serum) 
should be drawn from subjects for analysis of the humoral immune response at each 
pre-defined time point. After centrifugation, serum samples should be kept at -20°C/ 
–4°F or below until shipment.  
• 
A volume of approximately 25 mL of whole blood should be drawn from subjects 
for analysis of the CMI response at each pre-defined time point. The blood should be 
stored at the investigator’s site at room temperature. Samples will be shipped at room 
temperature (15 to 25°C/(59 to 77°F) to the designated laboratory for cell separation 
to be started within 24 hours.  
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• 
The overall volume of blood that will be collected from each subject during the 
entire duration of each study part is approximately 210 mL for Part A and 
approximately 300 mL for Part B (at Visit 8 blood will be collected from a subset of 
subjects)( Amended, 13 May 2020) 
5.6.3.12. 
Check and record concomitant medication/vaccination and intercurrent 
medical conditions  
Concomitant medication/vaccination must be checked and recorded in the eCRF as 
described in Section 6.6. 
Intercurrent medical conditions must be checked and recorded in the eCRF as described 
in Section 6.7. 
5.6.3.13. 
Distribution of eDiary devices  
• 
Subject eDiary assignment and use: 
− 
eDiaries will be distributed at Visit 1 for the collection of the body temperature 
and local and general solicited symptoms after each vaccination. They will be 
returned at the end of the unsolicited follow-up period after Dose 2 (at Visit 6 
[Day 91]). Refer to Section 7.1.3 for guidelines. 
− 
Each subject will be shown how to use the device – this will include how to 
access the eDiary, performing test data entry on sample questions, and how to 
charge and store the device. 
− 
The subject will self-select a numeric access code secret to himself/herself. The 
same individual should make the assessments and complete the Subject eDiary 
throughout the course of the study. 
− 
The subject will select an alarm time that suits his/her daily routines whilst 
ensuring compliance with protocol requirements.  
• 
Subject eDiary instructions provided by the site must ensure that the subject 
understands the following: 
− 
Timely completion of the Subject eDiary on a daily basis is a critical component 
to study participation. 
− 
The Subject eDiary will allow certain time windows for completion of each 
day’s observations. 
− 
The Subject eDiary employs the use of audio-visual alarms to ensure timely 
completion of data entry. 
− 
The trained and assigned user of the Subject eDiary must not share access codes 
with anyone. 
− 
A helpdesk will be provisioned for users of Subject eDiary in case of technical 
issues, though it must be stressed that the helpdesk is not a replacement for 
normal medical care and no medical issues can be discussed with the agents. 
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− 
The Subject eDiary itself must never be considered a substitute for direct 
medical care and any concerns must be communicated to site staff as soon as 
possible. 
5.6.3.14. 
Distribution of paper diary cards 
Paper diary cards will be distributed at each vaccination visit for the subjects to note 
down any unsolicited symptom (i.e., any symptom not reported as solicited and already 
captured in the eDiary) they may have experienced as well as any medication taken in the 
30-day period following each vaccination. Refer to Section 7.1.3 for guidelines. 
5.6.3.15. 
Recording of AEs and SAEs 
Solicited AEs will be recorded by the subjects in the eDiaries. 
Non-serious unsolicited AEs will be recorded by the investigator in the Non-Serious 
Adverse Event section of the eCRF. 
Any serious adverse event (SAE, solicited or unsolicited) will be recorded by the 
investigator in the Expedited Adverse Event report in the eCRF. 
Refer to Section 7.3 for the detailed procedures for the investigator to record AEs and 
SAEs. Refer to Section 7.4 for guidelines and how to report SAE reports to GSK 
Biologicals. 
5.6.3.16. 
Study conclusion 
The investigator will: 
• 
review data collected to ensure accuracy and completeness. 
• 
complete the Study Conclusion screen in the eCRF. 
5.7. 
Detailed description of study procedures applicable for 
Part A only 
5.7.1. 
Pregnancy test  
Female subjects of childbearing potential are to have a pregnancy test at the Screening 
Visit, prior to any study vaccine administration (at Visits 1 and 4) and at the end of the 
study (Visit 6). The study vaccine may only be administered if the pregnancy test is 
negative.  
Note: Pregnancy test must be performed even if the subject is menstruating at the time of 
the study visit. 
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5.7.2. 
Recording of pregnancies  
Refer to Section 7.3 for procedures for the investigator to record pregnancies. Refer to 
Section 7.4 for guidelines and how to report pregnancy reports to GSK Biologicals. 
5.8. 
Detailed description of study procedures applicable for 
Part B only 
5.8.1. 
Surveillance for RSV-RTI and nasal/throat swab sampling 
Active and passive surveillance for RTI will be carried out during the RSV season period 
approximately from October to March throughout the entire duration of Part B of the 
study, i.e., from Visit 1 (after Dose 1) until the end of the study (Visit 8 [Month 14]).  
• 
Active Surveillance: Study participants will be contacted by the investigator/study 
staff every 2 weeks to identify if they have experienced RTI symptoms (e.g., cough, 
runny nose, fever or difficulty to breath).  
• 
Passive surveillance (spontaneous referral): 
− 
Subjects will be instructed to contact spontaneously the investigator/site staff 
and as soon as possible in case of RTI symptoms (e.g., cough, runny nose, fever 
or difficulty to breath) during the RSV season. 
− 
At each study visit during the RSV season period, subjects should be reminded 
to contact the investigator/study staff in case of RTI symptoms (e.g., cough, 
runny nose, fever or difficulty to breath). 
In case of at least 3 RTI symptoms reported by the subject (refer to Section 8.3 for the list 
of symptoms):  
• 
The subject will be asked to collect a nasal swab at home within 48 hours after the 
start of symptoms and contact the investigator/study staff. 
• 
The self-collected nasal swab should be returned to the site staff. Refer to the SPM 
for details.  
• 
The investigator/study staff will schedule an assessment visit for nasal and throat 
swab specimen collection by qualified staff from the study team. The assessment 
visit should take place as soon as possible after the start of symptoms (ideally within 
48 hours, but no later than 7 days).  
• 
The swab samples will allow to assess the potential RSV infection by quantitative 
PCR at a sponsor or sponsor-designated laboratory. Episodes should be treated 
accordingly to local standard of care. 
• 
In the event that it is not possible to schedule an assessment visit, the assessment 
visit page of the eCRF should be filled in as completely as possible using available 
medical records. Refer to Section 8 for further details on RTI surveillance during 
Part B. 
Refer to the SPM for more details about nasal/throat swab sampling. 
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5.8.2. 
Recording of potential immune-mediated diseases (pIMDs) 
PIMDs will be recorded by the investigator in the Expedited Adverse Event report in the 
eCRF. 
Refer to Section 7.3 for the detailed procedures for the investigator to record pIMDs. 
Refer to Section 7.4.5 for guidelines and how to report pIMD reports to GSK Biologicals. 
5.9. 
Biological sample handling and analysis 
Please refer to the SPM for details on biospecimen management (handling, storage and 
shipment). Refer to Section 5.10 for measures for biological samples collection that 
may be implemented during special circumstances (Amended, 13 May 2020). 
Samples will not be labelled with information that directly identifies the subject but will 
be coded with the identification number for the subject (subject number). 
• 
Collected samples will be used for protocol mandated research and purposes related 
to the improvement, development and quality assurance of the laboratory tests 
described in this protocol. This may include the management of the quality of these 
tests, the maintenance or improvement of these tests, the development of new test 
methods, as well as making sure that new tests are comparable to previous methods 
and work reliably. 
• 
It is also possible that future findings may make it desirable to use the samples 
acquired in this study for future research, not described in this protocol. Therefore, 
all subjects in countries where this is allowed will be asked to give a specific consent 
to allow GSK or a contracted partner to use the samples for future research. Future 
research will be subject to the laws and regulations in the respective countries and 
will only be performed once an independent Ethics Committee or Review Board has 
approved this research. 
Information on further investigations and their rationale can be obtained from GSK 
Biologicals.  
Any sample testing will be done in line with the consent of the individual subject. 
Refer also to the Investigator Agreement, where it is noted that the investigator cannot 
perform any other biological assays except those described in the protocol or its 
amendment(s).  
If additional testing is performed, the marker priority ranking given in Section 5.9.4 may 
be changed. 
Collected samples will be stored for a maximum of 20 years (counting from when the last 
subject performed the last study visit), unless local rules, regulations or guidelines require 
different timeframes or different procedures, which will then be in line with the subject 
consent. These extra requirements need to be communicated formally to and discussed 
and agreed with GSK Biologicals. 
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5.9.1. 
Use of specified study materials 
When materials are provided by GSK Biologicals, it is MANDATORY that all clinical 
samples (including serum samples) be collected and stored exclusively using those 
materials in the appropriate manner. The use of other materials could result in the 
exclusion of the subject from the per-protocol analysis (See Section 10.5 for the 
definition of cohorts to be analysed). The investigator must ensure that his/her personnel 
and the laboratory(ies) under his/her supervision comply with this requirement. However, 
when GSK Biologicals does not provide material for collecting and storing clinical 
samples, appropriate materials from the investigator’s site must be used. Refer to the 
Module on Clinical Trial Supplies in the SPM. 
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5.9.2. 
Biological samples 
Table 9 
Biological samples 
Sample type 
Timepoint 
Subset* 
Quantity 
Unit 
Part A 
Blood for humoral immune response 
visit 1 (Pre-Vacc) 
visit 3 (PI D31) 
visit 4 (PI D61) 
visit 6 (PII D91) 
All enrolled subjects 
20 
mL 
Blood for CMI 
visit 1 (Pre-Vacc) 
visit 3 (PI D31) 
visit 4 (PI D61) 
visit 6 (PII D91) 
All enrolled subjects 
25 
mL 
Blood for hematology/biochemistry 
screening (Pre-Day 1) 
visit 1 (Pre-Vacc) 
visit 2 (PI D8) 
visit 4 (PI D61) 
visit 5 (PII D68) 
All screened subjects 
All enrolled subjects 
5.5 
mL 
Blood for serological status to CMV 
visit 1 (Pre-Vacc) 
All enrolled subjects 
3.5 
mL 
Urine** 
screening (Pre-Day 1) 
visit 1 (Pre-Vacc) 
visit 4 (PI D61) 
visit 6 (PII D91) 
All screened female subjects 
All enrolled female subjects 
- 
- 
Total quantity of blood for each subject in Part A 
 211 
mL 
Part B 
Blood for humoral immune response 
visit 1 (Pre-Vacc) 
visit 3 (PI D31) 
visit 4 (PI D61) 
visit 6 (PII D91) 
visit 7 (PII M8) 
visit 8 (PII M14) 
All enrolled subjects*** 
20 
mL 
Blood for CMI 
visit 1 (Pre-Vacc) 
visit 3 (PI D31) 
visit 4 (PI D61) 
visit 6 (PII D91) 
visit 7 (PII M8) 
visit 8 (PII M14) 
All enrolled subjects*** 
25 
mL 
Blood for hematology/biochemistry 
screening (Pre-Day 1) 
visit 1 (Pre-Vacc) 
visit 2 (PI D8) 
visit 4 (PI D61) 
visit 5 (PII D68) 
All screened subjects 
All enrolled subjects 
5.5 
mL 
Blood for serological status to CMV 
visit 1 (Pre-Vacc) 
All enrolled subjects 
3.5 
mL 
Nasal swab specimen collected by 
subject at home 
- 
Event-driven 
- 
- 
Nasal/throat swab specimen 
collected by qualified staff 
Assessment visit for 
potential RSV-RTI  
Event-driven 
- 
- 
Total quantity of blood for each subject in Part B 
 301 
mL 
* Refer to Section 5.9.4.1 for a description of the subsets that will be used for testing of RSVPreF3 RSB1 specific 
antibodies, CD4+/CD8+ CMI and memory B-cells at specific time points in Part B.  
** A serum pregnancy test instead of a urine pregnancy test should only be considered if required by local or ethics 
committee regulations. 
*** At Visit 8, blood samples for humoral and CMI determination will be collected from all subjects in part B1; 
and from a subset of subjects in part B2, who received a selected level of antigen dose and Placebo. 
See Section 5.10 for changes to study procedures to be considered during special circumstances. (Amended, 
13 May 2020) 
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5.9.3. 
Laboratory assays 
Please refer to APPENDIX A for a detailed description of the assays performed in the 
study. Please refer to APPENDIX B for the address of the clinical laboratories used for 
sample analysis. 
RSV humoral immune responses 
Serological assays for the determination of functional antibodies against RSV-A and B 
will be performed by neutralization assays. Further characterization of the humoral 
immune response will be performed by use of enzyme-linked immunosorbent assays 
(ELISAs), including measurement of IgG antibodies binding to the RSVPreF3 protein 
and antibodies competing with monoclonal antibodies specific for binding to RSB1 site 
on RSVPreF3 (see Table 10). (Amended, 13 May 2020) 
The assays will be performed at a GSK Biologicals’ laboratory or in a laboratory 
designated by GSK Biologicals.  
Table 10 
Humoral Immunity (Antibody determination) (Amended, 13 May 
2020) 
System 
Component 
Method 
Kit / 
Manufacturer 
Unit 
Cut-
off$ 
Laboratory 
Serum 
Respiratory 
Syncytial Virus A Ab  NEUTRALIZATION 
In-house 
ED60  
18  
GSK Biologicals* 
or NÉOMED-LABS 
Serum 
Respiratory 
Syncytial Virus B Ab 
NEUTRALIZATION 
In-house 
ED60  
30 
GSK Biologicals* 
or NÉOMED-LABS 
Serum 
RSVPreF3-specific 
IgG antibody 
concentrations 
ELISA 
In house at 
Neomed Labs 
ELU/mL 
25 
Neomed Labs 
Serum 
RSVPreF3 RSB1 
specific Ab 
Competition ELISA 
In-house 
g/mL 
2.11 
GSK Biologicals* 
or NÉOMED-LABS 
Ab: antibody; ELISA: enzyme-linked immunosorbent assay; RSV: respiratory syncytial virus;  
ED60: Estimated Dose: serum dilution giving a 60% reduction of the signal compared to a control without serum 
* GSK Biologicals laboratory refers to the Clinical Laboratory Sciences (CLS) in Rixensart, Belgium; Wavre, 
Belgium;Marburg, Germany. 
RSV cell-mediated immunity  
Evaluation of the CD4+ and CD8+ T-cell responses will be performed by use of an 
Intracellular Cytokine Staining (ICS) assay performed on peripheral blood mononuclear 
cells (PBMC) samples at GSK Biologicals’ laboratory or in a laboratory designated by 
GSK Biologicals (see Table 11). Evaluation of B memory cells will be performed by 
ELISpot. 
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Table 11 
Cell-mediated Immunity (CMI)  
System 
Component 
Challenge 
Method 
Unit 
Laboratory 
PBMC 
IL-2, CD40L, 4-1BB, TNF-, 
IFN-, IL-13, IL-17 secreting 
CD4+ and CD8+ T-cells 
Peptide pool 
covering 
RSVPreF3 
ICS 
Events/106 cells 
GSK Biologicals* or 
designated laboratory 
PBMC 
B-cell memory quantification 
RSVPreF3 
ELISPOT 
Frequency of 
RSVPreF3-specific 
memory 
B-cells/106 B-cells 
GSK Biologicals* or 
designated laboratory 
PBMC: peripheral blood mononuclear cells; ICS: Intracellular cytokine staining 
CD40L: cluster of differentiation 40 ligand; IFN-: interferon gamma, IL (IL-2; IL-13; IL-17): interleukin;  
TNF-: tumor necrosis factor alpha; 41BB (CD137) 
* GSK Biologicals laboratory refers to the CLS in Rixensart, Belgium; Wavre, Belgium; Marburg, Germany. 
Hematology and biochemistry 
Hematology and biochemistry assays for safety assessment will be performed in a central 
laboratory (see Table 12).  
Table 12 
Hematology/biochemistry 
System 
Discipline 
Component 
Method 
Scale** 
Laboratory 
Whole 
blood 
Hematology 
Leukocytes (White Blood Cells) 
As per central 
laboratory 
procedure 
Quantitative 
Q2 Solutions 
Neutrophils* 
Lymphocytes* 
Basophils* 
Monocytes* 
Eosinophils* 
Hemoglobin 
Platelets 
Erythrocytes (Red Blood Cells) 
Serum 
Biochemistry 
Alanine Aminotransferase (ALT) 
Aspartate Aminotransferase (AST) 
Creatinine 
Blood Urea Nitrogen (BUN) 
Uric Acid 
*For White Blood Cell (WBC) differential count. 
**Grading of laboratory parameters will be based on the Food and Drug Administration (FDA) Guidance for Industry 
“Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials” 
(refer to APPENDIX C). Basophils, monocytes, erythrocytes and uric acid are not included in the FDA Toxicity Grading 
Scale and will not be graded. 
RSV molecular biology 
For identified RTI cases under active or passive surveillance, the potential RSV infection 
will be assessed by quantitative reverse transcription PCR (qRT-PCR) testing of 
nasal/throat swab specimen (see Table 13). Swab samples that are positive by RSV qRT-
PCR will be tested by a multiplex PCR (panel of viruses) for detection of potential viral 
co-infection. Further assessment of samples negative by RSV qRT-PCR may be 
performed with multiplex PCR if deemed necessary. 
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Table 13 
Molecular Biology (PCR tests) 
Component 
Kit / Manufacturer 
Method 
Unit 
Laboratory 
System: Nasal/throat swab specimen 
Respiratory Syncytial Virus A RNA 
Respiratory Syncytial Virus B RNA 
In-house 
Quantitative 
RT-PCR 
Copies/ml  
GSK 
Biologicals* 
or designated 
laboratory 
Influenza A virus (Flu A) 
Influenza B virus (Flu B) 
Human respiratory syncytial virus A (RSV A) 
Human respiratory syncytial virus B (RSV B) 
Human Influenza A virus subtype H1 (Flu A-H1) 
Human Influenza A virus subtype H3 (Flu A-H3) 
Human Influenza A virus subtype H1pdm09  
(Flu A-H1pdm09) 
Human adenovirus (AdV) 
Human metapneumovirus (hMPV) 
Human enterovirus (HEV) 
Human parainfluenza virus 1 (PIV1) 
Human parainfluenza virus 2 (PIV2) 
Human parainfluenza virus 3 (PIV3) 
Human parainfluenza virus 4 (PIV4) 
Human bocavirus 1/2/3/4 (HBoV) 
Human rhinovirus A/B/C (HRV) 
Human coronavirus 229E (229E) 
Human coronavirus NL63 (NL63) 
Human coronavirus OC43 (OC43) 
Allplex Respiratory 
Panel or alternative 
Multiplex 
PCR 
Qualitative assay 
(positive/negative) 
GSK 
Biologicals* 
or designated 
laboratory 
Quantitative RT-PCR: quantitative reverse transcription polymerase chain reaction; RSV: respiratory syncytial virus 
* GSK Biologicals laboratory refers to the CLS in Rixensart, Belgium; Wavre, Belgium; Marburg, Germany. 
Additional testing on blood or nasal/throat swab samples 
Additional testing on serum and frozen PBMC samples to characterise the immune 
response to RSV/to the investigational RSV vaccine/vaccine components may be 
performed if deemed necessary for accurate interpretation of the data and/or should such 
test(s) become available in the GSK Biologicals’ laboratory or a laboratory designated by 
GSK Biologicals.  
Additional viral/bacterial diagnosis testing on the nasal/throat swabs, such as (but not 
limited to) multiplex PCR, sequencing and/or high-throughput sequencing, may be done, 
if deemed necessary for accurate interpretation of the data and/or should such assays 
become available at GSK Biologicals’ laboratory or a laboratory designated by GSK 
Biologicals. 
Additional testing may include, but is not limited to, the following: 
• 
Further characterisation of the pathogens detected in the nasal/throat swabs (e.g. 
genotyping, strain identification). 
• 
Further characterization of the immune response directed against different epitopes 
of RSV F proteins.  
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• 
Further characterization of the immune response by evaluation of cross-reactive 
neutralizing antibodies to human metapneumovirus (hMPV). 
• 
Characterisation of the impact of vaccination on possible new immunological 
markers for protection (e.g. antibody affinity/avidity, ADCC). 
• 
Host transcriptome signature: evaluation of mRNA and/or microRNA signatures by 
microarray and/or RNA sequencing. 
• 
Translational research using next generation technologies. 
Additional exploratory testing on the vaccine formulations and/or on the disease under 
study may be performed within the framework of the study if deemed necessary for 
accurate interpretation of the data or should such assay(s) become available at GSK 
Biologicals’ laboratory or a laboratory designated by GSK Biologicals. These assays may 
not be represented in the objectives/endpoints of the study protocol and may be described 
in ancillary study protocol(s), as needed. 
The GSK Biologicals’ clinical laboratories have established a Quality System supported 
by procedures. The activities of GSK Biologicals’ clinical laboratories are audited 
regularly for quality assessment by an internal (sponsor-dependent) but laboratory-
independent Quality Department. 
5.9.4. 
Biological samples evaluation 
For blood sample collection, the following ranking applies: 
1. Sample for hematology/biochemistry testing,  
2. Sample for serological status to CMV testing (at Visit 1), 
3. Sample for humoral immune responses, 
4. Sample for CMI responses. 
5.9.4.1. 
Immunological read-outs (Amended, 13 May 2020) 
Testing of RSVPreF3 IgG antibodies will be performed on blood samples from all 
subjects, in both Part A and Part B, except at Month 14 (Visit 8). 
Testing of RSV-A neutralizing antibodies will be performed on blood samples from all 
subjects, in both Part A and Part B, except at Month 8 (Visit 7) and Month 14 (Visit 8). 
Testing of RSV-B neutralizing antibodies will be performed on blood samples from all 
subjects in Part B. 
Testing of RSVPreF3 RSB1 specific antibodies will be performed on blood samples from 
a subset of subjects at Day 31 or Day 91 in Part B who received the selected vaccine 
formulation and placebo (N200). 
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Testing of CD4+/CD8+ CMI will be performed on blood samples from all subjects in 
both Part A and Part B, except at Month 8 (Visit 7) and Month 14 (Visit 8).  
At Month 8 (Visit 7) blood sample testing for humoral response pertaining to RSV-A 
neutralizing antibodies and CMI response will be performed for all subjects in Part B1; 
and for a subset of subjects in Part B2, who received a selected level of antigen dose 
and Placebo (N460). Blood sample testing pertaining to the RSVPreF3 IgG antibodies 
will be performed for all subjects at Month 8 (Visit 7). 
At Month 14 (Visit 8) humoral and CMI response testing will be performed for all 
subjects in Part B1; and for a subset of subjects in Part B2, who received a selected 
level of antigen dose and Placebo (N460).  
Testing of memory B-cells will be performed on blood samples from a subset of subjects 
in Part B who received the selected level of antigen dose or placebo (N400).  
Testing of CMV IgG antibodies will be performed on blood samples from all subjects at 
Visit 1 (Day 1), in both Part A and Part B. 
In case of insufficient blood sample volume to perform assays for all immunological 
read-out components, the samples will be analysed according to priority ranking provided 
in Table 14 for Part A and Table 15 for Part B.  
Table 14 
Immunological read-outs in Part A 
Blood sampling time point 
Sub-cohort 
No. 
subjects 
Component 
Components 
priority rank  
Type of contact 
and time point 
Sampling time 
point 
Humoral immunity (on serum samples) 
visit 1 (Day 1) 
Pre-Vacc  
All subjects 
 48 
RSV-A neutralizing antibody 
1 
Anti-RSVPreF3-specific IgG antibody 
2 
visit 3 (Day 31) 
PI D31  
All subjects 
 48 
RSV-A neutralizing antibody 
1 
Anti-RSVPreF3-specific IgG antibody 
2 
visit 4 (Day 61) 
PI D61  
All subjects 
 48 
RSV-A neutralizing antibody 
1 
Anti-RSVPreF3-specific IgG antibody 
2 
visit 6 (Day 91) 
PII D91  
All subjects 
 48 
RSV-A neutralizing antibody 
1 
Anti-RSVPreF3-specific IgG antibody 
2 
Cell-mediated immunity (on PBMC samples) 
visit 1 (Day 1) 
Pre-Vacc  
All subjects 
 48 
CD4+/CD8+ 
- 
visit 3 (Day 31) 
PI D31  
All subjects 
 48 
CD4+/CD8+ 
- 
visit 4 (Day 61) 
PI D61 
All subjects 
 48 
CD4+/CD8+ 
- 
visit 6 (Day 91) 
PII D91  
All subjects 
 48 
CD4+/CD8+ 
- 
Pre-Vacc: Pre-vaccination; PI DX: Post-Dose 1 Study Day X; PII DX: Post-Dose 2 Study Day X; M: Month 
PBMC: Peripheral Blood Mononuclear Cells 
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Table 15 
Immunological read-outs in Part B (Amended, 13 May 2020) 
Blood sampling time point* 
Sub-cohort 
No. 
subjects 
Component 
Components 
priority rank  
Type of contact 
and time point 
Sampling time 
point 
Humoral immunity (on serum samples) 
visit 1 (Day 1) 
Pre-Vacc  
All subjects 
 1000 
RSV-A neutralizing antibody 
1 
Anti-RSVPreF3-specific IgG antibody 
2 
RSV-B neutralizing antibody 
3 
Subset 
 200 
RSVPreF3 RSB1 specific antibody 
4 
visit 3 (Day 31) 
PI D31  
All subjects 
 1000 
RSV-A neutralizing antibody 
1 
Anti-RSVPreF3-specific IgG antibody 
2 
visit 4 (Day 61) 
PI D61  
All subjects 
 1000 
RSV-A neutralizing antibody 
1 
Anti-RSVPreF3-specific IgG antibody 
2 
visit 6 (Day 91) 
PII D91  
All subjects 
 1000 
RSV-A neutralizing antibody 
1 
Anti-RSVPreF3-specific IgG antibody 
2 
RSV-B neutralizing antibody 
3 
Subset 
 200 
RSVPreF3 RSB1 specific antibody 
4 
visit 7 (Month 8)** 
PII M8  
Subset 
 460 
RSV-A neutralizing antibody 
1 
All subjects 
~1000 
Anti-RSVPreF3-specific IgG antibody 
2 
visit 8 (Month 
14)*** 
PII M14  
Subset 
 460 
RSV-A neutralizing antibody 
1 
Anti-RSVPreF3-specific IgG antibody 
2 
Cell-mediated immunity (on PBMC samples) 
visit 1 (Day 1) 
Pre-Vacc  
All subjects 
 1000 
CD4+/CD8+ 
1 
Subset 
 400 
Memory B-cells 
2 
visit 3 (Day 31) 
PI D31  
All subjects 
 1000 
CD4+/CD8+ 
1 
Subset 
 400 
Memory B-cells 
2 
visit 4 (Day 61) 
PI D61 
All subjects 
 1000 
CD4+/CD8+ 
- 
visit 6 (Day 91) 
PII D91  
All subjects 
 1000 
CD4+/CD8+ 
1 
Subset 
 400 
Memory B-cells 
2 
visit 7 (Month 8)** 
PII M8  
Subset 
 460 
CD4+/CD8+ 
- 
visit 8 (Month 
14)*** 
PII M14 
Subset 
 460 
CD4+/CD8+  
1 
Subset 
 400 
Memory B-cells 
2 
Pre-Vacc: Pre-vaccination; PI DX: Post-Dose 1 Study Day X; PII DX: Post-Dose 2 Study Day X; M: Month 
PBMC: Peripheral Blood Mononuclear Cells 
* Testing of additional time points for RSVPreF3 RSB1 specific antibodies, RSV-B neutralizing antibodies and memory 
B-cells might be performed, should the results indicate that further investigation of the immune response is necessary. 
** At Visit 7, blood samples for RSV-A neutralizing antibody determination, and CMI determination will be 
tested from a subset of subjects (all subjects in part B1; and a subset of subjects in part B2, who received a 
selected level of antigen dose and Placebo). 
*** At Visit 8, blood samples for antibody and CMI determination will be collected and tested from all subjects 
in part B1; and from a subset of subjects in part B2, who received a selected level of antigen dose and 
Placebo.  
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5.9.4.2. 
Haematology/Blood Chemistry and CMV serology 
Table 16 
Hematology and biochemistry read-outs and CMV serology testing 
Blood sampling time point 
Sub-cohort 
No. 
subjects 
Component 
Type of contact 
and time point 
Sampling time 
point 
Part A 
screening visit* 
Pre-Day 1  
All screened 
subjects 
 48 
Hematology: leukocytes, neutrophils, lymphocytes, 
basophils, monocytes, eosinophils, hemoglobin, 
platelets, erythrocytes 
Biochemistry: ALT, AST, creatinine, BUN, uric acid 
visit 1 (Day 1) 
visit 2 (Day 8) 
visit 4 (Day 61) 
visit 5 (Day 68) 
Pre-Vacc 
PI D8  
PI D61  
PII D68  
All enrolled 
subjects 
 48 
visit 1 (Day 1) 
Pre-Vacc 
All enrolled 
subjects 
 48 
Anti-CMV IgG antibody 
Part B 
screening visit* 
Pre-Day 1  
All screened 
subjects 
 48 
Hematology: leukocytes, neutrophils, lymphocytes, 
basophils, monocytes, eosinophils, hemoglobin, 
platelets, erythrocytes 
Biochemistry: ALT, AST, creatinine, BUN, uric acid 
visit 1 (Day 1) 
visit 2 (Day 8) 
visit 4 (Day 61) 
visit 5 (Day 68) 
Pre-Vacc 
PI D8  
PI D61  
PII D68 
All enrolled 
subjects 
 1000 
visit 1 (Day 1) 
Pre-Vacc 
All enrolled 
subjects 
 1000 
Anti-CMV IgG antibody 
Pre-Vacc: Pre-vaccination; PI DX: Post-Dose 1 Study Day X; PII DX: Post-Dose 2 Study Day X 
ALT = Alanine Aminotransferase; AST = Aspartate Aminotransferase; BUN = Blood Urea Nitrogen 
CMV = Cytomegalovirus 
* In case Visit 1 occurs more than 30 days after the Screening Visit, a re-screening visit should be scheduled before 
Visit 1 during which blood sample collection for safety laboratory assessment must be repeated (maximum one re-
screening per subject is allowed). Only laboratory results from the re-screening visit, if it occurs, will be taken into 
consideration and recorded in the eCRF. Medical history, physical examination and review of inclusion/exclusion 
criteria must be repeated if a re-screening visit occurs. The subject can only be randomized once the investigator 
receives the results and confirms the eligibility criteria. 
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5.9.4.3. 
Molecular biology 
Table 17 
Molecular biology tests on nasal/throat swab specimen for Part B 
Sampling time point 
Sub-cohort 
No. subjects 
Component 
Type of contact 
(time point) 
Sampling 
time point 
Sampling of 
nasal swab by 
subject at home 
Assessment visit 
for potential RSV-
RTI 
Unscheduled 
Event-driven* 
Event-driven* RSV-A/B RNA 
All RSV-A/B 
positive swab 
samples** 
All RSV-A/B 
positive swab 
samples** 
Influenza A virus (Flu A) 
Influenza B virus (Flu B) 
Human respiratory syncytial virus A (RSV A) 
Human respiratory syncytial virus B (RSV B) 
Human Influenza A virus subtype H1 (Flu A-H1) 
Human Influenza A virus subtype H3 (Flu A-H3) 
Human Influenza A virus subtype H1pdm09 (Flu 
A-H1pdm09) 
Human adenovirus (AdV) 
Human metapneumovirus (hMPV) 
Human enterovirus (HEV) 
Human parainfluenza virus 1 (PIV1) 
Human parainfluenza virus 2 (PIV2) 
Human parainfluenza virus 3 (PIV3) 
Human parainfluenza virus 4 (PIV4) 
Human bocavirus 1/2/3/4 (HBoV) 
Human rhinovirus A/B/C (HRV) 
Human coronavirus 229E (229E) 
Human coronavirus NL63 (NL63) 
Human coronavirus OC43 (OC43) 
* RSV-A/B quantitative PCR (RSV-A/B RNA) will be performed on all specimen. 
** Respiratory Viruses Panel (Multiplex PCR) will be performed on all swabs RSV-A/B positive by qRT-PCR. Further 
assessment of RSV-A/B RNA negative samples may be performed with Multiplex PCR if deemed necessary. 
5.9.5. 
Immunological correlates of protection 
No generally accepted immunological correlate of protection has been demonstrated so 
far for the antigen used in the investigational RSV vaccine. 
5.10. 
Study procedures during special circumstances (Amended, 
13 May 2020) 
During special circumstances (e.g., COVID-19 pandemic), the specific guidance from 
local public health and other competent authorities regarding the protection of 
individuals’ welfare and safety must be applied. For the duration of such special 
circumstances, the following measures may be implemented for enrolled participants:  
• 
Instruction for the remaining scheduled visit (Visit 8): Planned study visit can 
proceed, if the study subjects are healthy and allowed to come to the site to have 
the blood sample and safety information collected. If the visit is impacted due to 
the national guidelines and/or site restrictions linked to the special circumstances, 
and it is not possible to collect the biological samples within the interval predefined 
in the protocol (see Table 8), the samples will be encoded as missing and encoded 
as protocol deviation. If the visit is impacted, the safety information (as per 
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protocol: SAEs, pIMDs, concomitant medications/vaccinations and intercurrent 
medical conditions) will be collected by site staff via telephone contact or other 
means of virtual contact, and this will not be considered as protocol deviation. 
• 
Instruction for collection of home self-swabs in case study participant experiences 
suspected respiratory tract infection (RTI) symptoms: In case the investigator 
determines this is not posing additional risk to the subjects or household members, 
the subjects will be instructed to perform the home self-swab and keep it in their 
freezer (preferred) or refrigerator until recovered, and able to bring it to the site. If 
there is a possibility, a healthy relative can bring the sample to the site to be 
processed. In case investigator judges this is not advisable due to the national 
guidelines and/or site restrictions linked to the special circumstances, the self-swab 
will not be collected and the sample will be encoded as missing. Samples that are 
not collected will be documented as protocol deviations. The investigator and/or 
the site staff will provide these instructions to the subjects during the active 
surveillance contacts carried out every 2 weeks during the RSV season period. 
• 
Instructions for assessment visit for suspected respiratory tract infection (RTI): 
Site staff will decide on the management of the cases (either having a site/different 
site location/home visit or by telephone contact) based on COVID-19 national 
guidelines and/or site restrictions linked to the special circumstances. If the nasal 
and throat samples cannot be collected at site, the sample will be encoded as 
missing. Samples that are not collected will be documented as protocol deviations. 
Biological samples will not be collected if they cannot be processed in a timely 
manner or appropriately stored until the intended use. 
Impact on the per protocol set for immunogenicity will be determined on a case by case 
basis. 
6. 
STUDY VACCINE AND ADMINISTRATION 
6.1. 
Description of study vaccine 
All candidate vaccines to be used have been developed and manufactured by GSK 
Biologicals.  
The Quality Control Standards and Requirements for each candidate vaccine are 
described in separate Quality Assurance documents (e.g. release protocols, certificate of 
analysis) and the required approvals have been obtained.  
The vaccines are labelled and packed according to applicable regulatory requirements. 
 
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Table 18 
Study vaccine for Part A and Part B - Step 1 
Treatment name 
Vaccine/ 
product name 
Formulation 
Presentation 
Volume to be 
administered 
Number 
of doses 
30 µg RSVPreF3 plain  
RSVPreF3 high dose  
RSVPreF3=120µg  
Freeze-dried antigen (174 µg/vial)  
0.5 ml 
2 
NaCl  
NaCl=150mM  
Liquid in monodose ampule or vial  
30 µg RSVPreF3/AS01E 
RSVPreF3 high dose  
RSVPreF3=120µg 
Freeze-dried antigen (174 µg/vial) 
0.5 ml 
2 
AS01E  
MPL=25µg; QS21=25µg; Liposomes  
Liquid in bidose vial  
30 µg RSVPreF3/AS01B 
RSVPreF3 high dose 
RSVPreF3=120µg 
Freeze-dried antigen (174 µg/vial) 
0.5 ml 
2 
AS01B  
MPL=50µg; QS21=50µg; Liposomes  
Liquid in monodose vial  
60 µg RSVPreF3 plain  
RSVPreF3 high dose 
RSVPreF3=120µg 
Freeze-dried antigen (174 µg/vial) 
0.5 ml 
2 
NaCl  
NaCl=150mM  
Liquid in monodose ampule or vial  
60 µg RSVPreF3/AS01E 
RSVPreF3 high dose 
RSVPreF3=120µg 
Freeze-dried antigen (174 µg/vial) 
0.5 ml 
2 
AS01E  
MPL=25µg; QS21=25µg; Liposomes  
Liquid in bidose vial  
60 µg RSVPreF3/AS01B 
RSVPreF3 high dose 
RSVPreF3=120µg 
Freeze-dried antigen (174 µg/vial) 
0.5 ml 
2 
AS01B  
MPL=50µg; QS21=50µg; Liposomes  
Liquid in monodose vial  
120 µg RSVPreF3 plain  
RSVPreF3 high dose 
RSVPreF3=120µg 
Freeze-dried antigen (174 µg/vial) 
0.5 ml 
2 
NaCl  
NaCl=150mM  
Liquid in monodose ampule or vial  
120 µg 
RSVPreF3/AS01E 
RSVPreF3 high dose 
RSVPreF3=120µg 
Freeze-dried antigen (174 µg/vial) 
0.5 ml  
2 
AS01E  
MPL=25µg; QS21=25µg; Liposomes  
Liquid in bidose vial  
120 µg 
RSVPreF3/AS01B 
RSVPreF3 high dose 
RSVPreF3=120µg 
Freeze-dried antigen (174 µg/vial) 
0.5 ml  
2 
AS01B  
MPL=50µg; QS21=50µg; Liposomes  
Liquid in monodose vial  
Placebo  
NaCl  
NaCl=150mM  
Liquid in monodose ampule or vial   
0.5 ml 
2 
AS01B = Adjuvant System AS01B; AS01E = Adjuvant System AS01E; MPL = 3-O-desacyl-4’-monophosphoryl lipid A  
QS-21: Quillaja saponaria Molina, fraction 21 (Licensed by GSK from Antigenics Inc, a wholly owned subsidiary of Agenus Inc., a Delaware, USA corporation) 
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Table 19 
Study vaccine for Part B - Step 2 
Treatment name 
Vaccine/ 
product name 
Formulation 
Presentation 
Volume to be 
administered 
Number 
of doses 
30 µg RSVPreF3 plain  
RSVPreF3 low dose  
RSVPreF3=30µg  
Freeze-dried antigen (44 µg/vial)  
0.5 ml  
2 
NaCl  
NaCl=150mM  
Liquid in monodose ampule or vial  
30 µg RSVPreF3/AS01E 
RSVPreF3 low dose  
RSVPreF3=30µg  
Freeze-dried antigen (44 µg/vial)  
0.5 ml  
2 
AS01E  
MPL=25µg; QS21=25µg; Liposomes  
Liquid in bidose vial  
30 µg RSVPreF3/AS01B 
RSVPreF3 low dose  
RSVPreF3=30µg  
Freeze-dried antigen (44 µg/vial)  
0.5 ml  
2 
AS01B  
MPL=50µg; QS21=50µg; Liposomes  
Liquid in monodose vial  
60 µg RSVPreF3 plain  
RSVPreF3 mid dose  
RSVPreF3=60µg  
Freeze-dried antigen (87 µg/vial)  
0.5 ml 
2 
NaCl  
NaCl=150mM  
Liquid in monodose ampule or vial  
60 µg RSVPreF3/AS01E 
RSVPreF3 mid dose  
RSVPreF3=60µg  
Freeze-dried antigen (87 µg/vial)  
0.5 ml 
2 
AS01E  
MPL=25µg; QS21=25µg; Liposomes  
Liquid in bidose vial  
60 µg RSVPreF3/AS01B 
RSVPreF3 mid dose  
RSVPreF3=60µg  
Freeze-dried antigen (87 µg/vial)  
0.5 ml 
2 
AS01B  
MPL=50µg; QS21=50µg; Liposomes  
Liquid in monodose vial  
120 µg RSVPreF3 plain  
RSVPreF3 high dose  
RSVPreF3=120µg  
Freeze-dried antigen (174 µg/vial) 
0.5 ml 
2 
NaCl  
NaCl=150mM  
Liquid in monodose ampule or vial  
120 µg 
RSVPreF3/AS01E 
RSVPreF3 high dose  
RSVPreF3=120µg  
Freeze-dried antigen (174 µg/vial) 
0.5 ml  
2 
AS01E  
MPL=25µg; QS21=25µg; Liposomes  
Liquid in bidose vial  
120 µg 
RSVPreF3/AS01B 
RSVPreF3 high dose  
RSVPreF3=120µg  
Freeze-dried antigen (174 µg/vial) 
0.5 ml  
2 
AS01B  
MPL=50µg; QS21=50µg; Liposomes  
Liquid in monodose vial  
Placebo  
NaCl  
NaCl=150mM  
Liquid in monodose ampule or vial  
0.5 ml 
2 
AS01B = Adjuvant System AS01B; AS01E = Adjuvant System AS01E; MPL = 3-O-desacyl-4’-monophosphoryl lipid A  
QS-21: Quillaja saponaria Molina, fraction 21 (Licensed by GSK from Antigenics Inc, a wholly owned subsidiary of Agenus Inc., a Delaware, USA corporation) 
 
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6.2. 
Storage and handling of study vaccine 
The study vaccine must be stored at the respective label storage temperature conditions in 
a safe and locked place. Access to the storage space should be limited to authorized study 
personnel. The storage conditions will be assessed during pre-study activities under the 
responsibility of the sponsor study contact. The storage temperature should be 
continuously monitored with calibrated (if not validated) temperature monitoring 
device(s) and recorded. Refer to the Module on Clinical Trial Supplies in the SPM for 
more details on storage of the study vaccine. 
Temperature excursions must be reported in degree Celsius. 
Any temperature excursion outside the range of 0.0 to +8.0C (for +2 to +8°C/+36 to 
+46°F label storage condition) impacting investigational medicinal products (IMPs) must 
be reported in the appropriate (electronic) temperature excursion decision form ([e]TDF). 
The impacted IMPs must not be used and must be stored in quarantine at label 
temperature conditions until usage approval has been obtained from the sponsor. 
In case of temperature excursion below +2.0°C down to 0.0°C impacting IMP(s), there is 
no need to report in (e)TDF, but adequate actions must be taken to restore the +2 to 
+8°C/+36 to +46°F label storage temperature conditions. The impacted IMP(s) may still 
be administered, but the site should avoid re-occurrence of such temperature excursion. 
Refer to the Module on Clinical Trial Supplies in the SPM for more details on actions to 
take. 
Refer to the Module on Clinical Trial Supplies in the SPM for details and instructions on 
the temperature excursion reporting and usage decision process, packaging and 
accountability of the study vaccine. 
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6.3. 
Dosage and administration of study vaccine 
Table 20 
Dosage and administration 
Type of contact 
and time point 
Study group 
Treatment name 
Volume to be 
administered 
Route1 
Site 
Location Laterality2 
Part A 
visit 1 (Day 1) 
visit 4 (Day 61) 
30-PLAIN_A  
30 µg RSVPreF3 plain  
0.5 ml 
IM  
Deltoid  
Non-
dominant  
60-PLAIN_A  
60 µg RSVPreF3 plain  
120-PLAIN_A  
120 µg RSVPreF3 plain  
Placebo_A  
Placebo  
Part B - Step 1 
visit 1 (Day 1) 
visit 4 (Day 61) 
30-PLAIN_B1  
30 µg RSVPreF3 plain 
0.5 ml 
IM  
Deltoid  
Non-
dominant  
30-AS01E_B1  
30 µg RSVPreF3/AS01E 
30-AS01B_B1  
30 µg RSVPreF3/AS01B  
60-PLAIN_B1  
60 µg RSVPreF3 plain  
60-AS01E_B1  
60 µg RSVPreF3/AS01E  
60-AS01B_B1  
60 µg RSVPreF3/AS01B  
120-PLAIN_B1  
120 µg RSVPreF3 plain  
120-AS01E_B1  120 µg RSVPreF3/AS01E  
120-AS01B_B1  120 µg RSVPreF3/AS01B  
Placebo_B1  
Placebo  
Part B - Step 2 
visit 1 (Day 1) 
visit 4 (Day 61) 
30-PLAIN_B2  
30 µg RSVPreF3 plain  
0.5 ml 
IM  
Deltoid  
Non-
dominant  
30-AS01E_B2  
30 µg RSVPreF3/AS01E  
30-AS01B_B2  
30 µg RSVPreF3/AS01B  
60-PLAIN_B2  
60 µg RSVPreF3 plain  
60-AS01E_B2  
60 µg RSVPreF3/AS01E  
60-AS01B_B2  
60 µg RSVPreF3/AS01B  
120-PLAIN_B2  
120 µg RSVPreF3 plain  
120-AS01E_B2  120 µg RSVPreF3/AS01E  
120-AS01B_B2  120 µg RSVPreF3/AS01B  
Placebo_B2  
Placebo  
1 Intramuscular (IM) 
2 The non-dominant arm is the preferred arm of injection. In case it is not possible to administer the vaccine in the non-
dominant arm, an injection in the dominant arm may be performed. 
Refer to the SPM for detailed instructions on study vaccine administration. 
6.4. 
Replacement of unusable vaccine doses 
In addition to the vaccine doses provided for the planned number of subjects (including 
over-randomization when applicable), at least 20% additional vaccine doses will be 
supplied to replace those that are unusable.  
The investigator will use SBIR to obtain the replacement vial/syringe number. The 
replacement numbers will be allocated by dose. The system will ensure, in a blinded 
manner, that the replacement vial/syringe matches the formulation the subject was 
assigned to by randomization. 
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6.5. 
Contraindications to subsequent vaccination 
The following events constitute absolute contraindications to further administration of the 
investigational RSV vaccine. If any of these events occur during the study, the subject 
must not receive additional doses of vaccine but may continue other study procedures at 
the discretion of the investigator (see Section 9.2.2).  
Contraindications for ALL subjects: 
• 
Anaphylaxis following the administration of vaccine(s). 
• 
Hepatomegaly, right upper quadrant abdominal pain or tenderness. 
• 
Decreased renal function since baseline, as defined by an increase in blood urea 
nitrogen or creatinine levels from values within normal range at pre-vaccination to 
Grade 2 abnormalities (based on the testing laboratory parameters) at 7 days post-
vaccination. 
• 
Any confirmed or suspected immunosuppressive or immunodeficient condition, 
including human immunodeficiency virus (HIV) infection.  
• 
Any condition that in the judgment of the investigator would make IM injection 
unsafe. 
• 
An SAE judged to be vaccine-related by the investigator. 
• 
Hematology parameters (complete blood cell count [red blood cells, white blood 
cells], white blood cells differential count [lymphocytes, neutrophils and 
eosinophils], platelets count or hemoglobin level) and/or biochemistry parameters 
(creatinine, blood urea nitrogen or liver enzymes [ALT or AST]) outside the normal 
laboratory ranges that persist after the administration of a previous study vaccine, 
unless the laboratory abnormalities are considered not clinically significant by the 
investigator. 
Specific contraindications for Part A: 
• 
Pregnancy (see Section 7.2.1). 
Specific contraindications for Part B: 
• 
Occurrence of a new pIMD or the exacerbation of an existing pIMD that, in the 
opinion of the investigator, may expose the subject to unacceptable risk from 
subsequent vaccination. In such cases, the investigator should use his/her clinical 
judgement prior to administering the next dose of the vaccine. Refer to Section 7.1.5 
for the definition of pIMDs. 
The following events constitute contraindications to administration of the investigational 
RSV vaccine at that point in time; if any of these events occur at the time scheduled for 
vaccination, the subject may be vaccinated at a later date, within the time window 
specified in the protocol (see Table 8 in Section 5.5), or the subject may be withdrawn at 
the discretion of the investigator (see Section 9.2.2).  
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Contraindications for ALL subjects: 
• 
Acute disease and/or fever at the time of vaccination.  
− 
Fever is defined as temperature  38.0°C / 100.4°F. The preferred location for 
measuring temperature in this study will be the oral cavity. 
− 
Subjects with a minor illness (such as mild diarrhoea, mild upper respiratory 
infection) without fever can be administered all vaccines. 
6.6. 
Concomitant medications/products and concomitant 
vaccinations 
At each study visit, the investigator or delegate should question the subject about any 
medication/product taken and vaccination received by the subject. 
6.6.1. 
Recording of concomitant medications/products and 
concomitant vaccinations 
The following concomitant medication(s)/product(s)/vaccine(s) must be recorded in 
the eCRF. 
• 
All concomitant medications/products, except vitamins and dietary supplements, 
administered during the 30-day period following each dose of study vaccine (Day 1 
to Day 30 and Day 61 to Day 90). 
• 
Any concomitant vaccination administered in the period starting from the first dose 
of study vaccine and ending at the last study visit (Day 1 to 91 for Part A and Day 1 
to Month 14 for Part B). 
• 
Prophylactic medication (i.e., medication administered in the absence of ANY 
symptom and in anticipation of a reaction to the vaccination). 
E.g. an anti-pyretic is considered to be prophylactic when it is given in the absence 
of fever and any other symptom, to prevent fever from occurring (fever is defined as 
temperature  38.0°C/100.4°F regardless the location of measurement). The 
preferred location for measuring temperature in this study will be the oral cavity.  
• 
Any concomitant medications/products/vaccines listed in Section 6.6.2. 
• 
For Part A, any concomitant medications/products/vaccines relevant to an SAE to 
be reported as per protocol or administered during the study period for the treatment 
of an SAE. In addition, concomitant medications relevant to SAEs need to be 
recorded on the expedited Adverse Event report. 
• 
For Part B, any concomitant medications/products/vaccines relevant to an 
SAE/pIMD to be reported as per protocol or administered during the study period for 
the treatment of an SAE/pIMD. In addition, concomitant medications relevant to 
SAEs and pIMD need to be recorded on the expedited Adverse Event report. 
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6.6.2. 
Concomitant medications/products/vaccines that may lead to the 
elimination of a subject from per-protocol analyses 
The use of the following concomitant medications/products/vaccines will not require 
withdrawal of the subject from the study but may determine a subject’s evaluability in the 
per-protocol analysis. See Section 10.5 for cohorts to be analysed. 
• 
Any investigational or non-registered product (drug or vaccine) other than the study 
vaccine used during the study period (up to Day 91 for Part A and up to Month 14 
for Part B).  
• 
Immunosuppressants or other immune-modifying drugs administered chronically 
(i.e., more than 14 consecutive days in total) during the study period (up to Day 91 
for Part A and up to Month 14 for Part B). For corticosteroids, this will mean 
prednisone  20 mg/day, or equivalent. Inhaled and topical steroids are allowed. 
• 
Long-acting immune-modifying drugs administered at any time during the study 
period (e.g. infliximab).  
• 
A vaccine not foreseen by the study protocol administered during the period starting 
30 days before the first dose and ending 30 days after the last vaccine dose*, except 
for inactivated and subunit influenza vaccines which can be administered up to 14 
days before or from 30 days after each vaccination.  
* In case an emergency mass vaccination for an unforeseen public health threat (e.g.: 
a pandemic) is organised by the public health authorities, outside the routine 
immunization program, the time period described above can be reduced if necessary 
for that vaccine provided it is licensed and used according to its Prescribing 
Information and according to the local governmental recommendations and provided 
a written approval of the sponsor is obtained. 
• 
Immunoglobulins and/or any blood products administered during the study period 
(up to Day 91 for Part A and up to Month 14 for Part B). 
6.7. 
Intercurrent medical conditions that may lead to elimination 
of a subject from per-protocol analyses 
At each study visit subsequent to the first vaccination, it must be verified if the subject 
has experienced or is experiencing any intercurrent medical condition (refer to glossary 
of terms for the definition of intercurrent medical condition). If it is the case, the 
condition(s) must be recorded in the AE section of the eCRF. 
At the time of analysis, subjects may be eliminated from the per-protocol cohort for 
immunogenicity if, during the study, they incur a condition that has the capability of 
altering their immune response or are confirmed to have an alteration of their initial 
immune status. 
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7. 
SAFETY 
The investigator or site staff is/are responsible for the detection, documentation and 
reporting of events meeting the criteria and definition of an AE or SAE as provided in 
this protocol.  
Each subject will be instructed to contact the investigator immediately should they 
manifest any signs or symptoms they perceive as serious. 
7.1. 
Safety definitions 
7.1.1. 
Definition of an adverse event 
An AE is any untoward medical occurrence in a clinical investigation subject, temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product. 
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with 
the use of a medicinal product. For marketed medicinal products, this also includes 
failure to produce expected benefits (i.e., lack of efficacy), abuse or misuse.  
Examples of an AE include: 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• 
New conditions detected or diagnosed after study vaccine(s) administration even 
though they may have been present prior to the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
vaccine(s) or a concurrent medication (overdose per se should not be reported as an 
AE/SAE). 
• 
Signs, symptoms temporally associated with study vaccine(s) administration. 
• 
Pre- or post-treatment events that occur as a result of protocol-mandated procedures 
(i.e., invasive procedures, modification of subject’s previous therapeutic regimen). 
AEs to be recorded as endpoints (solicited AEs) are described in Section 7.1.3. All other 
AEs will be recorded as UNSOLICITED AEs. 
Examples of an AE DO NOT include: 
• 
Medical or surgical procedures (e.g. endoscopy, appendectomy); the condition that 
leads to the procedure is an AE/SAE. 
• 
Situations where an untoward medical occurrence did not occur (e.g. social and/or 
convenience admission to a hospital, admission for routine examination). 
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• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.  
• 
Pre-existing conditions or signs and/or symptoms present in a subject prior to the 
first study vaccination. These events will be recorded in the medical history section 
of the eCRF. 
7.1.2. 
Definition of a serious adverse event  
An SAE is any untoward medical occurrence that: 
a. 
Results in death, 
b. Is life-threatening, 
Note: The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in 
which the subject was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, had it been more severe. 
c. 
Requires hospitalization or prolongation of existing hospitalization, 
Note: In general, hospitalization signifies that the subject has been admitted at the 
hospital or emergency ward for observation and/or treatment that would not have 
been appropriate in the physician’s office or in an out-patient setting. Complications 
that occur during hospitalization are also considered AEs. If a complication prolongs 
hospitalization or fulfils any other serious criteria, the event will also be considered 
serious. When in doubt as to whether ‘hospitalization’ occurred or was necessary, the 
AE should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition (known or 
diagnosed prior to informed consent signature) that did not worsen from baseline is 
NOT considered an AE. 
d. Results in disability/incapacity, OR 
Note: The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions. This definition is not intended to include experiences 
of relatively minor medical significance such as uncomplicated headache, nausea, 
vomiting, diarrhoea, influenza like illness, and accidental trauma (e.g. sprained 
ankle) which may interfere or prevent everyday life functions but do not constitute a 
substantial disruption. 
e. 
Is a congenital anomaly/birth defect in the offspring of a study subject. 
Medical or scientific judgement should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardise the 
subject or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These should also be considered serious. 
Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions 
that do not result in hospitalization. 
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7.1.3. 
Solicited adverse events 
Solicited AEs (see Table 21 and Table 22) occurring during the 7-day follow-up period 
after each vaccination (day of vaccination and 6 subsequent days) will be recorded by the 
subjects in the eDiaries. The data will be made available for site follow-up on the eDiary 
web-portal.  
The investigator will assess the causality of the general symptoms on the web-portal, 
after a discussion with the subject during a phone contact or a visit. The investigator 
should also enter on the portal the type of medical attention given for each of the solicited 
symptoms experienced by the subject. 
7.1.3.1. 
Solicited local (injection-site) adverse events 
The following local (injection-site) AEs will be solicited: 
Table 21 
Solicited local adverse events 
Pain at injection site 
Redness at injection site 
Swelling at injection site 
7.1.3.2. 
Solicited general adverse events 
The following general AEs will be solicited: 
Table 22 
Solicited general adverse events 
Fatigue 
Fever 
Gastrointestinal symptoms† 
Headache 
Myalgia 
Shivering 
Arthralgia 
† Gastrointestinal symptoms include nausea, vomiting, diarrhoea and/or abdominal pain. 
Note: Subjects will be instructed to measure and record the oral body temperature in the 
evening. Should additional temperature measurements be performed at other times of 
day, subjects will be instructed to record the highest temperature in the eDiary. 
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7.1.4. 
Clinical laboratory parameters and other abnormal assessments 
qualifying as adverse events or serious adverse events  
In absence of diagnosis, abnormal laboratory findings (e.g. clinical chemistry, 
hematology) or other abnormal assessments (e.g. physical examination signs or 
symptoms) that are judged by the investigator to be clinically significant will be recorded 
as AE or SAE if they meet the definition of an AE or SAE (refer to Sections 7.1.1 and 
7.1.2). Clinically significant abnormal laboratory findings or other abnormal assessments 
that are present at baseline and significantly worsen following the start of the study will 
also be reported as AEs or SAEs. 
The investigator will exercise his/ her medical and scientific judgment in deciding 
whether an abnormal laboratory finding or other abnormal assessment is clinically 
significant. As for other AEs/ SAEs, treatment for clinically significant abnormal 
laboratory findings or other assessments is at the sole discretion of the investigator and 
according to good medical practice. 
In case of invalid or missing results or clinically significant grade 3 and above abnormal 
laboratory findings that cannot be reasonably explained (e.g. due to a pre-existing or 
current medical condition), the investigator will be recommended to recall the subject in a 
timely manner (preferably within 7 days after investigator’s awareness/assessment of the 
abnormal findings, if applicable) for a repeat test to confirm the result.  
7.1.5. 
Adverse events of specific interest (Potential immune-mediated 
diseases) 
Potential immune-mediated diseases (pIMDs) are a subset of AEs that include 
autoimmune diseases and other inflammatory and/or neurologic disorders of interest 
which may or may not have an autoimmune aetiology. AEs that need to be recorded and 
reported as pIMDs include those listed in Table 23. 
However, the investigator will exercise his/her medical and scientific judgement in 
deciding whether other diseases have an autoimmune origin (i.e. pathophysiology 
involving systemic or organ-specific pathogenic autoantibodies) and should also be 
recorded as a pIMD. 
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Table 23 
List of potential immune-mediated diseases  
Neuroinflammatory disorders 
Musculoskeletal disorders 
Skin disorders 
• 
Cranial nerve neuropathy, 
including paralysis and paresis 
(e.g. Bell’s palsy). 
• 
Optic neuritis. 
• 
Multiple sclerosis. 
• 
Transverse myelitis. 
• 
Guillain-Barré syndrome, 
including Miller Fisher syndrome 
and other variants. 
• 
Acute disseminated 
encephalomyelitis, including site 
specific variants e.g.: non-
infectious encephalitis, 
encephalomyelitis, myelitis, 
myeloradiculoneuritis. 
• 
Myasthenia gravis, including 
Lambert-Eaton myasthenic 
syndrome. 
• 
Demyelinating peripheral 
neuropathies including: 
− 
Chronic inflammatory 
demyelinating 
polyneuropathy,  
− 
Multifocal motor 
neuropathy  
− 
Polyneuropathies 
associated with 
monoclonal gammopathy. 
• 
Narcolepsy. 
• 
Systemic lupus erythematosus 
and associated conditions 
• 
Systemic scleroderma 
(Systemic sclerosis), including: 
− 
Diffuse Scleroderma 
− 
CREST syndrome 
• 
Idiopathic inflammatory 
myopathies, including: 
− 
Dermatomyositis  
− 
Polymyositis  
• 
Anti-synthetase syndrome. 
• 
Rheumatoid Arthritis and 
associated conditions 
including:  
− 
Juvenile Idiopathic 
Arthritis 
− 
Still’s disease. 
• 
Polymyalgia rheumatica. 
• 
Spondyloarthropathies, 
including:  
− 
Ankylosing Spondylitis,  
− 
Reactive Arthritis 
(Reiter's Syndrome), 
− 
Undifferentiated 
Spondyloarthritis, 
− 
Psoriatic Arthritis, 
− 
Enteropathic arthritis. 
• 
Relapsing Polychondritis. 
• 
Mixed Connective Tissue 
disorder. 
• 
Gout. 
• 
Psoriasis. 
• 
Vitiligo. 
• 
Erythema nodosum. 
• 
Autoimmune bullous skin 
diseases (including 
pemphigus, pemphigoid 
and dermatitis 
herpetiformis). 
• 
Lichen planus. 
• 
Sweet’s syndrome. 
• 
Localised Scleroderma 
(Morphoea). 
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Vasculitis 
Blood disorders 
Others 
• 
Large vessels vasculitis 
including:  
− 
Giant Cell Arteritis 
(Temporal Arteritis), 
− 
Takayasu's Arteritis.  
• 
Medium sized and/or small 
vessels vasculitis including:  
− 
Polyarteritis nodosa, 
− 
Kawasaki's disease,  
− 
Microscopic Polyangiitis,  
− 
Wegener's 
Granulomatosis 
(granulomatosis with 
polyangiitis),  
− 
Churg–Strauss syndrome 
(allergic granulomatous 
angiitis or eosinophilic 
granulomatosis with 
polyangiitis),  
− 
Buerger’s disease 
(thromboangiitis 
obliterans),  
− 
Necrotizing vasculitis 
(cutaneous or systemic),  
− 
anti-neutrophil 
cytoplasmic antibody 
(ANCA) positive vasculitis 
(type unspecified), 
− 
Henoch-Schonlein 
purpura (IgA vasculitis),  
− 
Behcet's syndrome, 
− 
Leukocytoclastic 
vasculitis. 
• 
Autoimmune hemolytic 
anemia. 
• 
Autoimmune 
thrombocytopenia. 
• 
Antiphospholipid syndrome. 
• 
Pernicious anemia. 
• 
Autoimmune aplastic anemia. 
• 
Autoimmune neutropenia. 
• 
Autoimmune pancytopenia. 
• 
Autoimmune 
glomerulonephritis 
including: 
− 
IgA nephropathy,  
− 
Glomerulonephritis 
rapidly progressive,  
− 
Membranous 
glomerulonephritis,  
− 
Membranoproliferative 
glomerulonephritis,  
− 
Mesangioproliferative 
glomerulonephritis.  
− 
Tubulointerstitial 
nephritis and uveitis 
syndrome. 
• 
Ocular autoimmune 
diseases including: 
− 
Autoimmune uveitis  
− 
Autoimmune retinitis. 
• 
Autoimmune myocarditis. 
• 
Sarcoidosis. 
• 
Stevens-Johnson 
syndrome. 
• 
Sjögren’s syndrome. 
• 
Alopecia areata. 
• 
Idiopathic pulmonary 
fibrosis. 
• 
Goodpasture syndrome. 
• 
Raynaud’s phenomenon. 
Liver disorders 
Gastrointestinal disorders 
Endocrine disorders 
• 
Autoimmune hepatitis. 
• 
Primary biliary cirrhosis. 
• 
Primary sclerosing cholangitis. 
• 
Autoimmune cholangitis. 
• 
Inflammatory Bowel disease, 
including: 
− 
Crohn’s disease,  
− 
Ulcerative colitis,  
− 
Microscopic colitis,  
− 
Ulcerative proctitis. 
• 
Celiac disease. 
• 
Autoimmune pancreatitis. 
• 
Autoimmune thyroiditis 
(Hashimoto thyroiditis). 
• 
Grave's or Basedow’s 
disease. 
• 
Diabetes mellitus type I. 
• 
Addison’s disease. 
• 
Polyglandular autoimmune 
syndrome. 
• 
Autoimmune hypophysitis. 
When there is enough evidence to make any of the above diagnoses, the AE must be 
reported as a pIMD. Symptoms, signs or conditions which might (or might not) represent 
the above diagnoses, should be recorded and reported as AEs but not as pIMDs until the 
final or definitive diagnosis has been determined, and alternative diagnoses have been 
eliminated or shown to be less likely. 
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In order to facilitate the documentation of pIMDs in the eCRF, a pIMD standard 
questionnaire and a list of preferred terms (PTs) and PT codes corresponding to the above 
diagnoses will be available to investigators at study start. 
7.2. 
Events or outcomes not qualifying as adverse events or 
serious adverse events  
7.2.1. 
Pregnancy in Part A 
In Part A, female subjects who are pregnant or lactating at the time of vaccination must 
not receive additional doses of study vaccine but may continue other study procedures at 
the discretion of the investigator. 
While pregnancy itself is not considered an AE or SAE, any adverse pregnancy outcome 
or complication or elective termination of a pregnancy for medical reasons will be 
recorded and reported as an AE or an SAE. 
Note: The pregnancy itself should always be recorded on an electronic pregnancy report. 
The following should always be considered as SAE and will be reported as described in 
Sections 7.4.1 and 7.4.3: 
• 
Spontaneous pregnancy loss, including: 
− 
spontaneous abortion, (spontaneous pregnancy loss before/at 22 weeks of 
gestation) 
− 
ectopic and molar pregnancy 
− 
stillbirth (intrauterine death of foetus after 22 weeks of gestation). 
Note: the 22 weeks cut-off in gestational age is based on WHO-ICD 10 noted in the 
EMA Guideline on pregnancy exposure [EMA, 2006]. It is recognized that national 
regulations might be different. 
• 
Any early neonatal death (i.e., death of a live born infant occurring within the first 7 
days of life).  
• 
Any congenital anomaly or birth defect (as per [CDC MACDP] guidelines) 
identified in the offspring of a study subject (either during pregnancy, at birth or 
later) regardless of whether the foetus is delivered dead or alive. This includes 
anomalies identified by prenatal ultrasound, amniocentesis or examination of the 
products of conception after elective or spontaneous abortion. 
Furthermore, any SAE occurring as a result of a post-study pregnancy AND considered 
by the investigator to be reasonably related to the study vaccine will be reported to GSK 
Biologicals as described in Section 7.4.3. While the investigator is not obligated to 
actively seek this information from former study participants, he/she may learn of a 
pregnancy through spontaneous reporting. 
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7.3. 
Detecting and recording adverse events, serious adverse 
events and pregnancies 
Electronic Diaries (eDiaries) will be used by the subjects to capture solicited AE data and 
to notify investigators if other (unsolicited) signs or symptoms were experienced.  
Paper diary cards will be used by the subjects to capture the details of the unsolicited 
signs or symptoms. They will be reviewed by the investigator at the subsequent study 
visits (Day 8, Day 31, Day 68 or Day 91) and then reported as applicable in the AE 
section of the eCRF.  
The subject should be trained on how and when to complete each field of the electronic 
and paper diary. If a subject is illiterate or unable or not willing to complete the electronic 
and/or the paper him/herself, he/she may be helped by a designate (refer to the glossary 
of terms for the definition of designate). 
Subject Diary training should be directed at the individual(s) who will perform the 
measurements of AEs and who will enter the information into the Subject Diary. If a 
designate enters information into the Subject Diary, this person’s identity must be 
documented in the subject’s source record. Any individual that makes entries into the 
Subject Diary must receive training on completion of the Subject Diary at the time of the 
visit when Subject Diary is dispensed. This training must be documented in the subject’s 
source record. 
The same individual should complete the Subject eDiary throughout the course of the 
study. The subject should be trained on how to self-measure local solicited AEs and body 
temperature. The measurement of solicited local AEs is to be performed using the ruler 
provided by the site.  
7.3.1. 
Time period for detecting and recording adverse events, serious 
adverse events and pregnancies 
For Part A and Part B: 
All AEs starting within 30 days following administration of each dose of study vaccine 
(the day of vaccination and 29 subsequent days) must be recorded into the appropriate 
section of the eCRF, irrespective of intensity or whether or not they are considered 
vaccination-related. 
All AEs/SAEs leading to withdrawal from the study will be collected and recorded from 
the time of the first receipt of study vaccine until the subject is discharged from the study. 
The time period for collecting and recording SAEs will begin at the first receipt of study 
vaccine and will end 1 month following administration of the last dose of study vaccine 
for each subject in Part A and 12 months following administration of the last dose of 
study vaccine for each subject in Part B. See Section 7.4 for instructions on reporting of 
SAEs. 
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In addition to the above-mentioned reporting requirements and in order to fulfil 
international reporting obligations, SAEs that are related to study participation (i.e., 
protocol-mandated procedures, invasive tests, a change from existing therapy) or are 
related to a concurrent GSK medication/vaccine will be collected and recorded from the 
time the subject consents to participate in the study until she/he is discharged from the 
study. 
For Part A only: 
The time period for collecting and recording pregnancies will begin at the first receipt of 
study vaccine and will end 1 month following administration of the last dose of study 
vaccine. See section 7.4 for instructions on reporting of pregnancies. 
For Part B only: 
The time period for collecting and recording of pIMDs will begin at the first receipt of 
study vaccine and will end 12 months following administration of the last dose of study 
vaccine. See Section 7.4 for instructions on reporting of pIMDs. 
An overview of the protocol-required reporting periods for AEs, SAEs, pregnancies 
and/or pIMDs is given in  
Table 24 for Part A and Table 25 for Part B. 
Refer to Section 5.10 for measures for safety follow-up that may be implemented 
during special circumstances (Amended, 13 May 2020). 
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Table 24 
Reporting periods for collecting safety information in Part A 
Event 
SCR 
 
Visit 1 
Visit 2 
Visit 3 
 
Visit 4 
Visit 5 
Visit 6 
Pre-D1* 
 
Vacc 1 
 
 
 
Vacc 2 
 
End of FU for 
Part A 
Solicited local and general 
AEs 
 
 
 
 
 
 
 
 
 
 
 
Days 1-7 
 
 
Days 61-67 
 
 
 
 
 
 
 
 
 
 
Unsolicited AEs 
 
 
 
 
 
 
 
 
 
 
 
Days 1-30 
 
Days 61-90 
 
 
 
 
 
 
 
 
 
AEs/SAEs leading to 
withdrawal from the study 
 
 
 
 
 
 
 
 
 
 
Days 1-91 
 
 
 
 
 
 
 
 
 
SAEs  
 
 
 
 
 
 
 
 
 
 
Days 1-91 
 
 
 
 
 
 
 
 
 
SAEs related to study 
participation or concurrent 
GSK medication/vaccine  
 
 
 
 
 
 
 
 
 
Pre-Day 1* - Day 91 
 
 
 
 
 
 
 
 
 
Pregnancies 
 
 
 
 
 
 
 
 
 
 
Days 1-91 
 
 
 
 
 
 
 
 
 
Intercurrent medical 
conditions 
 
 
 
 
 
 
 
 
 
 
Days 1-91 
 
 
 
 
 
 
 
 
 
* i.e., consent obtained.  
Pre-D1: Pre-vaccination Day 1; FU: Follow-up; Vacc: Vaccination; SCR: Screening Visit 
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Table 25 
Reporting periods for collecting safety information in Part B 
Event 
SCR 
 
Visit 1 Visit 2 Visit 3 
 Visit 4 Visit 5 
Visit 6 
Visit 7 
Visit 8 
Pre-D1*  
Vacc 1 
 
 
 Vacc 2 
 
 
 
Study 
Conclusion 
Solicited local and 
general AEs 
 
 
 
 
 
 
 
 
 
 
 
 
 
Days 1-7 
 
 
Days 61-67 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Unsolicited AEs 
 
 
 
 
 
 
 
 
 
 
 
 
 
Days 1-30 
 
Days 61-90 
 
 
 
 
 
 
 
 
 
 
 
 
 
AEs/SAEs leading 
to withdrawal from 
the study 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 1 - Month 14 
 
 
 
 
 
 
 
 
 
 
 
SAEs  
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 1 - Month 14 
 
 
 
 
 
 
 
 
 
 
 
SAEs related to 
study participation 
or concurrent GSK 
medication/vaccine  
 
 
 
 
 
 
 
 
 
 
 
Pre-Day 1* - Month 14 
 
 
 
 
 
 
 
 
 
 
 
pIMDs  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 1 - Month 14 
 
 
 
 
 
 
 
 
 
 
 
Intercurrent 
medical conditions 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 1 - Month 14 
 
 
 
 
 
 
 
 
 
 
 
* i.e., consent obtained.  
Pre-D1: Pre-vaccination Day 1; Vacc: Vaccination 
SCR: Screening Visit 
7.3.2. 
Post-Study adverse events and serious adverse events 
A post-study AE/SAE is defined as any event that occurs outside of the AE/SAE 
reporting period defined in  
Table 24 for Part A and Table 25 for Part B. Investigators are not obligated to actively 
seek AEs or SAEs in former study participants. However, if the investigator learns of any 
SAE at any time after a subject has been discharged from the study, and he/she considers 
the event reasonably related to the study vaccine, the investigator will promptly notify the 
Study Contact for Reporting SAEs. 
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7.3.3. 
Evaluation of adverse events and serious adverse events 
7.3.3.1. 
Active questioning to detect adverse events and serious adverse 
events 
As a consistent method of collecting AEs, the subject should be asked a non-leading 
question such as: 
‘Have you felt different in any way since receiving the vaccine or since the previous 
visit?’ 
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g. hospital progress notes, laboratory and diagnostics reports) relative 
to the event. The investigator will then record all relevant information regarding an 
AE/SAE in the eCRF. The investigator is not allowed to send photocopies of the 
subject’s medical records to GSK Biologicals instead of appropriately completing the 
eCRF. However, there may be instances when copies of medical records for certain cases 
are requested by GSK Biologicals. In this instance, all subject identifiers will be blinded 
on the copies of the medical records prior to submission to GSK Biologicals. 
The investigator will attempt to establish a diagnosis pertaining to the event based on 
signs, symptoms, and/or other clinical information. In such cases, the diagnosis should be 
documented as the AE/SAE and not the individual signs/symptoms. 
7.3.3.2. 
Assessment of adverse events 
7.3.3.2.1. Assessment of intensity 
The intensity of the following solicited AEs will be assessed as described: 
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Table 26 
Intensity scales for solicited symptoms in adults  
Adverse Event 
Intensity grade 
Parameter 
Pain at injection site 
0 
None 
 
1 
Mild: Any pain neither interfering with nor preventing normal 
every day activities. 
 
2 
Moderate: Painful when limb is moved and interferes with every 
day activities. 
 
3 
Severe: Significant pain at rest. Prevents normal every day 
activities. 
Redness at injection site 
 
Record greatest surface diameter in mm 
Swelling at injection site 
 
Record greatest surface diameter in mm 
Fever* 
 
Record temperature in °C/°F 
Headache 
0 
Normal 
 
1 
Mild: Headache that is easily tolerated 
 
2 
Moderate: Headache that interferes with normal activity 
 
3 
Severe: Headache that prevents normal activity 
Fatigue 
0 
Normal 
 
1 
Mild: Fatigue that is easily tolerated 
 
2 
Moderate: Fatigue that interferes with normal activity 
 
3 
Severe: Fatigue that prevents normal activity 
Gastrointestinal symptoms 
0 
Normal 
(nausea, vomiting, diarrhoea 
and/or abdominal pain) 
1 
Mild: Gastrointestinal symptoms that are easily tolerated 
2 
Moderate: Gastrointestinal symptoms that interfere with normal 
activity 
 
3 
Severe: Gastrointestinal symptoms that prevent normal activity 
Arthralgia 
0 
Normal 
 
1 
Mild: Arthralgia that is easily tolerated 
 
2 
Moderate: Arthralgia that interferes with normal activity 
 
3 
Severe: Arthralgia that prevents normal activity 
Myalgia 
0 
Normal 
 
1 
Mild: Myalgia that is easily tolerated 
 
2 
Moderate: Myalgia that interferes with normal activity 
 
3 
Severe: Myalgia that prevents normal activity 
Shivering 
0 
Normal 
 
1 
Mild: Shivering that is easily tolerated 
 
2 
Moderate: Shivering that interferes with normal activity 
 
3 
Severe: Shivering that prevents normal activity 
*Fever is defined as temperature  38.0°C / 100.4°F (regardless of the location of measurement). The preferred 
location for measuring temperature in this study will be the oral cavity. 
The maximum intensity of local injection site redness/swelling and fever will be scored at 
GSK Biologicals as follows: 
 
Redness/swelling 
Fever 
0: 
 20 mm 
< 38.0°C (100.4°F) 
1: 
> 20 -  50 mm 
≥ 38.0°C (100.4°F) -  38.5°C (101.3°F) 
2: 
> 50 -  100 mm 
> 38.5°C (101.3°F) -  39.0°C (102.2°F) 
3: 
> 100 mm 
> 39.0°C (102.2°F) 
The investigator will assess the maximum intensity that occurred over the duration of the 
event for all unsolicited AEs (including SAEs) recorded during the study. The assessment 
will be based on the investigator’s clinical judgement. 
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The intensity should be assigned to one of the following categories: 
1 (mild) 
= 
An AE which is easily tolerated by the subject, causing minimal 
discomfort and not interfering with everyday activities. 
2 (moderate) 
= 
An AE which is sufficiently discomforting to interfere with 
normal everyday activities. 
3 (severe) 
= 
An AE which prevents normal, everyday activities  
In adults, such an AE would, for example, prevent attendance at 
work/school and would necessitate the administration of corrective 
therapy.) 
An AE that is assessed as Grade 3 (severe) should not be confused with an SAE. Grade 
3 is a category used for rating the intensity of an event; and both AEs and SAEs can be 
assessed as Grade 3. An event is defined as ‘serious’ when it meets one of the pre-
defined outcomes as described in Section 7.1.2. 
7.3.3.2.2. Assessment of causality 
The investigator is obligated to assess the relationship between study vaccine and the 
occurrence of each AE/SAE using clinical judgement.  
Alternative plausible causes, such as natural history of the underlying diseases, 
concomitant therapy, other risk factors, and the temporal relationship of the event to the 
study vaccine will be considered and investigated. The investigator will also consult the 
IB to determine his/her assessment. 
There may be situations when an SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK Biologicals. However, it is very 
important that the investigator always makes an assessment of causality for every event 
prior to submission of the Expedited Adverse Events Report to GSK Biologicals. The 
investigator may change his/her opinion of causality in light of follow-up information and 
update the SAE information accordingly. The causality assessment is one of the criteria 
used when determining regulatory reporting requirements. 
All solicited local (injection site) reactions will be considered causally related to 
vaccination. Causality of all other AEs should be assessed by the investigator using the 
following question: 
Is there a reasonable possibility that the AE may have been caused by the study vaccine? 
YES 
: 
There is a reasonable possibility that the study vaccine contributed 
to the AE.  
NO 
: 
There is no reasonable possibility that the AE is causally related to 
the administration of the study vaccine. There are other, more 
likely causes and administration of the study vaccine is not 
suspected to have contributed to the AE. 
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If an event meets the criteria to be determined as ‘serious’ (see Section 7.1.2), additional 
examinations/tests will be performed by the investigator in order to determine ALL 
possible contributing factors for each SAE. 
Possible contributing factors include: 
• 
Medical history. 
• 
Other medication. 
• 
Protocol required procedure. 
• 
Other procedure not required by the protocol. 
• 
Lack of efficacy of the vaccine, if applicable. 
• 
Erroneous administration. 
• 
Other cause (specify). 
7.3.3.3. 
Assessment of outcomes 
The investigator will assess the outcome of all unsolicited AEs (including SAEs) 
recorded during the study as: 
• 
Recovered/resolved. 
• 
Recovering/resolving. 
• 
Not recovered/not resolved. 
• 
Recovered with sequelae/resolved with sequelae. 
• 
Fatal (SAEs only). 
7.3.3.4. 
Medically attended visits 
The subject will be asked if he/she received medical attention defined as hospitalisation, 
or an otherwise unscheduled visit to or from medical personnel for any reason, including 
emergency room visits. 
7.4. 
Reporting of serious adverse events, pregnancies, and 
other events 
7.4.1. 
Prompt reporting of serious adverse events, pregnancies, and 
other events to GSK Biologicals 
SAEs that occur in the time period defined in Section 7.3 will be reported promptly to 
GSK within the timeframes described in Table 27, once the investigator determines that 
the event meets the protocol definition of an SAE. 
208851 | Protocol Amendment 1 19 May 2020 | TMF-1772243 | 1.0

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Documents 
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electronic Expedited 
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24 hours* 
electronic Expedited Adverse 
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Pregnancies  
2 weeks* 
electronic pregnancy report  
2 weeks* 
electronic pregnancy report  
pIMDs 
24 hours** ‡ 
electronic Expedited 
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24 hours* 
electronic Expedited Adverse 
Events Report 
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The investigator will always provide an assessment of causality at the time of the initial 
report. The investigator will be required to confirm the review of the SAE causality by 
ticking the ‘reviewed’ box in the electronic Expedited Adverse Events Report within 72 
hours of submission of the SAE. 
7.4.3.1. 
Back-up system in case the electronic reporting system does not work 
If the electronic reporting system does not work, the investigator (or delegate) must 
complete, then date and sign a paper Expedited Adverse Events Report and fax it to the 
Study Contact for Reporting SAEs (refer to the Sponsor Information) or to GSK 
Biologicals Clinical Safety and Pharmacovigilance department within 24 hours.  
This back-up system should only be used if the electronic reporting system is not working 
and NOT if the system is slow. As soon as the electronic reporting system is working 
again, the investigator (or delegate) must complete the electronic Expedited Adverse 
Events Report within 24 hours. The final valid information for regulatory reporting will 
be the information reported through the electronic SAE reporting system.  
7.4.4. 
Completion and transmission of pregnancy reports to GSK 
Biologicals 
Once the investigator becomes aware that a subject is pregnant, the investigator (or 
delegate) must complete the required information onto the electronic pregnancy report 
WITHIN 2 WEEKS. 
Note: Conventionally, the estimated gestational age (EGA) of a pregnancy is dated from 
the first day of the last menstrual period (LMP) of the cycle in which a woman conceives. 
If the LMP is uncertain or unknown, dating of EGA and the estimated date of delivery 
(EDD) should be estimated by ultrasound examination and recorded in the pregnancy 
report. 
7.4.5. 
Reporting of pIMDs to GSK Biologicals 
Once a pIMD is diagnosed (serious or non-serious) in a study subject, the investigator (or 
delegate) must complete the information in the electronic Expedited Adverse Events 
Report WITHIN 24 HOURS after he/she becomes aware of the diagnosis. The report 
allows to specify that the event is a pIMD and whether it is serious or non-serious. The 
report will always be completed as thoroughly as possible with all available details of the 
event, in accordance with the pIMD standard questionnaire provided. Even if the 
investigator does not have all information regarding a pIMD, the report should still be 
completed within 24 hours. Once additional relevant information is received, the report 
should be updated WITHIN 24 HOURS. 
The investigator will always provide an assessment of causality at the time of the initial 
report. The investigator will be required to confirm the review of the pIMD causality by 
ticking the ‘reviewed’ box in the electronic Expedited Adverse Events Report within 72 
hours of submission of the pIMD. 
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Refer to Section 7.4.3.1 for back-up system in case the electronic reporting system does 
not work. 
7.4.6. 
Updating of SAE, pregnancy, and pIMD information after removal 
of write access to the subject’s eCRF 
When additional SAE, pregnancy, or pIMD information is received after removal of the 
write access to the subject’s eCRF, new or updated information should be recorded on the 
appropriate paper report, with all changes signed and dated by the investigator. The 
updated report should be faxed to the Study Contact for Reporting SAEs (refer to the 
Sponsor Information) or to GSK Biologicals Clinical Safety and Pharmacovigilance 
department within the designated reporting time frames specified in Table 27. 
7.4.7. 
Regulatory reporting requirements for serious adverse events 
The investigator will promptly report all SAEs to GSK in accordance with the procedures 
detailed in Section 7.4.1. GSK Biologicals has a legal responsibility to promptly notify, 
as appropriate, both the local regulatory authority and other regulatory agencies about the 
safety of a product under clinical investigation. Prompt notification of SAEs by the 
investigator to the Study Contact for Reporting SAEs is essential so that legal obligations 
and ethical responsibilities towards the safety of other subjects are met. 
Investigator safety reports are prepared according to the current GSK policy and are 
forwarded to investigators as necessary. An investigator safety report is prepared for an 
SAE(s) that is both attributable to the study vaccine and unexpected. The purpose of the 
report is to fulfil specific regulatory and GCP requirements, regarding the product under 
investigation. 
7.5. 
Follow-up of adverse events, serious adverse events, and 
pregnancies 
7.5.1. 
Follow-up of adverse events and serious adverse events  
7.5.1.1. 
Follow-up during the study 
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject and provide additional relevant information on the subject’s condition to GSK 
Biologicals (within 24 hours for SAEs; refer to Table 27). 
All SAEs and pIMDs (serious or non-serious) documented at a previous visit/contact and 
designated as not recovered/not resolved or recovering/resolving will be reviewed at 
subsequent visits/contacts until the last visit of the subject. 
All AEs documented at a previous visit/contact and designated as not recovered/not 
resolved or recovering/resolving will be reviewed at subsequent visits/contacts until 30 
days after the last vaccination. 
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7.5.1.2. 
Follow-up after the subject is discharged from the study 
The investigator will follow subjects with SAEs, pIMDs (serious or non-serious), or 
subjects withdrawn from the study as a result of an AE, until the event has resolved, 
subsided, stabilised, disappeared, or until the event is otherwise explained, or the subject 
is lost to follow-up.  
If the investigator receives additional relevant information on a previously reported SAE, 
he/she will provide this information to GSK Biologicals using an electronic Expedited 
Adverse Events Report and/or pregnancy report as applicable. 
GSK Biologicals may request that the investigator performs or arranges the conduct of 
additional clinical examinations/tests and/or evaluations to elucidate as fully as possible 
the nature and/or causality of the AE or SAE. The investigator is obliged to assist. If a 
subject dies during participation in the study or during a recognised follow-up period, 
GSK Biologicals will be provided with any available post-mortem findings, including 
histopathology. 
7.5.2. 
Follow-up of pregnancies 
Pregnant subjects will be followed to determine the outcome of the pregnancy. At the end 
of the pregnancy, whether full-term or premature, information on the status of the mother 
and child will be forwarded to GSK Biologicals using the electronic pregnancy report and 
the Expedited Adverse Events Report if applicable. Generally, the follow-up period 
doesn’t need to be longer than six to eight weeks after the estimated date of delivery. 
Regardless of the reporting period for SAEs for this study, if the pregnancy outcome is an 
SAE, it should always be reported as SAE. 
7.6. 
Treatment of adverse events 
Treatment of any AE is at the sole discretion of the investigator and according to current 
good medical practice. Any medication administered for the treatment of an SAE / 
pIMDs should be recorded in Expedited Adverse Event Report of the subject’s eCRF 
(refer to Section 6.6). 
7.7. 
Unblinding 
GSK Biologicals’ policy (which incorporates ICH E2A guidance, EU Clinical Trial 
Directive and US Federal Regulations) is to unblind the report of any SAE which is 
unexpected and attributable/suspected to be attributable to the study vaccine, prior to 
regulatory reporting. The GSK Biologicals’ Central Safety Physician is responsible for 
unblinding the treatment assignment in accordance with the specified timeframes for 
expedited reporting of SAEs (refer to Section 7.4.1). 
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7.9. 
Subject card 
Study subjects must be provided with the address and telephone number of the main 
contact for information about the clinical study. 
The investigator (or delegate) must therefore provide a “subject card” to each subject. In 
an emergency situation this card serves to inform the responsible attending physician that 
the subject is in a clinical study and that relevant information may be obtained by 
contacting the investigator. 
Subjects must be instructed to keep subject cards in their possession at all times during 
the study duration. 
7.10. 
Holding rules and safety monitoring 
The study will be conducted in 2 parts, i.e., Part A in young adults aged 18-40 years and 
Part B in older adults aged 60-80 years. Part B of the study will be conducted in a 2-step 
staggered design to ensure maximum safety of the participating subjects. Figure 1 
provides an overview of the IDMC safety evaluations in each study part and staggered 
enrolment in Part B. 
The investigator is not permitted to start vaccinating the subjects in the next step in each 
part until the Sponsor communicates the favorable outcome of the respective safety 
evaluations by the IDMC. Screening procedures may however be performed to facilitate 
enrolment in Steps 1 and 2 of Part B. 
The IDMC safety evaluations will be performed based on unblinded data up to the 
specific time point of the evaluation, including: 
• 
Data as clean as possible;  
• 
Hematology and biochemistry parameters post-vaccination; 
• 
All safety data available by the time of a given safety evaluation. 
In addition, if any safety concern is identified by the investigator (i.e., meeting of holding 
rules see Section 7.10.4] or any other safety concern), he/she should inform GSK 
Biologicals immediately (within 24 hours), and vaccination may be put on hold at all 
sites as a consequence. 
Refer to APPENDIX D for an overview of the communication flow in case a holding rule 
is met, as identified by the Investigator or IDMC. 
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7.10.1. 
Part A 
• 
Approximately 48 young adults (12 per group) aged 18-40 years will be enrolled 
and vaccinated with the first dose with an interval of at least 60 minutes between 
participants to allow efficient suspension of vaccination in case of any safety 
concern. 
• 
If any safety concern is identified by the investigator (i.e., meeting of holding rules 
1a-1d [see Table 29] or any other safety concern), he/she should inform GSK 
Biologicals immediately (within 24 hours), and vaccination may be put on hold at all 
sites as a consequence. 
• 
All available data from Part A participants vaccinated with the first dose will be 
reviewed in a first IDMC meeting. This IDMC will perform a safety evaluation of all 
available data collected up to 30 days post-Dose 1. Holding rules described in 
Table 29 will apply.  
• 
If the IDMC evaluation outcome is favorable, the participants in Part A will be 
vaccinated with the second dose with an interval of at least 60 minutes between 
participants, to allow efficient suspension of vaccination in case of any safety 
concern. The vaccination in Part B of the study will also be initiated in case of 
favorable outcome of this first IDMC meeting (see Section 7.10.2.1). 
• 
All available data from participants in Part A who received the second vaccine dose 
will be reviewed in a second IDMC meeting. This IDMC will evaluate the safety 
data up to 7 days after Dose 2. Holding rules described in Table 29 will apply.  
• 
All participants will be closely observed for a minimum of 60 minutes after each 
vaccination. 
7.10.2. 
Part B 
7.10.2.1. 
Part B - Step 1 
• 
Upon favorable outcome of the first IDMC evaluation in Part A, a first wave of study 
participants aged 60-80 years (N100, approximately 10 per group, see Section 
7.10.5) will be enrolled and vaccinated with the first dose with an interval of at least 
60 minutes between participants, to allow efficient suspension of vaccination in case 
of any safety concern. 
• 
All participants will be closely observed for a minimum of 60 minutes after each 
vaccination. 
• 
If any safety concern is identified by the investigator (i.e., meeting of holding rules 
1a-1d see Table 29] or any other safety concern), he/she should inform GSK 
Biologicals immediately (within 24 hours), and vaccination may be put on hold at all 
sites as a consequence. 
• 
All available data from those 100 participants vaccinated with the first dose will be 
reviewed in a third IDMC meeting. This IDMC will perform a safety evaluation of 
all available data collected up to 7 days post-Dose 1. Holding rules described in 
Table 29 will apply.  
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• 
If the outcome of the second IDMC evaluation in Part A as well as this third IDMC 
evaluation in Part B is favorable, participants from Step 1 of Part B who received the 
first vaccine dose will receive the second dose and Step 2 of Part B will follow (see 
Section 7.10.2.2). 
The second vaccine dose in Step 1 of Part B should be administered with an interval 
of at least 60 minutes between participants, to allow efficient suspension of 
vaccination in case of any safety concern. 
7.10.2.2. 
Part B - Step 2 
• 
Upon favorable outcome of the second IDMC evaluation in Part A as well as the 
third IDMC evaluation in Part B, the remaining study participants (N900, 
approximately 90 per group) will be enrolled and vaccinated with the first dose. The 
60-minute interval for vaccination between participants does not apply at this step.  
• 
If any safety concern is identified by the investigator (i.e., meeting of holding rules 
1a-1c see Table 30] or any other safety concern), he/she should inform GSK 
Biologicals immediately (within 24 hours), and vaccination may be put on hold at all 
sites as a consequence. 
• 
A fourth IDMC meeting will review safety data collected up to 7 days post-Dose 2 
from participants in Step 1 who received the second vaccine dose. Holding rules 
described in Table 29 will apply. In addition, the IDMC will review all available 
safety data up to 7 days post-Dose 1 of all study participants enrolled and vaccinated 
at the time of this IDMC analysis. Holding rules described in Table 30 will apply.  
If this fourth IDMC evaluation outcome is favorable, the study participants enrolled in 
Step 2 will be administered the second vaccine dose. 
All participants will be closely observed for a minimum of 60 minutes after each 
vaccination. 
7.10.2.3. 
Additional safety monitoring in Part B 
A fifth IDMC meeting will be performed after all subjects in Part B have received their 
first dose. All available safety data up to 7 days post-Dose 1 of all participants enrolled 
and vaccinated in Part B will be reviewed. Holding rules described in Table 30 will 
apply. 
A sixth IDMC meeting will review all available safety data up to 7 days post-Dose 2 
when at least 50% to 75% of participants enrolled in Part B have received the second 
vaccine dose. Holding rules described in Table 30 will apply. 
If any safety concern is identified by the investigator or the sponsor, ad-hoc safety 
evaluations by the IDMC may be performed. 
During the persistence phase of Part B (Epoch 003), 2 IDMC meetings will be planned 
with an interval of approximately 6 months. 
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Figure 1 
Overview of IDMC safety evaluations in each study part and staggered enrolment in Part B 
 
SE: Safety evaluation by IDMC 
* The sixth IDMC evaluation will be based on all available safety data up to 7 days post-Dose 2 (data will be as clean as possible including Day 68 hematology and biochemistry 
parameters) when at least 50% to 75% of participants enrolled in Part B have received the second vaccine dose.  
 
Dose 1
(Day 1)
STEP 1
SE 3
up to Day 8
Favourable
outcome
STEP 2
Randomization
(1:1:1:1:1:1:1:1:1:1)
N=10 per group
Randomization
(1:1:1:1:1:1:1:1:1:1)
N=90 per group
Dose 1
(Day 1)
Favourable
outcome
Dose 2
(Day 61)
PART B
PART A
Dose 1
(Day 1)
Favourable
outcome
Randomization
(1:1:1:1)
N=12 per group
Favourable
outcome
SE 4
up to Day 68
Dose 2
(Day 61)
SE 1
up to Day 30
SE 5
up to Day 8
SE 6*
up to Day 68
Dose 2
(Day 61)
SE 2
up to Day 68
Favourable
outcome
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7.10.3. 
Safety evaluation by the IDMC 
As the investigational RSV vaccine formulations will be administered for the first time in 
humans, an IDMC will be appointed and operating under a charter, in addition to the 
existing project’s Safety Review Team. Safety holding rules have been defined. During 
the vaccination phase of the study (Parts A and B), there will be 6 planned IDMC 
meetings to review safety data. If considered as needed, ad hoc IDMC meetings between 
the planned meetings will be scheduled. During the persistence phase in Part B, the 
IDMC will meet at least every 6 months. 
The IDMC will review the protocol and Statistical Analysis Plan (SAP). Meetings will be 
documented and minutes of open sessions of the IDMC meetings made available to the 
sponsor. The IDMC may, if deemed necessary, convene a meeting with, or request 
further information from GSK Biologicals’ designated project representatives at any 
stage of the study. 
The IDMC will conduct unblinded reviews of all available safety data (as clean as 
possible) from the present study, while taking into account any other findings that could 
have an impact on the safety of the subjects, and will determine whether there is a safety 
signal that needs to be escalated to the sponsor.  
In addition to the RSV program targeting older adults, GSK is also developing a RSV 
vaccine for infant immunization (RSV maternal program) using the same antigen. An 
RSV maternal study may be running at a time that can overlap with the conduct of this 
study. Any relevant safety information arising from this maternal study will be shared 
with the IDMC.  
7.10.3.1. 
Outcome of the IDMC safety evaluation 
If no safety signal is observed, the favorable outcome of the safety evaluations will be 
documented and provided in writing, authorizing the investigator to proceed with the next 
step as defined in Figure 1. 
If a safety signal is observed during the safety evaluations or if any of the holding rules 
2a-2c is met, the IDMC Chair (or his/her representative) is responsible for the urgent 
communication to the sponsor, including the rationale for the decision to put the 
vaccination on hold or not. The study CRDL 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.  
7.10.3.2. 
Process of suspension of vaccination and/ or study modification 
In the event that a safety signal is observed, the sponsor might decide to cancel 
vaccination of all groups or selected groups. 
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In this case, for impacted groups: 
• 
Subjects who were already vaccinated will not receive the second study vaccine dose 
(if not yet administered) and continue all other visits as planned. 
• 
Subjects who signed an informed consent but did not receive any study vaccine will 
be informed that their study participation will be stopped. 
7.10.4. 
Study holding rules for the vaccination phase 
The safety holding rules for the vaccination phases of the study are defined in Table 29 
and Table 30. 
For subjects enrolled in Part A and in Step 1 of Part B, holding rules 1a-1d from Table 29 
will be assessed by the investigator on a continuous basis and meeting any of these 
holding rules will trigger a hold of vaccination irrespective of number of subjects 
enrolled and/or timing of the event relative to vaccination. Holding rules 2a-2c from 
Table 29 will be assessed by the IDMC during the safety evaluations on unblinded data. 
For subjects enrolled in Step 2 of Part B, holding rules 1a-1c from Table 30 will be 
assessed by the investigator on a continuous basis and meeting any of these holding rules 
will trigger a hold of vaccination, irrespective of the number of subjects enrolled and/or 
timing of the event relative to vaccination. For the overall safety data assessment after 
Dose 1 or 2 (in all the subjects who received the respective dose at that point), holding 
rules 1d, 2a-2c from Table 30 will be assessed by the IDMC during the safety evaluations 
on unblinded data. 
The sponsor may decide to stop vaccination in all groups or only in a specific study group 
while proceeding with vaccination in the other groups.  
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Table 29 
Study holding rules for Part A and Part B Step 1 (Dose 1 and Dose 2) 
Holding 
Rule 
Event 
Number of 
subjects/group/dose 
Part A  
Part B - 
Step 1 
1a 
Death or any life-threatening SAE  
≥ 1 
≥ 1 
1b 
Any non-life-threatening SAE that cannot reasonably be attributed to a 
cause other than vaccination 
≥ 1 
≥ 1 
1c 
Any local or general solicited AE leading to hospitalization, or fever > 
40°C (104°F) that cannot reasonably be attributed to a cause other than 
vaccination, or necrosis at the injection site, within the 7-day (Day 1-7) 
post-vaccination period 
≥ 1 
≥ 1 
1d 
Any withdrawal from the study (by investigator or subject request) 
following a Grade 3 AE that cannot reasonably be attributed to a cause 
other than vaccination 
≥ 1 
≥ 1 
2a 
Any Grade 3 solicited local AE lasting 48h or more in an investigational 
RSV vaccine group, within the 7-day (Day 1-7) post-vaccination period  
≥ 3/12 
(≥ 25%)* 
≥ 2/10** 
2b 
Any Grade 3 solicited general AE lasting 48h or more in an 
investigational RSV vaccine group, that cannot reasonably be attributed to 
a cause other than vaccination, within the 7-day (Day 1-7) post-
vaccination period 
≥ 3/12  
(≥ 25%)* 
≥ 2/10** 
2c 
Any  Grade 3 unsolicited AE in an investigational RSV vaccine group, 
that cannot reasonably be attributed to a cause other than vaccination, 
within the 7-day (Day 1-7) post-vaccination period  
OR 
Any  Grade 3 abnormality in pre-specified hematological or biochemical 
laboratory parameters in an investigational RSV vaccine group, up to the 
Day 8 post-vaccination visit.† 
≥ 3/12  
(≥ 25%)* 
≥ 2/10** 
† Grading of laboratory parameters will be based on the FDA Guidance for Industry “Toxicity Grading Scale for Healthy 
Adults and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials” (refer to APPENDIX C). Those 
laboratory parameters not included in the FDA Toxicity Grading Scale will not be graded. 
* In case of slow recruitment of subjects enrolled in Part A, the IDMC evaluations after each dose can be performed 
before all 48 subjects reach their Day 31 visit but based on no less than a total of 32 subjects (at least 8 per group). In 
this situation, holding rules 2a-2c will be reached when 2/8 (or 3/9, 3/10, 3/11) subjects have reported the specific 
endpoint in one group. 
** In case of slow recruitment of subjects enrolled in Step 1 of Part B, the IDMC evaluations after each dose can be 
performed before all 100 subjects reach their Day 8 visit but based on no less than a total of 80 subjects (at least 8 per 
group). In this situation, holding rules 2a-2c will be reached when 2/8 (or 2/9) subjects have reported the specific 
endpoint in one group. 
The holding rules described in Table 29 for participants enrolled in Part A are applicable 
during the first and second planned IDMC meetings, where safety data after Dose 1 and 2 
from these subjects are evaluated.  
The holding rules described in Table 29 for participants enrolled in Step 1 of Part B are 
applicable during the third and fourth planned IDMC meetings, where safety data after 
Dose 1 and 2 from these subjects are evaluated. These holding rules have been written 
under the assumption that the safety data of all subjects enrolled in Step 1 of Part B will 
be available. If the data from all subjects are not available, the holding rules will be 
assessed on a pro-rata basis, however the IDMC evaluation will not be performed with 
data from less than 80 subjects. 
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Table 30 describes the holding rules applicable for the whole study population (overall 
safety data after each dose) during the fourth, fifth and sixth planned IDMC meetings. 
Of note, no formal holding rules will be applied for other safety data such as: 
• 
SAEs that are not life-threatening and are not attributed to the study vaccination, 
• 
Missed visits due to vaccine-related AEs, 
• 
Grade 1 and Grade 2 solicited, unsolicited AEs in the 7-day follow-up period, 
unsolicited AEs collected from Day 8 to Day 30 after vaccination. 
However, these data, if available, will also be reviewed by the IDMC in order to allow 
for an overall assessment of the benefit/ risk ratio of vaccination (Amended, 13 May 
2020). 
Table 30 
Study holding rules for Part B (Steps 1 and 2 pooled) 
Holding 
Rule 
Event 
Number of 
subjects/group/ 
dose 
1a 
Death or any life-threatening SAE  
≥ 1 
1b 
Any non-life-threatening SAE that cannot reasonably be attributed to a cause 
other than vaccination 
≥ 1 
1c 
Any local or general solicited AE leading to hospitalization, or fever > 40°C 
(104°F) that cannot reasonably be attributed to a cause other than vaccination, 
or necrosis at the injection site, within the 7-day (Day 1-7) post-vaccination 
period 
≥ 1 
1d 
Any withdrawal from the study (by investigator or subject request) following a 
Grade 3 AE that cannot reasonably be attributed to a cause other than 
vaccination 
≥ 25% 
2a 
Any Grade 3 solicited local AE lasting 48h or more in an investigational RSV 
vaccine group, within the 7-day (Day 1-7) post-vaccination period  
≥ 25% 
2b 
Any Grade 3 solicited general AE lasting 48h or more in an investigational 
RSV vaccine group, that cannot reasonably be attributed to a cause other than 
vaccination, within the 7-day (Day 1-7) post-vaccination period 
≥ 25% 
2c 
Any  Grade 3 unsolicited AE in an investigational RSV vaccine group, that 
cannot reasonably be attributed to a cause other than vaccination, within the 7-
day (Day 1-7) post-vaccination period 
OR 
Any  Grade 3 abnormality in pre-specified hematological or biochemical 
laboratory parameters in an investigational RSV vaccine group, up to the Day 
8 post-vaccination visit.† 
≥ 25% 
† Grading of laboratory parameters will be based on the FDA Guidance for Industry “Toxicity Grading Scale for Healthy 
Adults and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials” (refer to APPENDIX C). Those 
laboratory parameters not included in the FDA Toxicity Grading Scale will not be graded. 
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7.10.5. 
Risk assessment 
7.10.5.1. 
Part A 
Figure 2 gives the probability of not meeting holding rule 1 and 2 for 12 subjects per 
study group in Part A. 
Figure 2 
Evaluations based on 12 subjects - Risk assessment curves for 
Part A 
 
The above figure illustrates that, with 12 subjects per study group: 
• 
Each holding rule 1a-1d has more than 89% chance of not being met for vaccination 
with a true incidence rate below 1% and has more than 70% chance of being met for 
vaccination with a true incidence rate above 10%. 
• 
Each holding rule 2a-2c has more than 89% chance of not being met for vaccination 
with a true incidence rate below 10% and more than 60% chance of being met for 
vaccination with a true incidence rate above 25%. 
In case of slow recruitment of subjects enrolled in Part A, the IDMC evaluations after 
each dose can be performed before all 48 subjects reach their Day 31 visit but based on 
no less than a total of 32 subjects (approximately 8 per group). In this situation, holding 
rules 2a-2c will be reached when 2/8 (or 3/9, 3/10, 3/11) subjects have reported the 
specific endpoint in one group (see Figure 4). 
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7.10.5.2. 
Part B 
Figure 3 gives the probability of not meeting holding rule 1 and 2 for 10 subjects per 
study group in Step 1 of Part B. 
Figure 3 
Evaluations based on 10 subjects - Risk assessment curve for one 
formulation based on the proposed safety holding rules for Part B - 
Step 1 
 
The above figure illustrates that, with 10 subjects per study group: 
• 
Each holding rule 1a-1d has more than 90% chance of not being met for vaccination 
with a true incidence rate below 1% and has more than 65% chance of being met for 
vaccination with a true incidence rate above 10%. 
• 
Each holding rule 2a-2c has more than 80% chance of not being met for vaccination 
with a true incidence rate below 8% and more than 75% chance of being met for 
vaccination with a true incidence rate above 25%. 
In case of slow recruitment of subjects enrolled in Step 1 of Part B, the IDMC 
evaluations after each dose can be performed before all 100 subjects reach their Day 7 
visit but based on no less than a total of 80 subjects (approximately 8 per group). In this 
situation, holding rules 2a-c will be reached when 2/8 (or 2/9) subjects have reported the 
specific endpoint in one group. 
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Figure 4 illustrates that, with 8 subjects per study group in Step 1 of Part B: 
• 
Each holding rule 1a-1d has more than 90% chance of not being met for vaccination 
with a true incidence rate below 1% and has more than 55% chance of being met for 
vaccination with a true incidence rate above 10%. 
• 
Each holding rule 2a-2c has more than 80% chance of not being met for vaccination 
with a true incidence rate below 10% and more than 60% chance of being met for 
vaccination with a true incidence rate above 25%. 
Figure 4 
Evaluations based on 8 subjects - Risk assessment curve for one 
formulation based on the proposed safety holding rules for Part B - 
Step 1 
 
Figure 5 illustrates the chance of not meeting the holding rule during the entire enrolment 
phase in Part B (after 50, 75 and 100 subjects per group) depending on the true incidence 
rate. 
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Figure 5 
Risk assessment curve for the Part B study population for one 
formulation based on the proposed safety holding rules (25%) 
 
8. 
RTI SURVEILLANCE DURING PART B OF THE STUDY 
RTI surveillance comprises active and passive surveillance and will only be carried out 
during Part B of the study. 
8.1. 
Active surveillance 
Active surveillance will only be carried out during the RSV seasons (approximately from 
October to March) throughout the entire Part B of the study. Study participants will be 
contacted by the investigator/study staff every 2 weeks to identify if they experience RTI 
symptoms (e.g., cough, runny nose, fever or difficulty to breath). 
In case of RTI symptoms (at least 3) reported by the subject, the subject will be asked to 
collect a nasal swab at home within 48 hours after the start of symptoms and contact the 
investigator/study staff, who will schedule an assessment visit for nasal and throat swab 
specimen collection by qualified staff from the study team. The assessment visit should 
take place as soon as possible after the start of symptoms (ideally within 48 hours, but no 
later than 7 days). Episodes should be treated accordingly to local standard of care. 
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In the event that it is not possible to schedule an assessment visit, the assessment visit 
page of the eCRF should be filled in as completely as possible using available medical 
records. 
8.2. 
Passive surveillance 
Passive surveillance will only be carried out during the RSV seasons (approximately 
from October to March) throughout the entire Part B of the study. Study participants will 
be instructed to contact the investigator/study staff in case of RTI symptoms (e.g., cough, 
runny nose, fever or difficulty to breath).  
In case of RTI symptoms (at least 3) reported by the subject, the subject will be asked to 
collect a nasal swab at home within 48 hours after the start of symptoms and contact the 
investigator/study staff, who will schedule an assessment visit for nasal and throat swab 
specimen collection by qualified staff from the study team. The assessment visit should 
take place as soon as possible after the start of symptoms (ideally within 48 hours, but no 
later than 7 days). Episodes should be treated according to local standard of care. 
In the event that it is not possible to schedule an assessment visit, the assessment visit 
page of the eCRF should be filled in as completely as possible using available medical 
records. 
8.3. 
Assessment Visit for potential RSV-RTI 
The purpose of the Assessment Visit for potential RSV-RTI is to objectively document 
signs and symptoms (e.g., cough, runny nose, fever or difficulty to breath) by an 
appropriately qualified person (i.e., medical or nursing) and to take nasal and throat 
swabs for detection of RSV infection. The visit should take place as soon as possible after 
the start of symptoms (ideally within 48 hours, but no later than 7 days).  
• 
Assessment visits may take place in the study participant’s home, the investigator’s 
clinical facility or a medical facility as appropriate to the circumstances in the 
judgment of the investigator. 
• 
If the reported symptoms are already of a level of severity that urgent care is 
indicated, the study participant should be redirected to the proper location to receive 
this care (e.g. Emergency Room) and an assessment visit could be scheduled to take 
place there at a suitable time.  
• 
For self-collection as well as staff-collection, swabs for analysis at sponsor 
laboratory should be collected when subjects show at least 3 of the following 
signs/symptoms: 
− 
Nasal congestion, 
− 
Sore throat, 
− 
Earache, 
− 
New or worsening cough, 
− 
New or worsening sputum, 
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− 
Dyspnea, 
− 
Rhinorrhea, 
− 
Wheezing (whistling, musical or puffing sound made on exhalation) or 
worsening of wheezing, 
− 
Rales (crackles), 
− 
Rhonchi (sound with musical pitch during inspiration or expiration), 
− 
Fever (temperature of  37.5°C) or feeling feverish.  
• 
During the assessment visit, the investigator/study staff will evaluate the clinical 
signs and symptoms of the RTI and measure the subject’s resting vital signs 
(systolic/diastolic blood pressure, pulse oximetry, heart rate, respiratory rate after at 
least 10 minutes of rest) and temperature. RTI symptoms include, but may not be 
limited to, the following: 
− 
Upper respiratory symptoms: nasal congestion, sore throat, rhinorrhea, 
earache. 
− 
Lower respiratory symptoms: new or worsening cough, new or worsening of 
sputum production, dyspnea, wheezing or worsening of wheezing, rales 
(crackles), rhonchi. 
− 
Systemic symptoms: myalgia, arthralgia, fatigue, headache, decreased appetite, 
feverishness, pain (localized at chest or abdomen at respiration). 
Signs and symptoms and onset date of first symptom should be recorded within the 
RTI episode screen in the eCRF. 
• 
Study participants will be instructed to contact the study staff if the severity of the 
already existing symptoms increases or if they develop difficulty in breathing or 
wheezing, and this may lead to a repeat assessment visit upon the judgment of the 
investigator. 
• 
The status and evolution of the case will be followed until case resolution, as per 
routine practice. 
• 
RTI data will be entered in the eCRF: 
− 
A new episode number and section will be created in the eCRF for each RTI 
episode. 
− 
All data pertaining to a same episode (including date of onset and end date) will 
be entered under the same eCRF episode number, even if observations are 
consolidated from several visits or contacts. 
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9. 
SUBJECT COMPLETION AND WITHDRAWAL 
9.1. 
Subject completion 
A subject who returns for the concluding visit foreseen in the protocol is considered to 
have completed the study. 
9.2. 
Subject withdrawal 
Withdrawals will not be replaced. 
9.2.1. 
Subject withdrawal from the study 
From an analysis perspective, a ‘withdrawal’ from the study refers to any subject who did 
not come back for the concluding visit foreseen in the protocol.  
All data collected until the date of withdrawal/last contact of the subject will be used for 
the analysis. 
A subject is considered a ‘withdrawal’ from the study when no study procedure has 
occurred, no follow-up has been performed and no further information has been collected 
for this subject from the date of withdrawal/last contact. 
Investigators will make an attempt to contact those subjects who do not return for 
scheduled visits or follow-up (e.g., 3 telephone calls and a certified letter to the last 
known address).  
Information relative to the withdrawal will be documented in the eCRF. The investigator 
will document whether the decision to withdraw a subject from the study was made by 
the subject himself/herself or by the investigator, as well as which of the following 
possible reasons was responsible for withdrawal: 
• 
Serious adverse event. 
• 
Unsolicited non-serious adverse event. 
• 
Solicited adverse event 
• 
Protocol violation (specify). 
• 
Consent withdrawal, not due to an adverse event*. 
• 
Moved from the study area. 
• 
Lost to follow-up. 
• 
Other (specify). 
*In case a subject is withdrawn from the study because he/she has withdrawn consent, the 
investigator will document the reason for withdrawal of consent, if specified by the 
subject, in the eCRF. 
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Subjects who are withdrawn from the study because of SAEs/AEs must be clearly 
distinguished from subjects who are withdrawn for other reasons. Investigators will 
follow subjects who are withdrawn from the study as result of an SAE/AE until 
resolution of the event (see Section 7.5.1.2). 
9.2.2. 
Subject withdrawal from study vaccine 
A ‘withdrawal’ from the study vaccine(s) refers to any subject who does not receive the 
complete treatment, i.e., when no further planned dose is administered from the date of 
withdrawal. A subject withdrawn from the study vaccine(s) may not necessarily be 
withdrawn from the study as further study procedures or follow-up may be performed 
(safety or immunogenicity) if planned in the study protocol.  
Information relative to premature discontinuation of the study vaccine(s) will be 
documented on the Vaccine Administration screen of the eCRF. The investigator will 
document whether the decision to discontinue further vaccination was made by the 
subject himself/herself or by the investigator, as well as which of the following possible 
reasons was responsible for withdrawal: 
• 
SAE. 
• 
Unsolicited non-serious AE. 
• 
Solicited AE. 
• 
Not willing to be vaccinated 
• 
Other (specify). 
9.3. 
Screen and baseline failures 
Screening failures are defined as subjects who are withdrawn from the study after giving 
informed consent, but who do not meet the inclusion and exclusion criteria. 
The following information will be collected for screening failures: 
• 
Informed consent. 
• 
Inclusion/exclusion criteria. 
• 
Demographic data. 
• 
Blood samples for hematology and biochemistry. 
• 
SAEs related to study participation, or to a concurrent GSK medication/vaccine. 
• 
Screening conclusion. 
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10. 
STATISTICAL METHODS 
The analysis described in this section will be presented by RSV vaccine formulation 
(referred as “group”, based on Steps 1 and 2 of Part B pooled), for Part A and Part B 
separately.  
10.1. 
Primary endpoints 
For Part A and Part B: 
• 
Occurrence of AEs from first vaccination up to 30 days after the second vaccination 
(Day 91): 
− 
Occurrence of each solicited local and general AE during a 7-day follow-up 
period (i.e., on the day of vaccination and 6 subsequent days) after each 
vaccination.  
− 
Occurrence of any unsolicited AE during a 30-day follow up period (i.e., on the 
day of vaccination and 29 subsequent days) after each vaccination.  
− 
Occurrence of any hematological (erythrocytes, WBC and differential count, 
platelets count and hemoglobin level) and biochemical (ALT, AST, creatinine, 
BUN and uric acid) laboratory abnormalities at Days 1, 8, 61 and 68. 
− 
Occurrence of all Grade 3 non-serious AEs (solicited and unsolicited) during the 
30-day follow-up period after each vaccination. 
− 
Occurrence of SAEs from Dose 1 up to 30 days after the second vaccine dose 
(Day 91).  
For Part B only: 
− 
Occurrence of pIMDs from Dose 1 up to 30 days after the second vaccine dose 
(Day 91). 
10.2. 
Secondary endpoints 
For Part A and Part B: 
• 
Humoral immune response with respect to components of the investigational vaccine 
at pre-vaccination (Day 1), 30 days post-Dose 1 (Day 31), on the day of second 
vaccination (Day 61) and 30 days post-Dose 2 (Day 91):  
− 
Neutralizing antibody titers against RSV serotype A. 
− 
RSVPreF3-specific IgG antibody concentrations.  
• 
Cell-mediated immune response profile with respect to components of the 
investigational vaccine at pre-vaccination (Day 1), 30 days post-Dose 1 (Day 31), 
pre-Dose 2 (Day 61) and 30 days post-Dose 2 (Day 91):  
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− 
Frequency of RSVPreF3-specific CD4+ T-cells identified as expressing at least 
2 markers among IL-2, CD40L, TNF-, IFN- in vitro. 
For Part B only: 
• 
Occurrence of RSV-associated RTI (as measured by qRT-PCR in nasal/throat swab 
samples collected during the assessment visit for potential RSV-RTI) during the 
RSV seasons, up to the end of follow-up. 
• 
Occurrence of SAEs from Dose 1 up to the end of follow-up.  
• 
Occurrence of pIMDs from Dose 1 up to the end of follow-up.  
10.3. 
Tertiary endpoints 
For Part A and Part B: 
• 
Cell-mediated immune response profile with respect to components of the 
investigational vaccine at pre-vaccination (Day 1), 30 days post-Dose 1 (Day 31), 
pre-Dose 2 (Day 61) and 30 days post-Dose 2 (Day 91): 
− 
Frequency of RSVPreF3-specific CD4+ and/or CD8+ T-cells identified as 
expressing one or any combination of immune marker(s) in vitro.  
For Part B only: 
• 
Humoral immune response with respect to components of the investigational vaccine 
at pre-vaccination (Day 1) and 30 days post-Dose 2 (Day 91): 
− 
Neutralizing antibody titers against RSV serotype B in all subjects.  
− 
RSVPreF3 RSB1 specific antibody concentrations in a subset of subjects who 
received the selected vaccine formulation or placebo. (Amended, 13 May 2020) 
• 
Cell-mediated immune response profile with respect to components of the 
investigational vaccine at pre-vaccination (Day 1), 30 days post-Dose 1 (Day 31) and 
30 days post-Dose 2 (Day 91):  
− 
Frequency of RSVPreF3-specific memory B-cells in a subset of subjects who 
received the selected level of antigen dose (3 RSV vaccine formulations) or 
placebo. 
• 
Persistence of the humoral immune response with respect to components of the 
investigational vaccine at Months 8 and 14: 
− 
Neutralizing antibody titers against RSV serotype A. 
− 
RSVPreF3-specific IgG antibody concentrations.  
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• 
Persistence of the cell-mediated immune response profile with respect to components 
of the investigational vaccine: 
− 
Frequency of RSVPreF3-specific CD4+ and/or CD8+ T-cells identified as 
expressing one or any combination of immune marker(s) in vitro, in all subjects 
(Month 8) and in a subset of subjects who received the selected level of antigen 
dose (3 RSV vaccine formulations) or placebo (Month 14). 
− 
Frequency of RSVPreF3-specific CD4+ T-cells identified as expressing at least 
2 markers among IL-2, CD40L, TNF-, IFN- in vitro, in all subjects (Month 8) 
and in a subset of subjects who received the selected level of antigen dose (3 
RSV vaccine formulations) or placebo (Month 14). 
− 
Frequency of RSVPreF3-specific memory B-cells at Month 14 in a subset of 
subjects who received the selected level of antigen dose (3 RSV vaccine 
formulations) or placebo. 
• 
Any further exploratory immunology to detect RSV-related immune responses, such 
as but not limited to:  
− 
Antibodies against specific protein F epitopes.  
− 
Potential new immunological markers for protection.  
− 
Cross-reactive neutralizing antibody titers against hMPV.  
• 
Occurrence of RSV-associated RTI, including co-infections with other respiratory 
viruses (as measured by multiplex PCR in self-collected nasal swab samples and 
nasal/throat swab samples collected during the assessment visit for potential RSV-
RTI) during the RSV seasons.  
• 
Occurrence of RSV-associated RTI as measured by qRT-PCR in self-collected nasal 
swab samples during the RSV seasons, up to the end of follow-up. 
10.4. 
Determination of sample size 
In Part A, the sample size of 12 subjects per group would provide a probability of 80% or 
90% to observe at least one AE, if the true AE rate is 12.6% or 17.5%, respectively. 
In Part B, the sample size of 100 subjects per group would provide a probability of 80% 
or 90% to observe at least one AE, if the true AE rate is 1.6% or 2.3%, respectively.  
The study is designed as a factorial design with 2 factors resulting in 9 RSV formulations 
(~100 subjects per RSV formulation in Part B, Step 1 and Step 2 pooled, referred as 
“group” in text below) (see Table 31). In addition, a placebo group will be evaluated 
(~100 subjects, Step 1 and Step 2 pooled).  
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Table 31 
Factorial design 
 
No adjuvant (Plain) 
Factor B: Adjuvant 
AS01E 
AS01B 
Factor A: Antigen dose 
30 µg 
100 
100 
100 
60 µg 
100 
100 
100 
120 µg 
100 
100 
100 
Considering a 10% rate of non-evaluable subjects, it is assumed that approximately 
90 subjects per group will be evaluable for the analysis of RSV-A neutralizing antibody 
titers and for the CD4+ T-cells response. 
The 9 RSV formulations will be first compared to the Placebo in terms of RSV-A 
neutralizing antibody titers at Day 91 using the Dunnett’s method via a one way ANOVA 
model. The sample size of 90 subjects per group (in 10 groups) achieves  90% power to 
detect a difference of at least 2.3-fold (alpha=0.025, SD=0.4, CV=115.6%, PASS 12.0.10 
Multiple comparisons Analysis using Dunnett’s adjustment for multiplicity).  
The effect of the second vaccination will then be evaluated by comparing the response 
one month post-Dose 2 (Day 91) and one month post-Dose 1 (Day 31) in terms of 
RSVPreF3-specific CD4+ T-cells and RSV-A neutralizing antibodies. This comparison 
will be done on the groups pooled according to their adjuvant content (3 groups of 270 
subjects: AS01B, AS01E and Plain). Table 32 below presents the power and fold increase 
that can be detected with a sample size of 270 subjects per pooled group. The sample size 
of 270 subjects per group achieves 90% power to detect a difference of at least 1.2 fold 
between Dose 2 and Dose 1. 
Table 32 
Effect of second vaccination: Power and fold increase with a sample 
size of 270 subjects per pooled group  
N/group 
N evaluable/group 
N Pooled groups 
Power 
Fold increase 
100 
90 
270 
90% 
1.2 
 
 
 
80% 
1.17 
Power calculation done in PASS 12.0.10: Paired T-test with alpha=0.025, SD=0.4 (CV=115.6%). 
The effect of the adjuvant will also be evaluated on the same pooled groups (according to 
adjuvant content: AS01B, AS01E, Plain) by comparing sequentially the 2 adjuvanted 
groups to the Plain group, in terms of RSVPreF3-specific CD4+ T-cells and RSV-A 
neutralizing antibody titers at Day 91. Table 33 below presents the power and fold 
increase that can be detected with a sample size of 270 subjects per pooled group. The 
sample size of 270 subjects per group achieves 90% power to detect a difference of at 
least 1.3-fold between one adjuvanted group and the Plain group. 
Table 33 
Effect of adjuvant: Power and fold increase with a sample size of 270 
subjects per pooled group  
N/group 
N evaluable/group 
N Pooled groups 
Power 
Fold increase 
100 
90 
270 
90% 
1.3 
80% 
1.25 
Power calculation done in PASS 12.0.10: Two-sample T-test assuming equal variance, with alpha=0.025, SD=0.4 
(CV=115.6%). 
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Finally, the antigen dose-response will be evaluated in each adjuvanted group in terms of 
RSV-A neutralizing antibody titers and RSVPreF3-specific CD4+ T-cells at Day 91. 
Table 34 below presents the power and fold increase that can be detected with a sample 
size of 90 per group. The sample size of 90 subjects per group would provide 90% power 
to detect a difference of at least 1.56 between 2 groups.  
Table 34 
Antigen dose-response: Power and fold increase with a sample size 
of 90 subjects per group  
N/group 
N evaluable/group 
Power 
Fold increase 
100 
90 
90% 
1.56 
 
 
85% 
1.51 
 
 
80% 
1.47 
Power calculation done in PASS 12.0.10: Two-sample T-test assuming equal variance, with alpha=0.025, SD=0.4 
(CV=115.6%). 
10.5. 
Cohorts for Analyses 
10.5.1. 
Exposed Set 
The Exposed Set (ES) will include all subjects with study vaccine administration 
documented. 
A safety analysis based on the ES will include all vaccinated subjects. 
An immunogenicity analysis based on ES will include all vaccinated subjects for whom 
immunogenicity data are available. 
The ES analysis will be performed per treatment actually administered. 
10.5.2. 
Per-protocol Set for analysis of immunogenicity 
The Per Protocol set (PPS) for analysis of immunogenicity will be defined by time point 
(to include all eligible subjects’ data up to the time of important protocol deviations). The 
PPS will include all evaluable subjects in the ES: 
• 
Meeting all eligibility criteria.  
• 
For whom the administration route of the vaccine was as according to protocol. 
• 
For whom the study vaccine was administered as per protocol. 
• 
Who did not receive a concomitant medication/ product leading to exclusion from a 
PP analysis, as described in Section 6.6.2, up to the considered time point. 
• 
Who did not present with a medical condition leading to exclusion from a PP 
analysis, as described in Section 6.7, up to the considered time point. 
• 
Who complied with the vaccination schedule, as specified in Table 8. 
• 
Who complied with the timings of the post-vaccination blood sampling for immune 
response evaluation, as specified in Table 8. 
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• 
For whom post-vaccination immunogenicity results are available for at least one 
assay component at the corresponding time points. 
10.6. 
Derived and transformed data 
Demography 
• 
For a given subject and a given demographic variable, missing measurements will 
not be replaced. 
Safety 
• 
For a given subject and the analysis of solicited symptoms during the 7-day 
follow-up period after vaccination, missing or non-evaluable measurements will not 
be replaced. Therefore, the analysis of the solicited symptoms based on the ES will 
include only vaccinated subjects with documented safety data (i.e., eDiary 
completed).  
• 
For analysis of unsolicited AEs, SAEs, pIMDs, pregnancies and concomitant 
medications, all vaccinated subjects will be considered. Subjects who did not report 
an event or concomitant medication will be considered as subjects without the event 
or the concomitant medication respectively. 
Immunogenicity 
• 
Any missing or non-evaluable immunogenicity measurement will not be replaced: 
− 
For the within-group assessment, the descriptive analysis performed for each 
assay at each time point will exclude subjects with a missing or non-evaluable 
measurement. Kinetics will be plotted on subjects with results available at all 
time points. 
− 
For the between group assessments, the Analysis of covariance (ANCOVA) 
model will be fitted based on the subjects having a result at both the baseline 
and the considered time point. 
• 
The geometric mean titers (GMTs)/geometric mean concentrations (GMCs) will be 
computed by taking the anti-logarithm of the arithmetic mean of the log10 
transformed titers/concentrations.  
• 
A seronegative subject will be defined as a subject whose antibody 
titer/concentration is below the cut-off value of the assay. A seropositive subject is a 
subject whose antibody titer/concentration is greater than or equal to the cut-off 
value of the assay. 
• 
The description of the handling of data below the lower limit of quantification for 
GMT/GMC calculation and fold increase will be described in the SAP. 
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10.7. 
Analysis of demographics 
Demographic characteristics (age at vaccination in years, gender, race and ethnicity) will 
be summarized by group using descriptive statistics: 
• 
Frequency tables will be generated for categorical variable such as race. 
• 
Mean, median, standard error and range will be provided for continuous data such as 
age. 
The distribution of subjects will be tabulated as a whole and per group and for each age 
category (60-69 years and 70-80 years in Part B only). 
Withdrawal status will be summarized by group using descriptive statistics: 
• 
The number of subjects enrolled into the study as well as the number of subjects 
excluded from PP analyses will be tabulated.  
• 
The numbers of withdrawn subjects will be tabulated according to the reason for 
withdrawal. 
10.8. 
Analysis of safety 
The percentage of subjects with at least one local AE (solicited and unsolicited), with at 
least one general AE (solicited and unsolicited) and with any AE during the 7-day or 
30-day follow-up period will be tabulated with exact 95% confidence interval (CI) after 
each dose and overall. The same computations will be done for Grade 3 AEs, for any AEs 
considered related to vaccination, for Grade 3 AEs considered related to vaccination and 
for Grade 3 non-serious AEs. 
The percentage of subjects with any AE (solicited and unsolicited) resulting in a 
medically attended visit during the 30-day follow-up period will also be tabulated after 
each dose and overall. 
The percentage of subjects reporting each individual solicited local AE (any grade and 
Grade 3) and solicited general AE (any grade, Grade 3, any related and Grade 3 related) 
during the 7-day follow-up period (i.e., on the day of vaccination and 6 subsequent days) 
will be tabulated for each group after each dose and overall.  
For fever, the number and percentage of subjects reporting fever by half degree (°C) 
cumulative increments during the 7-day follow-up period (i.e., on the day of vaccination 
and 6 subsequent days) will be tabulated for each group after each dose and overall. 
Similar tabulations will be performed for any fever with a causal relationship to 
vaccination and for Grade 3 (> 39.0°C/102.2°F) causally related fever. In addition, the 
prevalence of any and Grade 3 fever will be presented graphically over time after each 
vaccination. 
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For each group and for each hematology and biochemistry parameter: 
• 
The percentage of subjects having hematology and biochemistry results below or 
above the laboratory normal ranges will be tabulated by time point. 
• 
The summary of grading post-vaccination will be tabulated versus baseline. (Grades 
will be based on the FDA Guidance for Industry “Toxicity Grading Scale for Healthy 
Adults and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials”, 
see APPENDIX C. Those laboratory parameters not included on FDA Toxicity 
Grading Scale will not be graded). 
The percentage of subjects with any unsolicited AEs during the 30-day follow-up period 
(i.e., on the day of vaccination and 29 subsequent days) with its exact 95% CI will be 
tabulated by group and by Medical Dictionary for Regulatory Activities (MedDRA) 
preferred term. Similar tabulation will be done for Grade 3 unsolicited AEs, for any 
causally related unsolicited AEs, for Grade 3 causally related unsolicited AEs and for 
unsolicited AEs resulting in a medically attended visit. The verbatim reports of 
unsolicited AEs will be reviewed by a physician and the signs and symptoms will be 
coded according to the MedDRA Dictionary for Adverse Reaction Terminology. Every 
verbatim term will be matched with the appropriate Preferred Term. 
The percentage of subjects with at least one report of SAE classified by the MedDRA 
Preferred Terms and reported during the entire study period will be tabulated with exact 
95% CI. SAEs will also be described in details. 
For Part A only, pregnancy and pregnancy outcomes will be listed (if applicable).  
For Part B only, the percentage of subjects with at least one pIMD classified by the 
MedDRA Preferred Terms and reported during the entire study period will be tabulated 
with exact 95% CI. PIMDs will also be described in details. 
The percentage of subjects using concomitant medication (any medication, any 
antipyretic and any antipyretic taken prophylactically, respectively) during the 7-day 
follow-up period (i.e., on the day of vaccination and 6 subsequent days) and during the 
30-day follow-up period (i.e., on the day of vaccination and 29 subsequent days) will be 
summarized by group after each vaccine dose and overall. 
The analysis of safety will also be performed by age category (60-69 years and 70-80 
years in Part B only). 
10.9. 
Analysis of immunogenicity 
The primary analysis will be performed on the PPS for immunogenicity and, if in any 
study group the percentage of vaccinated subjects with serological results excluded from 
the PPS for analysis of immunogenicity is at least 10%, a second analysis will be 
performed on the ES.  
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10.9.1. 
Within groups evaluation - humoral immune response  
For each group, at each time point that blood samples are collected for humoral immune 
response and for each assay (unless otherwise specified):  
In Part A and Part B: 
• 
Percentage of subjects above pre-defined threshold and their exact 95% CI will be 
tabulated. 
• 
GMCs/GMTs and their 95% CI will be tabulated and represented graphically. 
• 
Geometric mean of ratios of antibody titer/concentrations at each individual post-
vaccination time point over pre-vaccination (Day 1) will be tabulated with 95% CI. 
• 
Antibody titer/concentration will be displayed using reverse cumulative curves.  
• 
The ratio of the RSVPreF3 ELISA antibody concentrations over the RSV-A 
neutralizing antibody titers will be computed and tabulated using descriptive 
statistics (Ratio of fold increase Post- over Pre-vaccination). 
In Part B only: 
• 
The distributions of antibody titers/concentrations will be tabulated. 
• 
Individual post-vaccination results (at Days 31, 61 and 91) versus pre-vaccination 
results (Day 1) will be plotted using scatter plots. Results of the placebo group will 
be used as a reference. 
• 
Distribution of the fold increase of the antibody titers/concentrations (post- over pre-
vaccination titers) will be tabulated. 
• 
The kinetics of GMT/GMCs will be plotted as a function of time for subjects with 
results available at all time points. 
The immunogenicity analysis will also be performed by age category (60-69 years and 
70-80 years) in Part B only. The humoral immune response by CMV status before 
vaccination might be explored in Parts A and B. 
10.9.2. 
Within groups evaluation - Cell-mediated immune response  
The following parameters will be summarised by group using descriptive statistics (N, 
geometric mean [GM], min, Q1, median, Q3, max) at each time point during which blood 
samples are collected for CMI:  
In Part A and Part B: 
• 
Frequency of RSVPreF3-specific CD4+ T-cells identified as expressing at least 2 
markers among IL-2, CD40L, TNF-, IFN-, upon in vitro stimulation and 
background substracted, measured by ICS using PBMCs. 
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• 
Frequency of CD4+ and/or CD8+ T-cells expressing any combination of immune 
marker(s) among CD40L, 41BB, IL-2, TNF-α, IFN-γ, IL-13, and IL-17, as 
measured by ICS using PBMCs.  
• 
Geometric mean ratios of frequency of RSVPreF3-specific CD4+ T-cells identified 
as expressing at least 2 marker(s) among IL-2, CD40L, TNF-, IFN- , at each 
post-vaccination time point over pre-vaccination (Day 1) will be tabulated with 95% 
CI.  
In Part B only:  
• 
Frequency of RSVPreF3-specific memory B-cells, as measured by ELISpot using 
PBMCs. 
This will be displayed overall and by pre-vaccination category: <Q1, Q1-Q3, >Q3, where 
Q1/Q3 are respectively the 25th and the 75th percentiles of the results at pre-vaccination 
computed on pooled groups. 
In addition, vaccine response in terms of RSVPreF3-specific CD4+ T-cells expressing at 
least 2 markers among IL-2, CD40L, TNF-, IFN-, will be explored and summarised by 
group. 
The descriptive immunogenicity analysis will also be performed by age category (60-69 
years and 70-80 years) in Part B only. The cell-mediated immune response by CMV 
status before vaccination might be explored in Parts A and B. 
10.9.3. 
Between groups evaluation (Part B only) 
Statistical analyses will be performed to compare the 9 RSV investigational vaccine 
formulations in terms of RSV-A neutralizing antibody titers and RSVPreF3-specific 
CD4+ T-cells at Day 91. 
Additional exploratory comparisons might also be performed on the RSVPreF3 ELISA 
antibody concentrations at Day 91. 
The between-groups analysis will be performed in several steps as follows: 
1. The 9 RSV formulations will be first compared to the Placebo in order to identify 
groups whose means are significantly different from the mean of the Placebo group, 
in terms of RSV-A neutralizing antibody titers at Day 91 (alpha=2.5%, Dunnett’s 
adjustment test for multiplicity).  
2. The effect of the second vaccination will be evaluated by comparing the means one 
month post-Dose 2 (Day 91) and one month post-Dose 1 (Day 31), on the groups 
pooled according to their adjuvant content (AS01B, AS01E and Plain), in terms of 
RSVPreF3-specific CD4+ T-cells and RSV-A neutralizing antibody titers. 
3. The RSV formulations will be then compared using an ANCOVA model. 
Appropriate contrasts will be implemented: 
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− 
To demonstrate the adjuvant effect (on pooled groups according to their 
adjuvant content: AS01B, AS01E, Plain), by testing sequentially AS01B and 
AS01E versus Plain (alpha=2.5% for each test) in terms of CD4+ T-cells 
expressing at least 2 markers and RSV-A neutralizing antibodies at Day 91 and, 
if applicable, by comparing AS01B vs AS01E. 
− 
To demonstrate linearity of increase in immune response when increasing the 
antigen dose in each adjuvanted group in terms of RSV-A neutralizing antibody 
and/or RSVPreF3-specific CD4+ T-cells at Day 91. 
Further ANCOVA t-tests would demonstrate superiority of 120 µg or 60 µg, should a 
quadratic effect be demonstrated. 
10.10. 
Analysis of RTI for Part B 
The analysis will be performed on the ES.  
Any RTI episode for which a visit for the assessment of potential RSV-RTI has been 
performed (with nasal/throat swab sampling) will be considered for the analysis. The 
assessment of RSV infection will be performed using qRT-PCR on nasal/throat swabs 
separately for samples collected by the subject and those collected by an appropriately 
qualified person (i.e., medical or nursing) at the assessment visit. 
The proportion of subjects with at least one RSV-associated RTI (with 95 % CI) will be 
calculated by group. 
Descriptive analyses (mean, median, min, max) of viral load assessed by quantitative 
PCR (RSV-A/B) of RSV-RTI will be performed by study group. 
The incidence rate of all-cause RTI (with 95% CI) will be calculated by group. These will 
also be presented by co-infection identified by multiplex PCR. 
10.11. 
Interpretation of analyses 
The analyses will be descriptive with the aim to characterize the difference in 
safety/reactogenicity or immunogenicity between groups.  
Exploratory comparisons between groups/adjuvants/doses should be interpreted with 
caution considering that there will be no adjustment for multiplicity of endpoints. 
10.12. 
Conduct of analyses 
Any deviation(s) or change(s) from the original statistical plan outlined in this protocol 
will be described and justified in the final study report. 
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10.12.1. 
Sequence of analyses 
In preparation of the planned IDMC evaluations, analyses of all available safety data (as 
clean as possible) will be performed (see Section 7.10 for more information). The blinded 
analyses will be done by the GSK study statistician and distributed to the study team. The 
unblinded analyses will be done by an Independent External Statistician (IES) to maintain 
the study blind and will be shared with IDMC members through a secured folder (refer to 
the IDMC charter). Only the outcome of the IDMC reviews will be communicated to the 
RSV study team (no safety signal or safety signal). No clinical study report will be 
written at this stage. 
The analyses will be performed stepwise: 
• 
A first analysis will be performed on all data available and as clean as possible, when 
data for at least primary and secondary endpoints up to Day 91 are available (except 
for cell-mediated immune response at pre-Dose 2 [Day 61] in Part A and Part B and 
the occurrence of RSV RTI in Part B). This will include results from all subjects in 
Part A and Part B. This analysis will be considered as final for those endpoints. A 
clinical study report will be written. 
At this point, the statistician will be unblinded (i.e., individual subject treatment 
assignments will be available), but no individual listings will be provided to the 
study team. Given that summary safety results may unblind some specific subjects, 
the study will be considered as single-blind from this point onwards, with subjects 
remaining blinded up to study end (Visit 8, Month 14). The investigators will not be 
provided with the individual data listings or with the randomization listings until the 
end of study analysis. 
During the last study visit, blood samples will be collected only from a subset of 
subjects (N460, all subjects in part B1 and subjects who received a selected level 
of antigen dose and Placebo in part B2). Therefore, the investigators, site and 
study staff will be partially unblinded at group level, but not at the individual level.  
In case there will be an extension study planned, with all or a subset of 
participants included, the investigators may be provided with the list of study 
subjects eligible to participate in such study, before the parent study ends. 
Therefore, the investigators, site and study staff will potentially receive an 
individual data listings for a subset. All subjects in this subset may be unblinded 
before the study ends. (Amended, 13 May 2020) 
• 
A second analysis will be performed when all safety data up to Month 8 (Visit 7) are 
available (data as clean as possible). At this time, the following analyses will be 
performed: 
− 
The safety analysis of data up to 6 months post-Dose 2. 
− 
The analysis of all qPCR data available at that time. 
− 
The analysis of any additional laboratory results up to one month post-Dose 2 
that may become available for all planned subjects in Part B. 
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• 
A third immunogenicity analysis will be performed when data for at least tertiary 
immunogenicity endpoints related to persistence (humoral and cell-mediated 
immunogenicity) up to Month 8 are available, to evaluate the persistence up to 
6 months post-Dose 2 in Part B.  
• 
A fourth analysis will be performed when data for at least tertiary immunogenicity 
endpoints related to persistence (humoral and cell-mediated immunogenicity) up to 
Month 14 (Visit 8) are available for the subjects enrolled in Step 1 of Part B. This 
analysis will include any additional laboratory results that may become available at 
that time. 
No individual listings will be provided before the final end of study analysis. 
• 
The final end of study analysis will be performed when all data for at least primary 
and secondary endpoints up to study conclusion are available (Month 14). All 
available tertiary endpoints will also be analysed in this step. Individual listings will 
only be provided at this stage. An integrated clinical study report containing all 
available data will be written and made available to the investigators. 
If the data for tertiary endpoints become available at a later stage, (an) additional 
\analysis/ analyses will be performed. These data will be documented in annex(es) to the 
study report and will be made available to the investigators at that time. 
10.12.2. 
Statistical considerations for interim analyses 
All analyses will be conducted on final data and therefore no statistical adjustment for 
interim analyses is required. 
11. 
ADMINISTRATIVE MATTERS 
To comply with ICH GCP administrative obligations relating to data collection, 
monitoring, archiving data, audits, confidentiality, public disclosure requirements and 
publications must be fulfilled.  
11.1. 
electronic Case Report Form instructions 
A validated GSK defined electronic data collection tool will be used as the method for 
data collection.  
In all cases, subject initials will not be collected nor transmitted to GSK. Subject data 
necessary for analysis and reporting will be entered/transmitted into a validated database 
or data system. Clinical data management will be performed in accordance with 
applicable GSK standards and data cleaning procedures. 
While completed eCRFs are reviewed by a GSK Biologicals’ Site Monitor at the study 
site, omissions or inconsistencies detected by subsequent eCRF review may necessitate 
clarification or correction by the investigator or appropriately qualified designee. In all 
cases, the investigator remains accountable for the study data.  
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The investigator will be provided with a CD-ROM of the final version of the data 
generated at the investigational site once the database is archived and the study report is 
complete and approved by all parties. 
11.2. 
Study Monitoring by GSK Biologicals 
GSK will monitor the study to verify that, amongst other items, the:  
• 
Data are authentic, accurate, and complete. 
• 
Safety and rights of subjects are being protected. 
• 
Study is conducted in accordance with the currently approved protocol, any other 
study agreements, GCP and all applicable regulatory requirements.  
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents. 
The investigator must ensure provision of reasonable time, space and qualified personnel 
for monitoring visits. 
Direct access to all study-site related and source data is mandatory for the purpose of 
monitoring review. The monitor will perform an eCRF review and a Source Document 
Verification (SDV). By SDV we understand verifying eCRF entries by comparing them 
with the source data that will be made available by the investigator for this purpose.  
The Source Documentation Agreement Form describes the source data for the different 
data in the eCRF. This document should be completed and signed by the site monitor and 
investigator and should be filed in the investigator’s study file. Any data item for which 
the eCRF will serve as the source must be identified, agreed and documented in the 
source documentation agreement form.  
Upon completion or premature discontinuation of the study, the monitor will conduct site 
closure activities with the investigator or site staff, as appropriate, in accordance with 
applicable regulations, GCP, and GSK procedures. 
11.3. 
Record retention 
Following closure of the study, the investigator must maintain all site study records 
(except for those required by local regulations to be maintained elsewhere) in a safe and 
secure location. The records must be easily accessible, when needed (e.g. audit or 
inspection), and must be available for review in conjunction with assessment of the 
facility, supporting systems, and staff. Where permitted by applicable laws/regulations or 
institutional policy, some or all of these records can be maintained in a validated format 
other than hard copy (e.g. microfiche, scanned, electronic); however, caution needs to be 
exercised before such action is taken. The investigator must ensure that all reproductions 
are legible and are a true and accurate copy of the original and meet accessibility and 
retrieval standards, including re-generating a hard copy, if required. Furthermore, the 
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investigator must ensure that an acceptable back-up of the reproductions exists and that 
there is an acceptable quality control procedure in place for making these reproductions. 
GSK will inform the investigator/institution of the time period for retaining these records 
to comply with all applicable regulatory requirements. The minimum retention time will 
meet the strictest standard applicable to a particular site, as dictated by ICH GCP, any 
institutional requirements, applicable laws or regulations, or GSK standards/procedures, 
otherwise, the minimum retention period will default to 25 years after completion of the 
study report. 
The investigator/institution must notify GSK of any changes in the archival 
arrangements, including, but not limited to archival at an off-site facility, transfer of 
ownership of the records in the event the investigator leaves the site.  
11.4. 
Quality assurance 
To ensure compliance with GCP and all applicable regulatory requirements, GSK may 
conduct a quality assurance audit. Regulatory agencies may also conduct a regulatory 
inspection of this study. Such audits/inspections can occur at any time during or after 
completion of the study. If an audit or inspection occurs, the investigator and institution 
agree to allow the auditor/inspector direct access to all relevant documents and to allocate 
his/her time and the time of his/her staff to the auditor/inspector to discuss findings and 
any relevant issues. 
11.5. 
Posting of information on publicly available clinical trial 
registers and publication policy 
GSK assures that the key design elements of this protocol will be posted on the GSK 
website and in publicly accessible database(s) such as clinicaltrials.gov, in compliance 
with the current regulations. 
GSK also assures that results of this study will be posted on the GSK website and in 
publicly accessible regulatory registry(ies) within the required time-frame, in compliance 
with the current regulations. The minimal requirement is to have primary endpoint 
summary results disclosed at latest 12 months post primary completion date (PCD) and to 
have secondary endpoint disclosed at latest 12 months after the last subject last visit 
(LSLV) as described in the protocol. 
As per EU regulation, summaries of the results of GSK interventional studies (Phase I-
IV) in adult population conducted in at least one EU member state will be posted on 
publicly available EMA registers within 12 months of EoS (as defined in the protocol) in 
the concerned EU member state. However, where, for scientific reasons detailed in the 
protocol, it is not possible to submit a summary of the results within one year in the 
concerned EU member state, the summary of results shall be submitted as soon as it is 
available. In this case, the protocol shall specify when the results are going to be 
submitted, together with a justification.  
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GSK also aims to publish the results of these studies in searchable, peer reviewed 
scientific literature and follows the guidance from the International Committee of 
Medical Journal Editors. 
11.6. 
Provision of study results to investigators 
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the study report. The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually-
agreeable location. 
GSK Biologicals will also provide the investigator with the full summary of the study 
results. The investigator is encouraged to share the summary results with the study 
subjects, as appropriate. 
11.7. 
Data Sharing 
Under the framework of the SHARE initiative, results of GSK studies may be combined 
with non- GSK studies, to investigate further about the study product(s) and other 
product(s), and /or the disease/condition under investigation and related diseases and 
conditions. 
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12. 
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inflammation to therapeutic giants - past, present and future. Cytokine Growth Factor 
Rev. 2014;25(4):453-72. 
Simoes EAF. Respiratory syncytial virus infection. Lancet. 1999; 354: 847–52. 
Stassijns J, Bollaerts K, Baay M, et al. A systematic review and meta-analysis on the 
safety of newly adjuvanted vaccines among children. Vaccine. 2016; 34:714-22. 
Steff AM, Monroe J, Friedrich K, et al. Pre-fusion RSV F strongly boosts pre-fusion 
specific neutralizing responses in cattle pre-exposed to bovine RSV. Nat Commun. 2017; 
8: 1085. 
Stubbe M, Vanderheyde N, Goldman M et al. Antigen-specific central memory CD4+ T 
lymphocytes produce multiple cytokines and proliferate in vivo in humans. J Immunol. 
2006;177(11):8185-90. 
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13. 
APPENDICES 
APPENDIX A 
LABORATORY ASSAYS 
Assay descriptions are provided below. Assays may possibly be adapted during assay 
development and/or qualification. 
RSV A/B neutralization assay 
The serum neutralization assay is a functional assay that measures the ability of serum 
antibodies to neutralize the cytopathic effects of RSV on the host cell line, hence RSV 
replication. 
First, virus neutralization is performed by incubating a fixed amount of RSV (A long 
strain [ATCC No. VR-26] or B strain 18537 [ATCC N°. VR-1580]) with serial dilutions 
of the test serum. Then, the serum-virus mixture is transferred onto a monolayer of Vero 
cells (African Green Monkey, kidney, Cercopitheus aethiops, ATCC CCL-81) and 
incubated for 3 days to allow infection of Vero cells by non-neutralized viruses and the 
formation of plaques in the cell monolayer. Following the fixation period, RSV-infected 
cells are detected using a primary antibody directed against RSV (anti-RSV IgG) and a 
secondary antibody conjugated with horse-radish peroxidase (HRP), allowing the 
visualization of plaques after coloration with TrueBlue peroxidase substrate. Viral 
plaques are counted using an automated microscope coupled to an image analyzer 
(Scanlab system with Axiovision software). For each serum dilution, a ratio, expressed as 
a percentage, is calculated between the number of plaques at that dilution and the number 
of plaques in the virus control wells (no serum added). The serum neutralizing antibody 
titer is expressed in ED60 (Estimated Dilution 60) and corresponds to the inverse of the 
interpolated serum dilution that yields a 60% reduction in the number of plaques 
compared to the virus control wells as described by others [Barbas, 1992; Bates, 2014]. 
RSVPreF3 ELISA 
The RSVPreF3 IgG ELISA is under development. The assay will be based on an indirect 
ELISA allowing the detection and the quantification of total IgG antibodies directed 
against RSVPreF3 in human serum samples. 
The principle of this assay will be as follows. The RSVPreF3 antigen will be adsorbed 
onto a 96-well polystyrene microplate. After a washing and a blocking step, dilutions of 
serum samples, controls and standards will be added to the coated microplate. A 
reference standard curve will be prepared using a pool of commercial human serum 
containing anti-RSV antibodies. After incubation, the microplate will be washed to 
remove unbound primary antibodies. Bound IgG will be detected by the addition of a 
secondary anti-human antibody conjugated to horseradish peroxidase (HRP). Bound 
antibodies are quantified by the addition of the HRP substrate, tetramethylbenzidine and 
hydrogen peroxide, whereby a colored product develops proportionally to the amount of 
anti-RSV F3 IgG antibodies present in the serum sample. The optical density of each 
sample dilution is then interpolated on the reference standard. The corresponding 
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antibody concentration, corrected for the dilution factor, is expressed in arbitrary ELISA 
Laboratory Units per milliliter (ELU/mL). 
Epitope specific competition assays 
Epitope specific competition assays are based on the competitive binding between a 
labelled epitope-specific monoclonal antibody and non-labelled antibodies present in 
serum samples and targeting the same epitope on a coated antigen. A competition assay 
specific for the RSB1 epitope, using RSVPreF3 protein as coating antigen, is under 
development. (Amended, 13 May 2020) 
The principle of competition assays is as follows: The RSVPreF3 protein antigen will be 
coated onto an assay plate. After blocking, dilutions of control serum or sample, as well 
as labelled, epitope specific, monoclonal antibody, are added to the coated plate. If 
epitope-specific antibodies are present in serum samples, they will compete with the 
monoclonal antibody for binding to the epitope on the antigen-coated plate. After 
washing, the bound, labelled antibody is then quantitated using a validated chromogenic 
detection system. The intensity of the detected signal is inversely proportional to the 
concentration of the epitope-specific antibodies present in the sample.  
The antibody concentrations are calculated for each control and sample by transforming 
the optical density values corresponding to the dilutions into a % competition value, and 
from this, the epitope-specific antibody concentration of the samples and controls is 
calculated. 
Intracellular staining (ICS) 
ICS has been used to assess CMI responses as previously described [Díez-Domingo, 
2010; Moris, 2011]. 
Briefly, thawed PBMCs are stimulated in vitro with pools of peptides (in this case pools 
of 15-mer peptides overlapping by 11 amino acids and spanning the sequence of the 
RSVPreF3 protein) or medium only in the presence of anti-CD28 and anti-CD49d 
antibodies. After 2 hours of incubation at 37C, Brefeldin A is added to inhibit cytokine 
secretion during an additional overnight incubation. Cells are subsequently harvested, 
stained for surface markers (CD4+ and CD8+) and then fixed. Fixed cells are then 
permeabilized and stained with labeled antibodies specific for the following immune 
markers:  
• 
CD3: phenotyping CD4 and CD8 T-cells; 
• 
CD40L (CD154), expressed on activated CD4 T-cells, and 41BB (CD137): 
expressed on activated CD4 or CD8 T-cells [Chattopadhyay, 2005; Frentsch, 2005; 
Samten, 2000; Stubbe, 2006]; 
• 
IL-2: key for the development, survival and function of T-cells [Boyman, 2012]; 
• 
TNF-α: anti-viral/intracellular factor, pro-inflammatory cytokine, cytotoxicity 
[Sedger, 2014]; 
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• 
IFN-γ: anti-viral factor, associated with the Th1-like profile and CD8 T-cells 
[Schoenborn, 2007]; 
• 
IL-13: associated with the Th2-like profile [Bao, 2015]; 
• 
IL-17: associated with the Th17-like profile [Korn, 2009]. 
The results are expressed as the frequency of CD4+ or CD8+ T-cells expressing, per 
million of CD4+ or CD8+ T-cells: 
• 
At least one/two immune marker(s) (to detect and measure the CD4+ or CD8+ T-cell 
response). 
• 
Any Th specific immune marker (to determine the Th profile of the CD4 response). 
B-cell ELISpot (Memory B-cell detection assay) 
Antigen-specific memory B-cells will be quantified using a B-cell ELISPOT assay 
adapted from Crotty et al. [Crotty, 2004]. Briefly, PBMCs are cultivated in the presence 
of a phosphorothioate oligonucleotide containing unmethylated CG motifs (CpG 7909) 
for 5 days to induce differentiation of circulating memory B lymphocytes into IgG 
secreting cells. These cells are then transferred onto plates coated with the relevant 
antigen, RSVPreF3, for the detection of antigen-specific antibody secreting cells. In 
addition, the total number of memory B cells, irrespective of their specificity, is 
established by plating cells onto anti-human IgG coated plates. Bound human IgG is then 
detected using enzyme coupled anti-human IgG antibody and the subsequent addition of 
enzymatic substrate. Spots in the form of coloured precipitate are counted to enumerate 
the antigen-specific and total antibody secreting cells. The results are expressed as the 
frequencies of antigen-specific memory B cells per million of total memory B cells. 
PCR 
• 
Quantitative PCR able to discriminate RSV-A and RSV-B subtypes 
Briefly, RSV A and RSV B RNAs extracted from the nasal/throat swabs are detected 
in a duplex PCR format using specific amplification primers and fluorescent probes 
designed in the RSV N gene, encoding the RSV nucleocapsid protein. The process 
involves nucleic acids extraction, conversion of RNA to complementary 
deoxyribonucleic acid by reverse transcription and detection by real-time PCR 
reaction using a calibration curve (absolute quantitation). The RSV viral load is 
reported as copies of RSV RNA per mL of sample. 
• 
Qualitative multiplex PCR for detection of a panel of viruses:  
A qualitative PCR multiplex assay is used for the detection and identification of 
multiple respiratory virus nucleic acids in the nasal/throat swabs. The following virus 
types and subtypes can be identified in the assay: 
− 
Influenza A virus (Flu A) 
− 
Influenza B virus (Flu B) 
− 
Human respiratory syncytial virus A (RSV A) 
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− 
Human respiratory syncytial virus B (RSV B) 
− 
Human Influenza A virus subtype H1 (Flu A-H1) 
− 
Human Influenza A virus subtype H3 (Flu A-H3) 
− 
Human Influenza A virus subtype H1pdm09 (Flu A-H1pdm09) 
− 
Human adenovirus (AdV) 
− 
Human metapneumovirus (MPV) 
− 
Human enterovirus (HEV) 
− 
Human parainfluenza virus 1 (PIV1) 
− 
Human parainfluenza virus 2 (PIV2) 
− 
Human parainfluenza virus 3 (PIV3) 
− 
Human parainfluenza virus 4 (PIV4) 
− 
Human bocavirus 1/2/3/4 (HBoV) 
− 
Human rhinovirus A/B/C (HRV) 
− 
Human coronavirus 229E (229E) 
− 
Human coronavirus NL63 (NL63) 
− 
Human coronavirus OC43 (OC43) 
Following total nucleic acids extraction, viruses are detected by multiplex real-time 
RT-PCR assays targeting the above mentioned viruses. A comparative analysis of 
the fluorescence intensities of each target is performed to detect the viruses present 
in the sample. 
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APPENDIX B 
CLINICAL LABORATORIES 
Table 35 
GSK Biologicals’ laboratories 
Laboratory 
Address 
GSK Biological’s Clinical Laboratory Sciences, 
Rixensart  
Biospecimen Reception - B7/44 
Rue de l'Institut, 89 - B-1330 Rixensart – Belgium  
GSK Biological’s Clinical Laboratory Sciences, 
Wavre-Nord Noir Epine 
Avenue Fleming, 20 - B-1300 Wavre - Belgium 
Table 36 
Outsourced laboratories 
Laboratory 
Address 
NÉOMED-LABS Inc.  
525, Cartier Ouest Laval 
Quebec Canada H7V 3S8 
NÉOMED-LABS Inc. 
Q Squared Solutions (Quest) LLC (US) 
27027 Tourney Road, Suite 2E 
Valencia, CA  91355 
USA 
Q Squared Solutions Limited 
The Alba Campus (Rosebank) 
Livingston 
West Lothian EH54 7EG 
Scotland, United Kingdom 
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APPENDIX C 
FDA GUIDANCE FOR INDUSTRY: TOXICITY 
GRADING SCALE FOR HEALTHY ADULT AND 
ADOLESCENT VOLUNTEERS ENROLLED IN 
PREVENTIVE VACCINE CLINICAL TRIALS 
(SEPTEMBER 2007) 
This guidance represents the Food and Drug Administration’s (FDA’s) current thinking 
on this topic. It does not create or confer any rights for or on any person and does not 
operate to bind FDA or the public. You can use an alternative approach if the approach 
satisfies the requirements of the applicable statutes and regulations. If you want to 
discuss an alternative approach, contact the appropriate FDA staff. If you cannot identify 
the appropriate FDA staff, call the appropriate number listed on the title page of this 
guidance. 
i. 
INTRODUCTION 
Preventive vaccines are usually developed to prevent disease in a healthy population. The 
Office of Vaccines Research and Review, Center for Biologics Evaluation and Research, 
regulates preventive vaccines under authority of section 351 of the Public Health Service 
Act (42 U.S.C. 262), as well as specific sections of the Federal Food, Drug, and Cosmetic 
Act, and reviews investigational new drug applications (INDs) and biologics license 
applications (BLAs). (See, for example, Title 21 Code of Federal Regulations (CFR) 
Parts 312, 600, and 601). Most of the clinical trials of preventive vaccines conducted to 
support INDs and BLAs enroll healthy volunteers in all phases of vaccine testing. The 
enrollment of healthy volunteers warrants a very low tolerance for risk in those clinical 
trials. 
This guidance provides you, sponsors, monitors, and investigators of vaccine trials, with 
recommendations on assessing the severity of clinical and laboratory abnormalities in 
healthy adult and adolescent volunteers enrolled in clinical trials. The grading system 
described in the table can also be useful in defining a particular study’s stopping rules 
(e.g., a certain number of AEs, as defined in the table, may call for stopping the study). 
Less extreme observations (e.g., mild) may not require discontinuing the study vaccine 
but can still contribute to evaluating safety by identifying parameters to focus upon in 
subsequent product development. Uniform criteria for categorizing toxicities in healthy 
volunteers can improve comparisons of safety data among groups within the same study 
and also between different studies. We, FDA, recommend using toxicity grading scale 
tables, provided below, as a guideline for selecting the assessment criteria to be used in a 
clinical trial of a preventive vaccine. We recommend incorporation of such appropriate, 
uniform, criteria into the investigational plan, case report forms, and study reports and 
correspondence with FDA, sponsors, monitors, investigators, and IRBs. 
This guidance finalizes the draft guidance of the same title dated April 2005 (70 FR 
22664, May 2, 2005). 
FDA’s guidance documents, including this guidance, do not establish legally enforceable 
responsibilities. Instead, guidances describe FDA’s current thinking on a topic and should 
be viewed only as recommendations, unless specific regulatory or statutory requirements 
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are cited. The use of the word should in FDA’s guidances means that something is 
suggested or recommended, but not required. 
ii. BACKGROUND 
Standardized toxicity assessment scales have been widely used to evaluate products 
treating specific diseases. For example, the National Cancer Institute’s Common Toxicity 
Criteria Scale and the Division of AIDS’ Toxicity Grading Scale standardize the 
evaluation of adverse events among patients with cancer and HIV/AIDS, respectively 
(Refs. 1, 2). The defined toxicity parameters in those scales are designed for patients who 
may already experience mild, moderate, or severe adverse clinical or laboratory events 
due to the disease process, and may not be appropriate for healthy volunteers. 
In the development of the toxicity grading scales for healthy volunteers, we chose 
parameter limit values based on published information, when such values were available 
(Refs. 1-6). For example, the Brighton Collaboration has developed case definitions and 
guidelines to evaluate some adverse events associated with administering vaccines (Ref. 
3). In some cases, parameter limit values were based on clinical experience and 
experience reviewing vaccine clinical trials that enroll normal healthy subjects. 
Toxicity grading scales for laboratory abnormalities should consider the local laboratory 
reference values when the parameter limit values are defined. The characterization of 
laboratory parameters among some populations of healthy adults and adolescents may 
require the exercise of clinical judgment, for example, consideration of the potential for 
ethnic differences in white blood cell (WBC) counts or gender differences in creatine 
phosphokinase (CPK) values. 
iii. TOXICITY GRADING SCALE TABLES 
Adverse events in a clinical trial of an investigational vaccine must be recorded and 
monitored and, when appropriate, reported to FDA and others involved in an 
investigation (sponsors, IRBs, and investigators). (See, for example, 21 CFR 312.32, 
312.33, 312.50, 312.55, 312.56, 312.60, 312.62, 312.64, and 312.66). Although the use of 
a toxicity grading scale for adverse events would not replace these regulatory 
requirements, using a scale to categories adverse events observed during a clinical trial 
may assist you in monitoring safety and making required reports. Nonetheless, we believe 
that categorization or grading of data as outlined in this document is supplementary to 
and should not replace full and complete data analysis. 
These guidelines for toxicity grading scales are primarily intended for healthy adult and 
adolescent volunteers. The parameters in the tables below are not necessarily applicable 
to every clinical trial of healthy volunteers. The parameters monitored should be 
appropriate for the specific study vaccine. For some preventive vaccines under 
development, it may be appropriate to include additional parameters to be monitored 
during a clinical trial or to alter the choice of values in the toxicity table. For example, 
additional parameters might be added based on one or more of the following: safety 
signals observed in pre-clinical toxicology studies, the biological plausibility of the 
occurrence of certain adverse events, or previous experience with a similar licensed 
product. 
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As discussed above, the tables do not represent a recommendation to monitor all the 
listed parameters in all clinical trials of healthy volunteers, nor do the tables represent all 
possible parameters to be monitored. In addition, these tables do not represent study 
inclusion or exclusion criteria. We recommend that the parameters monitored be 
appropriate for the study vaccine administered to healthy volunteers participating in the 
clinical trial. 
a. Tables for Clinical Abnormalities 
Note from the sponsor: The tables in this section of the guidance will not be used in this 
particular study. Instead, the parameters as provided in the current RSV OA=ADJ-002 
protocol are to be used. 
b. Tables for Laboratory Abnormalities 
The laboratory values provided in the tables below serve as guidelines and are dependent 
upon institutional normal parameters. Institutional normal reference ranges should be 
provided to demonstrate that they are appropriate. 
Table 37 
FDA toxicity grading scales for hematology/ biochemistry 
parameters evaluated in the current study RSV OA=ADJ-002 
Serum * 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life 
Threatening 
(Grade 4)** 
Blood Urea Nitrogen  
BUN mg/dL  
23 – 26  
27 – 31  
> 31  
Requires dialysis  
Creatinine – mg/dL  
1.5 – 1.7  
1.8 – 2.0  
2.1 – 2.5  
> 2.5 or requires 
dialysis  
Liver Function Tests –ALT, AST  
increase by factor  
1.1 – 2.5 x ULN  
2.6 – 5.0 x ULN  
5.1 – 10 x ULN  
> 10 x ULN  
* The laboratory values provided in the tables serve as guidelines and are dependent upon institutional normal 
parameters. Institutional normal reference ranges should be provided to demonstrate that they are appropriate. 
** The clinical signs or symptoms associated with laboratory abnormalities might result in characterization of the 
laboratory abnormalities as Potentially Life Threatening (Grade 4). For example, a low sodium value that falls within a 
Grade 3 parameter (125-129 mE/L) should be recorded as a Grade 4 hyponatremia event if the subject had a new 
seizure associated with the low sodium value. 
*** “ULN” is the upper limit of the normal range. 
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Hematology * 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life 
Threatening (Grade 4) 
Hemoglobin (Female) - gm/dL  
11.0 – 12.0  
9.5 – 10.9  
8.0 – 9.4  
< 8.0 
Hemoglobin (Female)  
change from baseline value - 
gm/dL  
Any decrease 
– 1.5  
1.6 – 2.0  
2.1 – 5.0  
> 5.0 
Hemoglobin (Male) - gm/dL  
12.5 – 13.5  
10.5 – 12.4  
8.5 – 10.4  
< 8.5 
Hemoglobin (Male)  
change from baseline value – 
gm/dL  
Any decrease 
– 1.5  
1.6 – 2.0  
2.1 – 5.0  
> 5.0 
WBC Increase - cell/mm
3 
10 800 – 
15 000  
15 001 – 
20 000  
20 001 – 25 000  
> 25 000 
WBC Decrease - cell/mm
3 
2 500 – 3 500  1 500 – 2 499  
1 000 – 1 499  
< 1 000 
Lymphocytes Decrease - 
cell/mm
3 
750 – 1 000  
500 – 749  
250 – 499  
< 250 
Neutrophils Decrease - 
cell/mm
3 
1 500 – 2 000  1 000 – 1 499  
500 – 999  
< 500 
Eosinophils - cell/mm
3 
650 – 1 500  
1 501 - 5 000  
> 5 000  
Hypereosinophilic 
Platelets Decreased - 
cell/mm
3 
125 000 – 
140 000  
100 000 – 
124 000  
25 000 – 99 000  
< 25 000 
* The laboratory values provided in the tables serve as guidelines and are dependent upon institutional normal 
parameters. Institutional normal reference ranges should be provided to demonstrate that they are appropriate. 
** “ULN” is the upper limit of the normal range. 
iv. REFERENCES for the APPENDIX C 
1. National Cancer Institute Common Toxicity Criteria, April 30, 1999. 
(http://ctep.cancer.gov/reporting/CTC-3.html)  
2. Division of AIDS Table for Grading Severity of Adult Adverse Experiences; August 
1992. (http://rcc.tech-res-intl.com/tox_tables.htm)  
3. The Brighton Collaboration. Finalized Case Definitions and Guidelines. 
(http://brightoncollaboration.org/internet/en/index/definition___guidelines.html)  
4. HIV Vaccine Trials Network Table for Grading Severity of Adverse Experiences; 
September 18, 2002. (http://rcc.tech-res-intl.com/tox_tables.htm)  
5. Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse 
Events, December 2004. 
(http://www3.niaid.nih.gov/research/resources/DAIDSClinRsrch/PDF/Safety/DAID
SAEGradingTable.pdf)  
6. Kratz A, Ferraro M, Sluss PM, Lewandrowski KB. Laboratory Reference Values. 
New England Journal of Medicine. 2004;351:1548-1563. 
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APPENDIX D COMMUNICATION FLOW IN CASE HOLDING RULES ARE 
MET 
In order to provide an effective study conduct, a proper communication plan will be set 
up between investigators, Local Operating Company (LOC) personnel, Central functions 
and the IDMC. This communication plan will allow an effective vaccination halt as well 
as restart or suspend of vaccination.  
Holding rules identified by Investigators  
If a holding rule is met at the site level, the study must be put on hold immediately in the 
respective center and the study Local Medical Lead (LML) in the LOC should be 
informed. The LOC will inform the central study team (study CRDL, Study Delivery 
Lead and Safety Physician), who will subsequently inform other LOCs and Investigators 
from all study centers. All vaccinations will cease as soon as possible, but all other 
procedures relating to safety and immunology will continue.  
Following an internal review as well as review by the IDMC, the Sponsor will decide to 
continue the conduct of, suspend or modify the study. This decision will be documented 
and provided in writing to the investigators.  
Holding rules identified by the IDMC 
If a holding rule is met following safety evaluation by the IDMC, the IDMC Chairman 
must notify the primary GSK contact immediately. The central study team (study CRDL, 
Study Delivery Lead and Safety Physician) will subsequently inform the LOCs and 
Investigators from all study centers. All vaccinations will cease immediately, but all other 
procedures relating to safety and immunology will continue. 
Following additional assessment by the IDMC, the Sponsor will decide to continue the 
conduct of, suspend or modify the study. This decision will be documented and provided 
in writing to the investigators.  
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PPD

CONFIDENTIAL 
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164 
during the active surveillance contacts carried out every 2 weeks during the RSV 
season period. 
• Instructions for assessment visit for suspected respiratory tract infection 
(RTI): Site staff will decide on the management of the cases (either having a 
site/different site location/home visit or by telephone contact) based on COVID-
19 national guidelines and/or site restrictions linked to the special circumstances. 
If the nasal and throat samples cannot be collected at site, the sample will be 
encoded as missing. Samples that are not collected will be documented as 
protocol deviations. Biological samples will not be collected if they cannot be 
processed in a timely manner or appropriately stored until the intended use. 
Additional changes:  
• 
As per the request from the regulatory (Belgian) authorities, clarification has 
been added to the holding rule wording for non-life-threatening SAEs in 
Section 7.10.4. The paragraph has been modified to add clarification that SAEs 
that are not related to study vaccination will not be considered for safety holding 
rules.  
• 
Blood collection and testing plan for samples arising at the last study visit (Visit 
8) have been updated, following the formulation selection and, based on data 
generated from the first analysis. At the last visit, blood samples will be collected 
for antibody and CMI determination from a subset of subjects (N460, from all 
subjects in part B1 [N100] and subjects who received a selected level of antigen 
dose and Placebo in part B2 [N360]). 
• 
Blinding instructions have been updated to reflect the impact of the change in 
blood collection and testing plan at the last study visit (Visit 8). During the last 
study visit, the blood samples will be collected only from a subset of subjects 
(N460, all subjects in part B1 and subjects who received a selected level of 
antigen dose and Placebo in part B2). Therefore, the investigators, site and study 
staff will be partially unblinded at group level, but not at the individual level.  
In case there will be an extension study planned, with all or a subset of 
participants included, the investigators may be provided with the list of study 
subjects eligible to participate in such study, before the parent study ends. 
Therefore, the investigators, site and study staff will potentially receive an 
individual data listings for a subset. All subjects in this subset may be unblinded 
before the study ends. 
• 
Missing cut-off values for some humoral assays have been included. The new 
naming for the competitive ELISA (RSVPreF3 RSB1 specific) has been 
implemented. 
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165 
Amended text has been included in bold italics and deleted text in strikethrough in 
the following sections: 
• 
Synopsis/Study Blinding, Section 1.2.2.4/Study Blinding, Section 3/Blinding, 
Section 5.3/Method of Blinding and Section 10.12.1/Sequence of Analyses, text 
added: During the last study visit, blood samples will be collected only from a 
subset of subjects (N460, all subjects in part B1 and subjects who received a 
selected level of antigen dose and Placebo in part B2). Therefore, the investigators, 
site and study staff will be partially unblinded at group level, but not at the 
individual level. 
• 
Across the document, site 0 has been be changed to RSB1 for the site specific 
RSVPreF3 competitive ELISA. 
• 
Section 3, text added: Refer to Section 5.10 for study procedures to be considered 
during special circumstances. 
− 
Text edited: Blood samples for humoral immunogenicity and CMI testing 
will be drawn from all subjects at Days 1, 31, 61, 91, Month 8 and from a subset 
at Month 14 (Visits 1, 3, 4, 6, 7 and 8). 
− 
part B step was incorrectly mentioned for a group: Groups 120-AS01E_B1 
and 120-AS01E_B12: subjects receiving 2 doses of the investigational RSV 
vaccine containing 120 g RSVPreF3 adjuvanted with AS01E 
• 
Section 5.1, text added: 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 and safety must be 
applied. For the duration of such special circumstances, additional measures may 
be implemented for enrolled participants. Refer to Section 5.10 for further details. 
• 
Section 5.6.3.11, text added: (at Visit 8 blood will be collected from a subset of 
subjects). Deleted text ‘all’ as blood will be collected from a subset at Visit 8: A 
volume of approximately 20 mL of whole blood (to provide 6.6 mL of serum) 
should be drawn from all subjects for analysis of the humoral immune response at 
each pre-defined time point. A volume of approximately 25 mL of whole blood 
should be drawn from all subjects for analysis of the CMI response at each pre-
defined time point. 
• 
Section 5.9, text added: Refer to Section 5.10 for measures for biological samples 
collection that may be implemented during special circumstances. 
• 
Table 10 has been updated and assay cut-off values been added. 
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166 
Table-10 
Humoral Immunity (Antibody determination) 
System 
Component 
Method 
Kit / 
Manufacturer 
Unit 
Cut-
off$ 
Laboratory 
Serum 
Respiratory 
Syncytial Virus A Ab  NEUTRALIZATION 
In-house 
ED60  
18  
GSK Biologicals* 
or NÉOMED-LABS 
Serum 
Respiratory 
Syncytial Virus B Ab 
NEUTRALIZATION 
In-house 
ED60  
30 
TBD 
GSK Biologicals* 
or NÉOMED-LABS 
Serum 
RSVPreF3-specific 
IgG antibody 
concentrations 
ELISA 
In house at 
Neomed Labs 
ELU/mL 
25 
TBD 
Neomed Labs 
Serum 
RSVPreF3 RSB1 
site 0 specific Ab 
Competition ELISA 
In-house 
g/mL 
2.11 
TBD 
GSK Biologicals* 
or NÉOMED-LABS 
Ab: antibody; ELISA: enzyme-linked immunosorbent assay; RSV: respiratory syncytial virus;  
ED60: Estimated Dose: serum dilution giving a 60% reduction of the signal compared to a control without serum 
TBD: To be determined 
* GSK Biologicals laboratory refers to the Clinical Laboratory Sciences (CLS) in Rixensart, Belgium; Wavre, 
Belgium;Marburg, Germany 
$  Assay cut offs could be subject to change and will be defined in the Statistical Analysis Plan 
• 
Section 5.9.4.1, text added: 
Testing of RSV-A neutralizing antibodies and RSVPreF3 IgG antibodies will be 
performed on blood samples from all subjects, in both Part A and Part B, except at 
Month 14 (Visit 8). 
Testing of RSV-A neutralizing antibodies and RSVPreF3 IgG antibodies will be 
performed on blood samples from all subjects, in both Part A and Part B, except at 
Month 8 (Visit 7) and Month 14 (Visit 8). 
Testing of RSV-B neutralizing antibodies will be performed on blood samples from all 
subjects in Part B. 
Testing of RSVPreF3 RSB1 specific antibodies will be performed on blood samples from 
a subset of subjects at Day 31 or Day 91 in Part B who received the selected vaccine 
formulation and placebo (N200). 
Testing of CD4+/CD8+ CMI will be performed on blood samples from all subjects in 
both Part A and Part B, except at Month 8 (Visit 7) and Month 14 (Visit 8).  
At Month 8 (Visit 7) blood sample testing for humoral response pertaining to RSV-A 
neutralizing antibodies and CMI response will be performed for all subjects in Part B1; 
and for a subset of subjects in Part B2, who received a selected level of antigen dose 
and Placebo (N460). Blood sample testing pertaining to the RSVPreF3 IgG antibodies 
will be performed for all subjects at Month 8 (Visit 7). 
At Month 14 (Visit 8) humoral and CMI response testing will be performed for all 
subjects in Part B1; and for a subset of subjects in Part B2, who received a selected 
level of antigen dose and Placebo (N460). testing might be performed only on blood 
samples from the subset of subjects who received the selected level of antigen dose or 
placebo (N400). 
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13-MAY-2020 
167 
• 
New section added: 
Section 5.10 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 and safety must be applied. For the duration of such special 
circumstances, the following measures may be implemented for enrolled participants:  
• 
Instruction for the remaining scheduled visit (Visit 8): Planned study visit can 
proceed, if the study subjects are healthy and allowed to come to the site to have 
the blood sample and safety information collected. If the visit is impacted due to 
the national guidelines and/or site restrictions linked to the special circumstances, 
and it is not possible to collect the biological samples within the interval predefined 
in the protocol (see Table 8), the samples will be encoded as missing and encoded 
as protocol deviation. If the visit is impacted, the safety information (as per 
protocol: SAEs, pIMDs, concomitant medications/vaccinations and intercurrent 
medical conditions) will be collected by site staff via telephone contact or other 
means of virtual contact, and this will not be considered as protocol deviation. 
• 
Instruction for collection of home self-swabs in case study participant experiences 
suspected respiratory tract infection (RTI) symptoms: In case the investigator 
determines this is not posing additional risk to the subjects or household members, 
the subjects will be instructed to perform the home self-swab and keep it in their 
freezer (preferred) or refrigerator until recovered, and able to bring it to the site. If 
there is a possibility, a healthy relative can bring the sample to the site to be 
processed. In case investigator judges this is not advisable due to the national 
guidelines and/or site restrictions linked to the special circumstances, the self-swab 
will not be collected and the sample will be encoded as missing. Samples that are 
not collected will be documented as protocol deviations. The investigator and/or 
the site staff will provide these instructions to the subjects during the active 
surveillance contacts carried out every 2 weeks during the RSV season period. 
• 
Instructions for assessment visit for suspected respiratory tract infection (RTI): 
Site staff will decide on the management of the cases (either having a site/different 
site location/home visit or by telephone contact) based on COVID-19 national 
guidelines and/or site restrictions linked to the special circumstances. If the nasal 
and throat samples cannot be collected at site, the sample will be encoded as 
missing. Samples that are not collected will be documented as protocol deviations. 
Biological samples will not be collected if they cannot be processed in a timely 
manner or appropriately stored until the intended use. 
Impact on the per protocol set for immunogenicity will be determined on a case by case 
basis. 
• 
Section 7.3.1, text added: Refer to Section 5.10 for measures for safety follow-up 
that may be implemented during special circumstances. 
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CONFIDENTIAL 
208851 (RSV OA=ADJ-002) 
Protocol Amendment 1 Final 
13-MAY-2020 
168 
• 
Table 7 footnote added: 4 At Visit 8, blood samples for antibody and CMI 
determination will be collected from all subjects in part B1; and from a subset of 
subjects in part B2 who received a selected level of antigen dose and Placebo. To 
refer to this footnote, a numeric reference been added (4) to the blood sampling solid 
bullets at Visit 8.  
Refer to Section 5.10 for study procedures to be considered during special 
circumstances. 
• 
Table 9, footnote text added: 
*** At Visit 8, blood samples for antibody and CMI determination will be collected 
from all subjects in part B1; and from a subset of subjects in part B2 who received 
a selected level of antigen dose and Placebo. To refer to this footnote, a numeric 
reference been added (***) to the blood sampling solid bullets at Visit 8. 
Refer to Section 5.10 for study procedures to be considered during special 
circumstances. 
• 
Planned number of subjects for humoral and CMI testing has been updated in 
Table 15:  
Table 15 
Immunological read-outs in Part B 
Blood sampling time point* 
Sub-cohort 
No. 
subjects 
Component 
Components 
priority rank  
Type of contact 
and time point 
Sampling time 
point 
Humoral immunity (on serum samples) 
visit 1 (Day 1) 
Pre-Vacc  
All subjects 
 1000 
RSV-A neutralizing antibody 
1 
Anti-RSVPreF3-specific IgG antibody 
2 
RSV-B neutralizing antibody 
3 
Subset 
 200 
RSVPreF3 RSB1 specific antibody 
4 
visit 3 (Day 31) 
PI D31  
All subjects 
 1000 
RSV-A neutralizing antibody 
1 
Anti-RSVPreF3-specific IgG antibody 
2 
visit 4 (Day 61) 
PI D61  
All subjects 
 1000 
RSV-A neutralizing antibody 
1 
Anti-RSVPreF3-specific IgG antibody 
2 
visit 6 (Day 91) 
PII D91  
All subjects 
 1000 
RSV-A neutralizing antibody 
1 
Anti-RSVPreF3-specific IgG antibody 
2 
RSV-B neutralizing antibody 
3 
Subset 
 200 
RSVPreF3 RSB1 specific antibody 
4 
visit 7 (Month 8)** 
PII M8  
Subset 
 460 
RSV-A neutralizing antibody 
1 
All subjects 
~1000 
Anti-RSVPreF3-specific IgG antibody 
2 
visit 8 (Month 
14)*** 
PII M14  
All subjects 
Subset 
~1000 
~460 
RSV-A neutralizing antibody 
1 
Anti-RSVPreF3-specific IgG antibody 
2 
Cell-mediated immunity (on PBMC samples) 
visit 1 (Day 1) 
Pre-Vacc  
All subjects 
 1000 
CD4+/CD8+ 
1 
Subset 
 400 
Memory B-cells 
2 
visit 3 (Day 31) 
PI D31  
All subjects 
 1000 
CD4+/CD8+ 
1 
Subset 
 400 
Memory B-cells 
2 
visit 4 (Day 61) 
PI D61 
All subjects 
 1000 
CD4+/CD8+ 
- 
visit 6 (Day 91) 
PII D91  
All subjects 
 1000 
CD4+/CD8+ 
1 
Subset 
 400 
Memory B-cells 
2 
visit 7 (Month 8)** 
PII M8  
All subjects 
Subset 
~1000 
 460 
CD4+/CD8+ 
- 
PII M14 
Subset 
~400 
CD4+/CD8+  
1 
208851 | Protocol Amendment 1 19 May 2020 | TMF-1772243 | 1.0

&21),'(17,$/
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Blood sampling time point* 
Sub-cohort 
No. 
subjects 
Component 
Components 
priority rank  
Type of contact 
and time point 
Sampling time 
point 
visit 8 (Month 
14)*** 
a 460 
Subset 
a 400 
Memory B-cells 
2 
Pre-Vacc: Pre-vaccination; PI DX: Post-Dose 1 Study Day X; PII DX: Post-Dose 2 Study Day X; M: Month 
PBMC: Peripheral Blood Mononuclear Cells 
* Testing of additional time points for RSVPreF3 RSB1 specific antibodies, RSV-B neutralizing antibodies and memory 
B-cells might be performed, should the results indicate that further investigation of the immune response is necessary. 
** At Visit 7, blood samples for RSV-A neutralizing antibody determination, and CMI determination will be 
tested from a subset of subjects (all subjects in part B1; and a subset of subjects in part B2, who received a 
selected level of antigen dose and Placebo). 
*** At Visit 8, blood samples for antibody and CMI determination will be collected and tested from all subjects 
in part B1; and from a subset of subjects in part B2, who received a selected level of antigen dose and 
Placebo. 
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CONFIDENTIAL 
208851 (RSV OA=ADJ-002) 
Protocol Amendment 1 Final 
13-MAY-2020 
170 
• 
Table 28, text edited: Toll free number Phone 
• 
The SMR database fields have been decoupled. The table with study intervention 
details has been updated based on GSK Vaccines’ implementation of the IDMP 
ISO requirements and it does not impact, subject’s safety, study conduct or study 
results. 
208851 | Protocol Amendment 1 19 May 2020 | TMF-1772243 | 1.0