Conditions: Respiratory Syncytial Virus Infections
Keywords: Safety Respiratory syncytial virus (RSV) Vaccine Reactogenicity Immunogenicity Infants
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 201
Healthy volunteers: yes

Brief summary:
The purpose of this study is to provide critical information on the safety, reactogenicity and immunogenicity profile of the investigational recombinant chimpanzee adenovirus Type 155-vectored RSV (ChAd155-RSV) vaccine in infants likely to be unexposed to RSV and will assess a single lower dose and a higher two dose regimen, before moving to future studies. This study will also assess if there is a risk of 'vaccine-induced enhanced RSV disease' after vaccination of these infants with the ChAd155-RSV vaccine.

Detailed description:

Arms:
arm 1: Subjects received the interventions as follows:

* Either 1 dose of experimental RSV (GSK3389245A) lower dose formulation at Day 1, followed by 1 dose of Placebo at Day 31 and any one the following active comparators: 2 doses of GSK's meningococcal group A, C, W-135 and Y conjugate vaccine (administered at Day 61 and at the end of RSV season 1) or 3 doses of GSK's multicomponent meningococcal B vaccine or Pfizer's meningococcal group A, C, W-135 and Y conjugate vaccine or GSK's pneumococcal polysaccharide conjugate vaccine (administered at Days 61, 121 and at the end of RSV season 1).
* Or 1 dose of experimental RSV (GSK3389245A) lower dose formulation at Day 1, followed by 1 dose of Placebo at Day 31. arm 2: Subjects received the interventions as follows:

* Either 2 doses of experimental RSV (GSK3389245A) higher dose formulation (administered at Day 1 and Day 31) and followed by any one the following active comparators: 2 doses of GSK's meningococcal group A, C, W-135 and Y conjugate vaccine (administered at Day 61 and at the end of RSV season 1) or 3 doses of GSK's multicomponent meningococcal B vaccine or Pfizer's meningococcal group A, C, W-135 and Y conjugate vaccine or GSK's pneumococcal polysaccharide conjugate vaccine (administered at Days 61, 121 and at the end of RSV season 1).
* Or 2 doses of experimental RSV (GSK3389245A) higher dose formulation administered at Day 1 and Day 31. arm 3: Subjects received either one of interventions schedules as follows:

* 3 doses of GSK's multicomponent meningococcal B vaccine (administered at Days 1, 61 and at the end of RSV season 1) and 2 doses of Placebo (administered at Days 31 and 121).
* 3 doses of Pfizer's meningococcal group A, C, W-135 and Y conjugate vaccine (administered at Days 1, 61 and at the end of RSV season 1) and 2 doses of Placebo (administered at Days 31 and 121).
* 3 doses of GSK's pneumococcal polysaccharide conjugate vaccine (administered at Days 31, 61 and at the end of RSV season 1) and 2 doses of Placebo (administered at Day 1 and Day 121).
* 2 doses of GSK's meningococcal group A, C, W-135 and Y conjugate vaccine (administered at Day 31 and at the end of RSV season 1) and 2 doses of Placebo (administered at Days 1 and 61) .
* 2 doses of Placebo alone (administered at Days 1 and 31).

Interventions: intervention 1: RSV (GSK3389245A) lower dose formulation vaccine intervention 2: RSV (GSK3389245A) higher dose formulation vaccine intervention 3: GSK's multicomponent meningococcal B vaccine intervention 4: Pfizer's meningococcal group A, C, W-135 and Y conjugate vaccine intervention 5: GSK's pneumococcal polysaccharide conjugate vaccine intervention 6: GSK's meningococcal group A, C, W-135 and Y conjugate vaccine intervention 7: Placebo
Intervention descriptions: intervention 1: 1 dose of RSV (GSK3389245A) lower dose formulation vaccine administered intramuscularly at Day 1. intervention 2: 2 doses of RSV (GSK3389245A) higher dose formulation vaccine administered intramuscularly, at Day 1 and Day 31. intervention 3: 3 doses of GSK's multicomponent meningococcal B vaccine administered intramuscularly, at Day 61, Day 121 and at the end of RSV season 1, or at Day 1, Day 61 and end of RSV season 1, depending on the vaccination schedule. intervention 4: 3 doses of Pfizer's meningococcal group A, C, W-135 and Y conjugate vaccine administered intramuscularly, at Day 61, Day 121 and at the end of RSV season 1, or at Day 1, Day 61 and end of RSV season 1, depending on the vaccination schedule. intervention 5: 3 doses of GSK's pneumococcal polysaccharide conjugate vaccine administered intramuscularly, at Day 61, Day 121 and at the end of RSV season 1, or at Day 31, Day 61 and end of RSV season 1, depending on the vaccination schedule. intervention 6: 2 doses of GSK's meningococcal group A, C, W-135 and Y conjugate vaccine administered intramuscularly, at Day 61 and at the end of RSV season 1, or at Day 31 and end of RSV season 1, depending on the vaccination schedule. intervention 7: 1 dose or 2 doses of Placebo administered intramuscularly at Day 31, or at Day 1 and Day 31, or at Day 1 and Day 61, or at Day 31 and Day 121, depending on the vaccination schedule.

Protocol document:
Prot_000.pdf: 
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Clinical Study Protocol
Sponsor:
GlaxoSmithKline Biologicals SA
Rue de l’Institut, 89
1330 Rixensart, Belgium
Primary study vaccine and 
number

GlaxoSmithKline (GSK) Biologicals’ respiratory 
syncytial virus (RSV) vaccine based on the RSV 
viral proteins F, N and M2-1 encoded by 
chimpanzee-derived adenovector (ChAd155-
RSV) (GSK3389245A)
Other study vaccines

GSK’s multicomponent meningococcal B
vaccine (recombinant, adsorbed) (Bexsero)

Pfizer’s meningococcal group A, C, W-135 and 
Y conjugate vaccine (Nimenrix)

GSK’s pneumococcal polysaccharide conjugate 
vaccine (Synflorix)

GSK’s meningococcal group A, C, W-135 and Y 
conjugate vaccine (Menveo)

Placebo (Formulation buffer S9b)
eTrack study number and 
abbreviated title
204894 (RSV PED-011)
Investigational New Drug 
(IND) number
16999
EudraCT number
2018-000431-27
Date of protocol
Final Version 1: 08 February 2018
Date of protocol amendment
Amendment 1 Final: 16 July 2018
Amendment 2 Final: 24 January 2019
Amendment 3 Final: 21 March 2019
Amendment 4 Final: 01 August 2019
Title
A study to evaluate safety, reactogenicity and 
immunogenicity of GSK Biologicals’ RSV 
investigational vaccine based on viral proteins 
encoded by chimpanzee-derived adenovector 
(ChAd155-RSV) (GSK3389245A) in infants.
Detailed title 
A Phase 1/2, randomized, observer-blind, controlled, 
multi-center study to evaluate safety, reactogenicity 
and immunogenicity of GSK Biologicals’ respiratory 
syncytial virus (RSV) investigational vaccine based 
on the RSV viral proteins F, N and M2-1 encoded by 
chimpanzee-derived adenovector (ChAd155-RSV) 
(GSK3389245A), when administered intramuscularly 
as a single dose or as two doses according to a 0, 1-
month schedule, to infants aged 6 and 7 months.
 
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eTrack study number and 
abbreviated title
204894 (RSV PED-011)
Investigational New Drug 
(IND) number
16999
EudraCT number 
2018-000431-27
Detailed title
A Phase 1/2, randomized, observer-blind, controlled, 
multi-center study to evaluate safety, reactogenicity 
and immunogenicity of GSK Biologicals’ respiratory 
syncytial virus (RSV) investigational vaccine based 
on the RSV viral proteins F, N and M2-1 encoded by 
chimpanzee-derived adenovector (ChAd155-RSV) 
(GSK3389245A), when administered intramuscularly 
as a single dose or as two doses according to a 0, 1-
month schedule, to infants aged 6 and 7 months.
Co-ordinating authors 

 (Scientific Writer)

 (Scientific Writer)

 (Scientific Writer, Keyrus 
Biopharma contractor for GSK Biologicals)

 (Expert Scientific Writer)
Contributing authors
(Amended 1 August 2019)

 (Clinical Research and 
Development Lead)

 (Clinical Research and 
Development Lead)

 (Lead Statistician)

 (Project Statistician)

(Project Statistician)

 (Study Delivery Lead)

 (Study Delivery Lead)

 (Study Delivery Lead)

 (Study Delivery Lead)

 (Clinical Trial Supply Manager)

 (Clinical Read-out Team 
Leader)

 (Clinical Read-out Team Leader)

 (Clinical Laboratory Sciences 
[CLS] Study Manager, Business & Decision Life 
Sciences contractor for GSK Biologicals)
 
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eTrack study number and 
abbreviated title
204894 (RSV PED-011)
Investigational New Drug 
(IND) number
16999
EudraCT number 
2018-000431-27
Detailed title 
A Phase 1/2, randomized, observer-blind, controlled, 
multi-center study to evaluate safety, reactogenicity 
and immunogenicity of GSK Biologicals’ respiratory 
syncytial virus (RSV) investigational vaccine based 
on the RSV viral proteins F, N and M2-1 encoded by 
chimpanzee-derived adenovector (ChAd155-RSV) 
(GSK3389245A), when administered intramuscularly 
as a single dose or as two doses according to a 0, 1-
month schedule, to infants aged 6 and 7 months.
Contributing authors 

 (Central Safety Physician)

 (Central Safety 
Scientist)

 (Oversight Data Manager, Keyrus 
Biopharma contractor for GSK Biologicals)

 (Global Regulatory 
Representative)

 (Global Patent Representative)

 (Clinical and Epidemiology 
Research and Development Project Lead)

 (Clinical and 
Epidemiology Research and Development 
Project Lead)
GSK Biologicals’ Protocol DS v 15.0
© 2018-2019 GSK group of companies or its licensor
 
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Protocol Amendment 4 Sponsor Signatory Approval
eTrack study number and 
Abbreviated Title
204894 (RSV PED-011)
IND number
16999
EudraCT number
2018-000431-27
Date of protocol amendment
Amendment 4 Final: 01 August 2019
Detailed Title 
A Phase 1/2, randomized, observer-blind, controlled, 
multi-center study to evaluate safety, reactogenicity 
and immunogenicity of GSK Biologicals’ respiratory 
syncytial virus (RSV) investigational vaccine based 
on the RSV viral proteins F, N and M2-1 encoded by 
chimpanzee-derived adenovector (ChAd155-RSV) 
(GSK3389245A), when administered intramuscularly 
as a single dose or as two doses according to a 0, 1-
month schedule, to infants aged 6 and 7 months.
Sponsor signatory
Antonio Gonzalez Lopez (Clinical and Epidemiology 
Research & Development Project Lead)
Signature
Date
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Protocol Amendment 4 Rationale
Amendment number:
Amendment 4
Rationale/background for changes:

The per protocol set definition in the synopsis was updated. 

Clarification was added on recruiting sufficient subjects with negative RSV 
exposure status. 

Clarification was added to RTI and LRTI episode definitions. 

Table 24 was updated to clarify the visit window intervals.

Additional wording was added to indicate that for countries where it is not 
acceptable to provide copies of medical records to the sponsors, the investigator 
will transcribe the required information in a manner that respects the subject’s 
anonymization.

In addition, some typographical errors have been corrected throughout the 
protocol.
 
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Protocol Amendment 4 Investigator Agreement
I agree:

To conduct the study in compliance with this protocol, any future protocol 
amendments or protocol administrative changes, with the terms of the clinical trial 
agreement and with any other study conduct procedures and/or study conduct 
documents provided by GlaxoSmithKline (GSK) Biologicals.

To assume responsibility for the proper conduct of the study at this site.

That I am aware of, and will comply with, ‘Good Clinical Practice’ (GCP) and all 
applicable regulatory requirements.

To ensure that all persons assisting me with the study are adequately informed about 
the GSK Biologicals’ study vaccines and other study-related duties and functions as 
described in the protocol.

To acquire the reference ranges for laboratory tests performed locally and, if required 
by local regulations, obtain the laboratory’s current certification or Quality 
Assurance procedure manual.

To ensure that no clinical samples (including serum samples) are retained onsite or 
elsewhere without the approval of GSK Biologicals and the express written informed 
consent of the subject and/or the subject’s legally acceptable representative.

To perform no other biological assays on the clinical samples except those described 
in the protocol or its amendment(s). 

To co-operate with a representative of GSK Biologicals in the monitoring process of 
the study and in resolution of queries about the data.

That I have been informed that certain regulatory authorities require the sponsor to 
obtain and supply, as necessary, details about the investigator’s ownership interest in 
the sponsor or the investigational vaccines, and more generally about his/her 
financial ties with the sponsor. GSK Biologicals will use and disclose the 
information solely for the purpose of complying with regulatory requirements.
Hence I:

Agree to supply GSK Biologicals with any necessary information regarding 
ownership interest and financial ties (including those of my spouse and dependent 
children).

Agree to promptly update this information if any relevant changes occur during the 
course of the study and for one year following completion of the study.

Agree that GSK Biologicals may disclose any information it has about such 
ownership interests and financial ties to regulatory authorities.

Agree to provide GSK Biologicals with an updated Curriculum Vitae and other 
documents required by regulatory agencies for this study.
 
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eTrack study number and 
Abbreviated Title
204894 (RSV PED-011)
IND number
16999
EudraCT number 
2018-000431-27
Date of protocol amendment
Amendment 4 Final: 01 August 2019
Detailed Title
A Phase 1/2, randomized, observer-blind, controlled, 
multi-center study to evaluate safety, reactogenicity 
and immunogenicity of GSK Biologicals’ respiratory 
syncytial virus (RSV) investigational vaccine based 
on the RSV viral proteins F, N and M2-1 encoded by 
chimpanzee-derived adenovector (ChAd155-RSV) 
(GSK3389245A), when administered intramuscularly 
as a single dose or as two doses according to a 0, 1-
month schedule, to infants aged 6 and 7 months.
Investigator name
Signature
Date
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Sponsor Information
1.
Sponsor
GlaxoSmithKline Biologicals
Rue de l’Institut, 89
1330 Rixensart, Belgium
2.
Sponsor Medical Expert for the Study
Refer to the local study contact information document.
3.
Sponsor Study Monitor
Refer to the local study contact information document.
4.
Sponsor Study Contact for Reporting of a Serious Adverse Event
GSK Biologicals Central Back-up Study Contact for Reporting SAEs: refer to protocol 
Section 9.4.2.
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 9.8.
 
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SYNOPSIS
Detailed title 
A Phase 1/2, randomized, observer-blind, controlled, multi-
center study to evaluate safety, reactogenicity and 
immunogenicity of GSK Biologicals’ respiratory syncytial 
virus (RSV) investigational vaccine based on the RSV viral 
proteins F, N and M2-1 encoded by chimpanzee-derived 
adenovector (ChAd155-RSV) (GSK3389245A), when 
administered intramuscularly as a single dose or as two doses 
according to a 0, 1-month schedule, to infants aged 6 and 7 
months.
Indication
Active immunization of infants for the prevention of any 
lower respiratory tract infections (LRTI; bronchiolitis and 
[broncho]pneumonia) associated with respiratory syncytial 
virus (RSV).
Rationale for the 
study and study 
design

Rationale for the study
GSK Biologicals is developing the pediatric candidate RSV 
vaccine (ChAd155-RSV vaccine) to protect infants from RSV 
diseases.
The purpose of this study is to provide critical information on 
the safety, reactogenicity and immunogenicity profile of the 
ChAd155-RSV vaccine in infants likely to be unexposed to 
RSV before moving to a proof-of-concept trial in infants. An 
important aspect of this phase I/II study will be to compare a 
single lower dose of 1.5x1010 viral particles (vp) and two 
higher doses of 5x1010 vp according to a 0, 1 month schedule 
administered to infants aged 6 and 7 months likely to be 
unexposed to RSV, which is powered to statistically exclude a 
level of risk of ‘vaccine-induced enhanced RSV disease’, 
associated with historic FI-RSV vaccine trials.

Rationale for the study design
Study population: The immunogenicity, safety and 
reactogenicity of the pediatric candidate RSV vaccine 
(ChAd155-RSV vaccine) has been evaluated in healthy adults 
aged 18 to 45 years (study 201974 [RSV PED-001; 
NCT02491463]). A clinical study is currently being 
conducted in RSV-seropositive infants aged 12 to 23 months 
(study 204838 [RSV PED-002]). The safety profile of the 
ChAd155-RSV vaccine in adults (study 201974 [RSV PED-
001; NCT02491463]) has been evaluated and determined to 
be satisfactory by an Independent Data Monitoring 
Committee (IDMC). Should there be a satisfactory safety 
profile of the ChAd155-RSV vaccine in RSV-seropositive 
infants, as evaluated by an IDMC on Day 60 data (i.e., 30 
days post-Dose 2 of the highest dose level) of the study RSV 
PED-002, the present study will be performed. This study will 
 
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be conducted in infants aged 6 and 7 months, (having a low 
chance of natural exposure to RSV before inclusion in the 
study). Although potentially both RSV-exposed and RSV-
unexposed subjects will be enrolled, the primary analysis for 
incidence of LRTI will be conducted in infants with a
negative RSV exposure status (at screening based on in-
stream baseline serological testing). This study will support 
the decision to age de-escalate to the targeted population 
(infants as from 6 weeks of age) in the subsequent study.
Control vaccines: Active comparators are included as a 
control for the reactogenicity, safety and immunogenicity 
assessments. The choice of one of four control vaccines, as 
active comparators has been driven by the fact that, in most 
countries at least one of these vaccines meet the criteria of 
being of medical benefit, and where possible licensed for 
infants and used with a similar dose and schedule as the 
investigational RSV vaccine, while not being part of a 
national immunization program. The choice of which active 
control comparator vaccine to be used will be done at the 
country level and will be used according to its approved label.
A placebo group was added to accommodate a request from 
countries that were not able to identify a suitable active 
comparator.
Study blinding: Given the different appearance and storage 
conditions of the investigational RSV vaccine and active 
control comparator vaccines, double blinding is not possible 
and the study will be conducted in an observer-blind manner.
When all data up to Day 61 are available, a statistical analysis 
will be performed. This analysis may lead to the unblinding of 
some subjects. As a consequence, after Day 61, the study 
cannot be considered as observer-blind, but will be conducted 
in a single blind manner, with subjects’ parent(s)/ legally 
acceptable representative(s) (LAR[s]) remaining blinded up to 
the last study visit (end of the second RSV transmission 
season), while the investigator will still not have access to the 
individual subject treatment allocation up to the last study 
visit (end of the second RSV transmission season), except in 
case of emergency unblinding.

Regimen, dose and route of administration:
This study will evaluate two regimens of the ChAd155-RSV 
vaccine; either one lower dose of 1.5x1010 vp or two doses of 
5x1010 vp will be administered. For the two dose schedule, an 
interval of approximately one month between dosing will be 
used. A single dose arm was added in this 6-7 month-old 
 
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study population before going to target population in 
subsequent studies. 
The dose levels to be evaluated in this study have previously 
been administered to RSV-seropositive infants aged 12 to 23 
months (study RSV PED-002 [204838]) and will have been 
shown to have a satisfactory safety profile and reviewed by 
the IDMC. These doses might be modified following review 
by the IDMC of the safety data from study RSV PED-002 
(204838). However, if no significant safety concerns are 
identified with the highest ChAd155-RSV vaccine dose of 
5x1010 vp administered in the RSV PED-002 study, that dose 
will be the highest does level evaluated in this study.
In the bovine RSV challenge model in seronegative, 
colostrum-restricted newborn calves, both a single and two 
dose regimen of 5x1010 vp ChAd155-RSV have been 
evaluated. The two dose regimen was given at an interval of 
four weeks apart. Both regimens showed a similar level of 
protection against challenge with bovine RSV, but the two 
dose regimen showed higher immunogenicity. Neither 
regimen was associated with pulmonary pathology. 
In this study, infants aged 6 and 7 months will be 
administered the first dose of the ChAd155-RSV vaccine 
before the RSV season to increase the probability of enrolling 
infants unexposed to RSV, and then followed up through the 
RSV season. The second dose will be given one month after 
the first dose. 
Objectives
Primary

To evaluate the safety and reactogenicity of the RSV 
investigational vaccine when administered IM as one
(1.5x1010 vp) dose or as two (5x1010 vp) doses according 
to a 0, 1-month schedule, up to 60 days after Dose 1 (i.e., 
Day 61) in infants aged 6 and 7 months.
Secondary

To evaluate the occurrence of RSV respiratory tract 
infections of any severity from Visit 1 (Day 1, after Dose 
1) up to the end of the first RSV transmission season, in 
infants aged 6 and 7 months.

To evaluate the safety of the RSV investigational vaccine 
when administered IM as one (1.5x1010 vp) dose or as 
two (5x1010 vp) doses according to a 0, 1-month
schedule, from study start (Day 1) up to the end of the 
second RSV transmission season in infants aged 6 and 7 
months.
 
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
To evaluate the occurrence of RSV respiratory tract 
infections from Visit 1 (Day 1, after Dose 1) up to the end 
of the second RSV transmission season, in infants aged 6 
and 7 months.

To evaluate the occurrence of very severe RSV-LRTI 
from Visit 1 (Day 1, after Dose 1) up to the end of the 
first RSV transmission season in RSV infected infants 
aged 6 and 7 months with a negative RSV exposure status 
(at screening based on in-stream baseline serological 
testing).

To evaluate the humoral immunogenicity induced by the 
RSV investigational vaccine when administered IM as 
one (1.5x1010 vp) dose or as two (5x1010 vp) doses 
according to a 0, 1-month schedule, from study start 
(Day 1) up to the end of the first RSV transmission 
season, in infants aged 6 and 7 months.
Tertiary

If deemed necessary, to further characterize the immune 
response of the RSV investigational vaccine when one 
(1.5x1010 vp) dose or two (5x1010 vp) doses are 
administered IM according to a 0, 1-month schedule to
infants aged 6 and 7 months.
Study design

Experimental design: Phase I/II, observer-blind, 
randomized, controlled, multi-centric study with three 
parallel groups.

Duration of the study: approximately 24 months.

Epoch 001: Screening Visit starting up to 30 days 
before first vaccination and ending on Day -1.

Epoch 002: primary starting at Visit 1 (Day 1) and 
ending at Visit 5 (Day 61).

Epoch 003: follow-up starting after Visit 5 (Day 61)* 
and ending at Visit 7 (end of the first RSV 
transmission season).

Epoch 004: follow-up starting after Visit 7 (end of 
the first RSV transmission season)* and ending at 
Visit 8 (end of the second RSV transmission season).
*Any safety, immunogenicity and disease surveillance 
data collected beyond Visit 5 (Day 61) will be collected 
in Epoch 003. Any safety, immunogenicity and disease 
surveillance data collected beyond Visit 7 (end of the first 
RSV transmission season) will be collected in Epoch 004.
 
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
Primary Completion Date (PCD): Visit 5 (Day 61).

End of Study (EoS): Last testing results released of 
samples collected at Visit 8 (end of the second RSV 
transmission season) related to primary and secondary 
endpoints.*
* Up to Visit 8 (end of the second RSV season), there 
will be monthly nasal swab to detect asymptomatic RSV 
infections during the RSV season or if following active or 
a passive surveillance contacts, a subject presents 
symptoms of respiratory tract infection (RTI), a nasal 
swab will be collected.

Study population: healthy infants, born at term, aged 6 
and 7 months (from the day they complete 6 months of 
life for a period of 2 months; for example a child born 01-
Jan-2019 is eligible for the period 01-Jul-2019 through to 
31-Aug-2019).

Study groups:
Synopsis Table 1
Study groups and epochs foreseen in the study
Study groups
Target
Numbers of 
subjects
Age (Min/Max)
Epochs
Epoch 001
Epoch 002
Epoch 003
Epoch 004
1D RSV + Bexsero
50
6 – 7 months
N/A
x
x
x
1D RSV + Nimenrix
6 – 7 months
N/A
x
x
x
1D RSV + Synflorix
6 – 7 months
N/A
x
x
x
1D RSV + Menveo
6 – 7 months
N/A
x
x
x
1D RSV + Placebo
6 – 7 months
N/A
x
x
x
2D RSV + Bexsero
50
6 – 7 months
N/A
x
x
x
2D RSV + Nimenrix
6 – 7 months
N/A
x
x
x
2D RSV + Synflorix
6 – 7 months
N/A
x
x
x
2D RSV + Menveo
6 – 7 months
N/A
x
x
x
2D RSV + Placebo
6– 7 months
N/A
x
x
x
Bexsero
50
6 – 7 months
N/A
x
x
x
Nimenrix
6 – 7 months
N/A
x
x
x
Synflorix
6 – 7 months
N/A
x
x
x
Menveo
6 – 7 months
N/A
x
x
x
Placebo
6 – 7 months
N/A
x
x
x
1D: 1 Dose (1.5x1010 vp/dose); RSV: ChAd155-RSV vaccine; 2D: 2 Dose (5x1010 vp/dose); N/A: Not Applicable. 
 
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Synopsis Table 2
Study groups and treatment foreseen in the study
Treatment name
1D RSV ChAd
2D RSV ChAd
Bexsero
Nimenrix
Synflorix
Menveo
FB
Vaccine/ 
Product name
1D ChAd155-RSV 
1.5X1010vp/dose
2D ChAd155-RSV
5X1010 vp/dose
Bexsero
Nimenrix
Synflorix
Menveo
FB
Study Groups
1D RSV + Bexsero
x
x
x
1D RSV + Nimenrix
x
x
x
1D RSV + Synflorix
x
x
x
1D RSV + Menveo
x
x
x
1D RSV + Placebo
x
x
2D RSV + Bexsero
x
x
2D RSV + Nimenrix
x
x
2D RSV + Synflorix
x
x
2D RSV + Menveo
x
x
2D RSV + Placebo
x
Bexsero
x
x
Nimenrix
x
x
Synflorix
x
x
Menveo
x
x
Placebo
x
ChAd155-RSV: Chimpanzee Adenovirus Type 155 RSV vaccine; FB: Formulation buffer S9b; RSV ChAd: ChAd155-
RSV vaccine; 1D: 1 Dose (1.5x1010 vp/dose); 2D: 2 Dose (5x1010 vp/dose). 

Controls: active comparator vaccines (Bexsero, or 
Nimenrix, or Synflorix, or Menveo, or Placebo
(Formulation buffer [FB])*
* The choice of active comparator vaccine or Placebo
is done at the country level.

Vaccination schedules:
RSV investigational vaccine:

In the 1 Dose (1D) groups, a single lower dose of 
1.5x1010 vp will be administered IM at Day 1 (Visit 1). 
Formulation buffer will be administered in the 1D 
groups at Day 31 (Visit 3). In the 2 Dose (2D) groups, 
two doses of 5x1010 vp will be administered IM 
according to a 0, 1-month schedule, (i.e., at Day 1 
[Visit 1] and Day 31 [Visit 3]) (see Synopsis Table 3). 
Dose 1 will be administered before the first RSV 
season and the second dose will be given one month 
after the first dose (RSV seasons will be determined 
for each country based on local epidemiological data
and documented in the Study Procedures Manual 
[SPM]. The RSV season is defined as the period of the 
year when 70% of the RSV cases have occurred in 
previous years. For the calculation, where available, 
data from up to the ten previous years should be 
 
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applied. If the data permit calculation of the actual date 
of the beginning of the season, rather than 
approximation to the nearest month, this is desirable. 
Comparator or Placebo:

In countries where Bexsero or Nimenrix is used as a 
control, two doses will be administered IM with at 
least a 2 month interval between these primary doses. 
A booster dose will be administered IM in the second 
year of life at Visit 7, with an interval of at least 2 
months between the primary series and booster dose.
The first Bexsero or Nimenrix dose will be 
administered at Day 1 (Visit 1) (in the groups 
receiving only Bexsero or Nimenrix, respectively). In 
the groups receiving only Bexsero or Nimenrix, the 
second dose will be at Day 61 (Visit 5). The first 
Bexsero or Nimenrix dose to be administered to the 
1D and 2D RSV groups will be at Day 61 (Visit 5), 
following the 1 or 2 RSV vaccine doses, respectively.
The second dose of Bexsero or Nimenrix in the 1D and 
2D groups will be at Day 121 (Visit 6). Formulation 
buffer will be administered, when neither RSV vaccine 
nor comparator is scheduled, at the 5th vaccination 
visits (see Synopsis Table 3).

In countries where Synflorix is used as a control, two 
doses will be administered IM with at least a 1 month 
interval between these primary doses. A booster dose 
will be administered IM in the second year of life at 
Visit 7. The first Synflorix dose will be administered at 
Day 31 (Visit 3) (in the group receiving only
Synflorix). In the group receiving only Synflorix, the 
second dose will be at Day 61 (Visit 5). The first
Synflorix dose to be administered to the 1D and 2D 
RSV groups will be at Day 61 (Visit 5), following the 
1 or 2 RSV vaccine doses, respectively. The second 
dose of Synflorix in the 1D and 2D groups will be at 
Day 121 (Visit 6). Formulation buffer will be 
administered, when neither RSV vaccine nor 
comparator is scheduled, at the 5 vaccination visits 
(see Synopsis Table 3).

In countries where Menveo is used as a control, two 
doses will be administered IM at least 3 months apart 
with the second dose in the second year of life at 
Visit 7. The first Menveo dose will be administered at 
Day 31 (Visit 3) (in the group receiving only Menveo). 
The first Menveo dose to be administered to the 1D 
and 2D RSV groups will be at Day 61 (Visit 5), 
 
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following the 1 or 2 RSV vaccine doses, respectively. 
Since the second Menveo dose has to be administered 
in the second year of life at Visit 7, no administration 
will be performed at Day 121 (Visit 6). Formulation 
buffer will be administered, when neither RSV vaccine 
nor comparator is scheduled, at the 4 vaccination visits 
(see Synopsis Table 3). 

In countries where Placebo is used as a control, one 
dose will be administered IM at Day 31 (Visit 3) in the 
1D RSV + Placebo group and two IM doses will be

administered IM according to a 0, 1-month schedule 
at Day 1 (Visit 1) and Day 31 (Visit 3) in the Placebo 
group (see Synopsis Table 3). 
Synopsis Table 3
Vaccines administered and vaccination schedules
Groups
Age* (Months) / (Visit, Day)
6-7 / (V1, D1)
7-8 / (V3, D31) 8-9 / (V5, D61)
10-11 / (V6, D121)**
14-18 / V7
1D RSV + Bexsero
1D RSV ChAd FB
Bexsero
Bexsero
Bexsero
2D RSV + Bexsero
2D RSV ChAd 2D RSV ChAd Bexsero
Bexsero
Bexsero
Bexsero
Bexsero
FB
Bexsero
FB
Bexsero
1D RSV + Nimenrix
1D RSV ChAd FB
Nimenrix
Nimenrix
Nimenrix
2D RSV + Nimenrix
2D RSV ChAd 2D RSV ChAd Nimenrix
Nimenrix
Nimenrix
Nimenrix
Nimenrix
FB
Nimenrix
FB
Nimenrix
1D RSV + Synflorix
1D RSV ChAd FB
Synflorix
Synflorix
Synflorix
2D RSV + Synflorix
2D RSV ChAd 2D RSV ChAd Synflorix
Synflorix
Synflorix
Synflorix
FB
Synflorix
Synflorix
FB
Synflorix
1D RSV + Menveo
1D RSV ChAd FB
Menveo
Menveo
2D RSV + Menveo
2D RSV ChAd 2D RSV ChAd Menveo
Menveo
Menveo
FB
Menveo
FB
Menveo
1D RSV + Placebo
1D RSV ChAd FB
2D RSV + Placebo
2D RSV ChAd 2D RSV ChAd
Placebo
FB
FB
V: Visit; D: Day; 1D: 1 Dose (1.5x1010 vp/dose); 2D: 2 Dose (5x1010 vp/dose); RSV ChAd: ChAd155-RSV vaccine;
FB: Formulation buffer S9b.
* Assumes enrolled at 6 and 7 months of age for the vaccine Dose 1 to be administered before the first RSV season 
(RSV seasons will be determined for each country based on local epidemiological data).
** In countries where Menveo or Placebo is used as a comparator, no administration will be performed at Day 121 and 
therefore in those countries there will be no Visit 6 and it will be administered at the end of the first RSV season at 
Visit 7.

Treatment allocation: infants will be randomized using a 
centralized randomization system on internet (SBIR) before 
first vaccination and after assessment of eligibility (i.e., 
after screening conclusion). The randomization algorithm 
will use a minimization procedure accounting for country 
as a minimization factor and the grouping 
comparator/placebo as a stratification factor.
 
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
Blinding: not applicable for Epoch 001 (Screening Visit), 
observer-blind in Epoch 002 and single-blind in Epoch 003
and Epoch 004.
Synopsis Table 4
Blinding of study epochs
Study Epochs
Blinding
Epoch 001
N/A
Epoch 002
observer-blind
Epoch 003
single-blind
Epoch 004
single-blind
N/A: Not applicable.

Sampling schedule:

Blood samples for hematology/biochemistry will be 
taken from all infants at Screening (up to 30 days 
before first vaccination to Day -1). Blood samples for 
hematology/biochemistry may be taken from infants 
at any timepoints, if deemed necessary by the 
investigator.

Blood samples for humoral immunogenicity will be 
taken from all subjects at Screening and on Day 31, 
Day 61, and at the visit occurring at the end of the first 
RSV transmission season.

Blood sample for assessment of mechanism of illness 
(potential enhanced RSV disease [ERD]) will be 
taken from subjects hospitalized for LRTI (required 
only for RSV-positive subjects using a locally 
available RSV test).

Nasal swab: there will be monthly nasal swab to detect 
asymptomatic RSV infections during the RSV season 
and if following active or a passive surveillance 
contacts, a subject presents symptoms of respiratory 
tract infection (RTI), a nasal swab will be collected (as 
well as a sample for local testing i.e., the type of 
sample to be determined locally [e.g., swab, etc.]).

Study visits: Other than the screening visit and assessment 
visits for active/passive surveillance, there will be 8 study 
visits except in countries where Menveo or Placebo is used 
as a control where there will be 7 study visits.

In countries where Menveo is used as a comparator, no 
administration will be performed at Day 121 and 
therefore in those countries there will be no Visit 6 and 
Menveo will be administered at the end of the first 
RSV season at Visit 7.

In countries where Placebo is used as a control, no 
vaccine administration will be performed after Visit 3 
 
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and therefore in those countries there will be no Visit 
6. There will be a Visit 5 and Visit 7 for countries 
using Placebo and all other study procedures will occur 
at these visits except vaccination.

Visit 2 (Day 8), Visit 4 (Day 38), and Visit 8 no blood 
sampling for immune response and no vaccine 
administration) may take place in the subject’s home 
or at the investigators clinical facility as appropriate to 
the circumstances in the judgment of the investigator. 
For authorized sites only, Visit 5 (Day 61) and Visit 7 (both 
with blood sampling) may also take place in the subject’s 
home or at the investigators clinical facility as appropriate 
to the circumstances in the judgment of the investigator. 

Type of study: self-contained.

Data collection: Electronic Case Report Form (eCRF).

Safety monitoring: internal safety review committee 
(iSRC) and IDMC.

Surveillance for RSV-RTI, difficulty in breathing, and 
wheezing episodes.
Surveillance period will be carried out from Visit 1 (after 
Dose 1) until the last study visit (end of the second RSV 
transmission season). In order to detect asymptomatic 
RSV-RTI, monthly nasal swabs for analysis at sponsor 
laboratory will be performed for all subjects during the 
RSV season. In order to timely detect RSV-RTI and to 
ensure cases are timely captured by the study sites, both 
active and passive surveillance will be conducted:

Passive surveillance: parent(s)/LAR(s) are instructed 
to contact the investigator/study staff as soon as the 
subject experiences new RTI symptoms (cough, runny 
nose or blocked nose) or worsening of RTI symptoms, 
or in case of difficulty in breathing or wheezing.

Active surveillance: parent(s)/LAR(s) of all the 
subjects will be contacted by the investigator/study 
staff on a regular basis (weekly during the RSV season 
and every month outside the RSV season) to identify 
any potential RSV-RTI and to remind the 
parent(s)/LAR(s) of the subjects to report any new 
occurrence of RTI symptoms (cough, runny nose, 
blocked nose), or in case of difficulty in breathing or 
wheezing as soon as possible.
 
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
Surveillance for spontaneous or excessive bleeding.
Subjects’ parent(s)/LAR(s) will be instructed to contact the 
investigator/study staff if their child presents symptoms of 
spontaneous bleeding or easy bruising or if their child 
develops a rash, within 30 days after either vaccination 
(Visit 1 and Visit 3), in order to detect any 
thrombocytopenic petechiae or purpura. The investigator 
will, based on his/her medical judgment, measure the total 
blood count and appropriately investigate infants with 
clinical suspicion of low platelets.
Case definition
During the analysis of the study, all cases identified during the 
surveillance of RSV-RTI will be definitively classified as either 
RTI, LRTI, severe LRTI or very severe LRTI according to the 
standardized case definitions (see Synopsis Table 5) based on 
the available World Health Organization (WHO) case 
definitions.
Synopsis Table 5
Case definitions for data analysis
Case
At sea level up to 2500 meters elevation
Above 2500 meters elevation
RSV-RTI
Runny nose OR blocked nose OR cough
AND 
Confirmed RSV infection 4
Same
RSV-LRTI
History of cough OR difficulty breathing 1
AND
SpO2 < 95% 2, OR RR increase 3
AND
Confirmed RSV infection 4
Same but with SpO2 <92%
severe RSV-LRTI
Meeting the case definition of RSV-LRTI 
AND
SpO2 < 93% 2, OR lower chest wall in-drawing
Same but with SpO2 <90%
very severe RSV-LRTI
Meeting the case definition of RSV-LRTI 
AND 
SpO2 < 90% 2, OR inability to feed, OR failure 
to respond / unconscious
Same but with SpO2 <88%
RSV hospitalization
Confirmed RSV infection 5
AND
Hospitalized for acute medical condition 6
Same
All-cause LRTI
History of cough OR difficulty breathing 1
AND 
SpO2 < 95% 2, OR RR increase 3
Same but with SpO2 <92%
Definitions based on [Modjarrad, 2016]
LRTI = lower respiratory tract infections; RR = respiratory rate; RTI = respiratory tract infections; SpO2 = Blood oxygen 
saturation by pulse oximetry.
1 Based on history reported by parents.
2 The lowest value during the course of illness will be used.
3 RR increase defined as:
50/minute (2 to 11 months of age)
40/minute (12 months of age or above)
The highest value during the course of the illness will be used.
4 RSV infection confirmed on nasal swab positive for RSV A or B by quantitative Reverse Transcription Polymerase 
Chain Reaction (qRT-PCR).
5 RSV sampling and testing is based on medical judgment of medical practitioner or driven by algorithm.
6 Hospitalization is defined as a medical decision that the infant requires admission for observation or treatment.
 
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Number of subjects
The target will be to enroll approximately 150 infants likely to 
be previously unexposed to RSV with about 50 infants for each 
of three randomization groups. If necessary, the sample size 
may be increased through additional recruitment in order to 
achieve a sufficient number of RSV infected infants, with a 
negative RSV exposure status (at screening based on in-stream 
baseline serological testing), in each RSV vaccine group. Dose 
1 of the ChAd155-RSV vaccine should be administered before 
the first RSV season and second dose will be given one month 
after the first dose (RSV seasons will be determined for each 
country based on local epidemiological data and documented in 
the SPM. The RSV season is defined as the period of the year 
when 70% of the RSV cases have occurred in previous years. 
For the calculation, where available, data from up to the ten 
previous years should be applied. If the data permit calculation 
of the actual date of the beginning of the season, rather than 
approximation to the nearest month, this is desirable.)
(Amended 1 August 2019).
Endpoints
Primary

Occurrence of adverse events (AEs) from first vaccination 
(Day 1) up to Day 61.

Occurrence of each solicited local and general AE, 
during a 7-day follow-up period after each vaccination 
(i.e., the day of vaccination and 6 subsequent days).

Occurrence of any unsolicited AE, during a 30-day 
follow-up period after each vaccination (i.e., the day of 
vaccination and 29 subsequent days).

Occurrence of any serious adverse event (SAE) from 
Day 1 up to Day 61.

Occurrence of episode of spontaneous or excessive 
bleeding (AE of special interest), during a 30-day 
follow-up period after each vaccination.
Secondary

Occurrence of RSV-RTI, RSV-LRTI, severe RSV-LRTI 
and very severe RSV-LRTI (according to standardized case 
definitions) as from first vaccination (Day 1) up to the end 
of the first RSV transmission season.

Occurrence of RSV-RTI, RSV-LRTI, severe RSV-LRTI 
and very severe RSV-LRTI (according to standardized case 
definitions) as from first vaccination (Day 1) up to the end 
of the second RSV transmission season.
 
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
Occurrence of SAEs from first vaccination (Day 1) up to 
the end of the second RSV transmission season.

Occurrence of RSV-LRTI (AE of special interest) as from 
first vaccination (Day 1) up to the end of the first RSV 
transmission season, and up to the end of the second RSV 
transmission season.

Occurrence of very severe RSV-LRTI (according to 
standardized case definitions) among RSV infected infants 
with a negative RSV exposure status (at screening based on 
in-stream baseline serological testing) from first 
vaccination (Day 1) up to the end of the first RSV 
transmission season.

Humoral response to the investigational RSV vaccine, pre-
vaccination (Screening), post-Dose 1 (Day 31) and post-
Dose 2 (Day 61 and at the end of the first RSV 
transmission season):

Neutralizing antibody titers against RSV-A.

RSV F antibody concentrations.
Tertiary

Humoral response to the investigational RSV vaccine, pre-
vaccination (Screening), post-Dose 1 (Day 31) and post-
Dose 2 (Day 61).

Palivizumab-competing antibody concentrations.

Any further exploratory immunology to detect disease-
related or vaccine-related immune responses, such as but 
not limited to:

Anti-vector immunity: neutralization.
 
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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
1.1.1.
RSV disease burden....................................................................39
1.1.2.
Current management of RSV disease in infants...........................39
1.1.3.
History of enhanced RSV disease with formalin-
inactivated RSV vaccines ............................................................40
1.1.3.1.
Clinical symptoms of FI-RSV enhanced RSV 
disease.......................................................................40
1.1.3.2.
Serum immune responses to the FI-RSV 
vaccine and to subsequent RSV infection...................42
1.1.3.3.
Pathological observations of RSV disease in 
FI-RSV vaccinated children ........................................42
1.1.3.4.
Animal models for “FI-RSV enhanced RSV 
disease”......................................................................43
1.1.3.5.
Pathophysiology of “FI-RSV enhanced RSV 
disease”......................................................................43
1.1.4.
Rationale for a viral vector-based RSV vaccine ...........................44
1.1.5.
Antigens selected for the vaccine ................................................45
1.1.6.
Pre-clinical experience.................................................................45
1.1.7.
Clinical experience.......................................................................46
1.2.
Rationale for the study and study design ....................................................46
1.2.1.
Rationale for the study.................................................................46
1.2.2.
Rationale for the choice of study population.................................47
1.2.2.1.
Study population.........................................................47
1.2.2.2.
Choice of study population .........................................47
1.2.2.3.
In-stream serological testing of baseline 
samples to determine exposure status 
(Amended 1 August 2019)..........................................47
1.2.3.
Rationale for regimen, dose and route of administration ..............48
1.2.4.
Rationale for safety monitoring plan.............................................49
1.2.4.1.
Rationale for RSV disease surveillance......................49
1.2.4.2.
Rationale for monitoring for spontaneous or 
excessive bleeding .....................................................50
1.2.5.
Rationale for study blinding..........................................................51
1.2.6.
Rationale for the use of controls ..................................................51
1.2.7.
Rationale for ChAd155 RSV vaccine recipients receiving 
active comparator vaccine ...........................................................52
1.3.
Benefit : Risk Assessment ..........................................................................52
1.3.1.
Risk Assessment .........................................................................52
 
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1.3.2.
Benefit Assessment.....................................................................53
1.3.3.
Overall Benefit:Risk Conclusion...................................................54
2.
OBJECTIVES.........................................................................................................54
2.1.
Primary objective ........................................................................................54
2.2.
Secondary objectives..................................................................................55
2.3.
Tertiary objectives.......................................................................................55
3.
STUDY DESIGN OVERVIEW ................................................................................56
4.
CASE DEFINITION ................................................................................................64
4.1.
RTI case definitions ....................................................................................64
5.
STUDY COHORT...................................................................................................65
5.1.
Number of subjects.....................................................................................65
5.2.
Inclusion criteria for enrolment....................................................................65
5.3.
Exclusion criteria for enrolment...................................................................66
6.
CONDUCT OF THE STUDY ..................................................................................68
6.1.
Regulatory and ethical considerations, including the informed 
consent process..........................................................................................68
6.2.
Subject identification and randomization.....................................................69
6.2.1.
Subject identification....................................................................69
6.2.2.
Randomization of treatment.........................................................69
6.2.2.1.
Randomization of supplies..........................................69
6.2.2.2.
Treatment allocation to the subject.............................69
6.2.2.2.1.
Study group and treatment 
number allocation ...................................69
6.2.2.2.2.
Treatment number allocation for 
subsequent doses ..................................70
6.3.
Method of blinding ......................................................................................71
6.4.
General study aspects ................................................................................71
6.5.
Outline of study procedures ........................................................................72
6.6.
Detailed description of study procedures ....................................................77
6.6.1.
Informed consent.........................................................................77
6.6.2.
Screening visit .............................................................................77
6.6.3.
Check inclusion and exclusion criteria .........................................77
6.6.4.
Collect demographic data ............................................................78
6.6.5.
Medical history.............................................................................78
6.6.6.
Physical examination ...................................................................78
6.6.7.
Growth monitoring .......................................................................78
6.6.8.
Check contraindications, warnings and precautions to 
vaccination...................................................................................78
6.6.9.
Assess pre-vaccination body temperature ...................................78
6.6.10.
Randomization.............................................................................79
6.6.11.
Study vaccines administration......................................................79
6.6.12.
Sampling......................................................................................79
6.6.12.1.
Blood sampling for humoral immunity.........................79
6.6.12.2.
Blood sampling for hematology and 
biochemistry ...............................................................80
6.6.12.3.
Nasal swab or other specimen for PCR assay............82
6.6.13.
Surveillance for RSV-RTI and wheezing ......................................82
 
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6.6.14.
Check and record concomitant medication/vaccination................83
6.6.15.
Recording of AEs, AEs of special interest and SAEs ...................83
6.6.16.
Screening conclusion...................................................................83
6.6.17.
Signing of investigator signature form by investigator ..................84
6.6.18.
Study conclusion..........................................................................84
6.7.
Biological sample handling and analysis.....................................................84
6.7.1.
Use of specified study materials ..................................................85
6.7.2.
Biological samples.......................................................................86
6.7.3.
Laboratory assays .......................................................................86
6.7.4.
Biological samples evaluation......................................................90
6.7.4.1.
Immunological read-outs ............................................90
6.7.5.
Immunological correlates of protection.........................................92
7.
STUDY VACCINES AND ADMINISTRATION ........................................................92
7.1.
Description of study vaccines......................................................................92
7.2.
Storage and handling of study vaccines......................................................94
7.3.
Dosage and administration of study vaccines .............................................94
7.4.
Replacement of unusable vaccine doses....................................................96
7.5.
Contraindications to subsequent vaccination ..............................................97
7.6.
Concomitant medications/products and concomitant vaccinations..............97
7.6.1.
Recording of concomitant medications/products and 
concomitant vaccinations.............................................................98
7.6.2.
Concomitant medications/products/vaccines that may lead 
to the elimination of a subject from per-protocol analyses............99
8.
HEALTH ECONOMICS ..........................................................................................99
9.
SAFETY.................................................................................................................99
9.1.
Safety definitions ......................................................................................100
9.1.1.
Definition of an adverse event....................................................100
9.1.2.
Definition of a serious adverse event .........................................101
9.1.3.
Solicited adverse events............................................................102
9.1.3.1.
Solicited local (injection-site) adverse events............102
9.1.3.2.
Solicited general adverse events..............................102
9.1.4.
Clinical laboratory parameters and other abnormal 
assessments qualifying as adverse events or serious 
adverse events ..........................................................................102
9.1.5.
Adverse events of special interest..............................................103
9.1.5.1.
Spontaneous or excessive bleeding .........................103
9.1.5.2.
RSV-LRTI.................................................................103
9.2.
Surveillance for RSV-RTI, difficulty in breathing and wheezing 
episodes ...................................................................................................103
9.2.1.
Passive surveillance ..................................................................105
9.2.2.
Surveillance for asymptomatic RSV-RTI ....................................105
9.2.3.
Active surveillance .....................................................................106
9.2.4.
Assessment visit........................................................................107
9.2.5.
Subject hospitalized for LRTI .....................................................107
9.3.
Detecting and recording adverse events, adverse events of special 
interest and serious adverse events..........................................................108
9.3.1.
Time period for detecting and recording adverse events, 
adverse events of special interest and serious adverse 
events........................................................................................108
 
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9.3.2.
Post-Study adverse events and serious adverse events............110
9.3.3.
Evaluation of adverse events and serious adverse events.........110
9.3.3.1.
Active questioning to detect adverse events 
and serious adverse events......................................110
9.3.3.2.
Assessment of adverse events.................................111
9.3.3.2.1.
Assessment of intensity........................111
9.3.3.2.2.
Assessment of causality .......................112
9.3.3.3.
Assessment of outcomes..........................................113
9.3.3.4.
Medically attended visits...........................................113
9.4.
Reporting of serious adverse events and adverse events of special 
interest......................................................................................................114
9.4.1.
Prompt reporting of serious adverse events and adverse 
events of special interest to GSK Biologicals .............................114
9.4.2.
Contact information for reporting serious adverse events 
and adverse events of special interest.......................................114
9.4.3.
Completion and transmission of SAE reports to GSK 
Biologicals .................................................................................115
9.4.3.1.
Back-up system in case the electronic 
reporting system does not work................................115
9.4.4.
Reporting of adverse events of special interest to GSK 
Biologicals .................................................................................115
9.4.4.1.
RSV-LRTI.................................................................115
9.4.4.2.
Spontaneous or excessive bleeding .........................116
9.4.5.
Updating of serious adverse event and adverse event of 
special interest information after removal of write access 
to the subject’s eCRF.................................................................116
9.4.6.
Regulatory reporting requirements for serious adverse 
events........................................................................................116
9.5.
Follow-up of adverse events, serious adverse events and adverse 
events of special interest ..........................................................................117
9.5.1.
Follow-up during the study.........................................................117
9.5.1.1.
Follow-up after the subject is discharged from 
the study...................................................................117
9.6.
Treatment of adverse events ....................................................................117
9.7.
Unblinding.................................................................................................118
9.8.
Emergency unblinding ..............................................................................118
9.9.
Subject card..............................................................................................119
9.10.
Holding rules and safety monitoring..........................................................119
9.10.1.
Limited vaccination ....................................................................119
9.10.2.
Internal safety review committee (iSRC) oversight.....................119
9.10.3.
Independent Data Monitoring Committee (IDMC) oversight.......120
9.10.4.
Holding rules..............................................................................122
9.10.5.
Procedure if the trial is put on hold.............................................124
10. SUBJECT COMPLETION AND WITHDRAWAL...................................................124
10.1.
Subject completion ...................................................................................124
10.2.
Subject withdrawal....................................................................................124
10.2.1.
Subject withdrawal from the study .............................................124
10.2.2.
Subject withdrawal from study vaccine ......................................125
10.3.
Extension study ........................................................................................126
10.4.
Screen and baseline failures.....................................................................126
 
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11. STATISTICAL METHODS....................................................................................126
11.1.
Primary endpoints.....................................................................................126
11.2.
Secondary endpoints ................................................................................127
11.3.
Tertiary endpoints.....................................................................................127
11.4.
Determination of sample size....................................................................127
11.5.
Cohorts for Analyses ................................................................................129
11.5.1.
Exposed Set ..............................................................................129
11.5.2.
Exposed Set of subjects with a negative RSV exposure 
status.........................................................................................130
11.5.3.
Per-protocol Set for analysis of immunogenicity.........................130
11.5.4.
Pooled groups in the study ........................................................132
11.6.
Derived and transformed data...................................................................132
11.6.1.
Demography..............................................................................132
11.6.2.
Safety ........................................................................................132
11.6.3.
Immunogenicity..........................................................................133
11.6.4.
RTI and LRTI.............................................................................133
11.7.
Analysis of demographics.........................................................................134
11.8.
Analysis of safety......................................................................................134
11.8.1.
Within groups assessment.........................................................134
11.8.2.
Between groups assessment.....................................................136
11.9.
Analysis of immunogenicity.......................................................................136
11.9.1.
Within groups assessment.........................................................136
11.9.1.1.
Analysis of secondary objectives..............................136
11.9.1.2.
Analysis of tertiary objective .....................................137
11.10. Analysis of RTI and LRTI..........................................................................137
11.11. Interpretation of analyses..........................................................................138
11.12. Conduct of analyses .................................................................................138
11.12.1. Sequence of analyses................................................................139
11.12.2. Statistical considerations for interim analyses............................139
12. ADMINISTRATIVE MATTERS .............................................................................139
12.1.
electronic Case Report Form instructions .................................................139
12.2.
Study Monitoring by GSK Biologicals........................................................140
12.3.
Record retention .......................................................................................141
12.4.
Quality assurance.....................................................................................141
12.5.
Posting of information on publicly available clinical trial registers and 
publication policy ......................................................................................141
12.6.
Provision of study results to investigators .................................................142
12.7.
Data Sharing.............................................................................................142
13. COUNTRY SPECIFIC REQUIREMENTS.............................................................142
13.1.
Requirements for Belgium ........................................................................142
14. REFERENCES.....................................................................................................143
 
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LIST OF TABLES
PAGE
Table 1
Overview of impact of FI-RSV vaccination on age-related RSV 
disease ..................................................................................................41
Table 2
Vaccines administered and vaccination schedules.................................58
Table 3
Study groups and epochs foreseen in the study.....................................59
Table 4
Study groups and treatment foreseen in the study .................................60
Table 5
Blinding of study epochs ........................................................................62
Table 6
Case definitions for data analysis...........................................................64
Table 7
List of study procedures .........................................................................72
Table 8
Target intervals between study visits......................................................77
Table 9
Biological samples .................................................................................86
Table 10
Humoral Immunity (Antibody determination)...........................................87
Table 11
Molecular Biology (PCR tests)................................................................88
Table 12
Hematology and biochemistry tests........................................................89
Table 13
Immunological read-outs........................................................................90
Table 14
Molecular biology for nasal swab and specimen analysis.......................91
Table 15
Study vaccines.......................................................................................93
Table 16
Dosage and administration.....................................................................95
Table 17
Solicited local adverse events ..............................................................102
Table 18
Solicited general adverse events..........................................................102
Table 19
Reporting periods for collecting safety information (Amended 1 
August 2019)........................................................................................109
Table 20
Intensity scales for solicited symptoms in infants..................................111
Table 21
Timeframes for submitting serious adverse event and adverse 
events of special interest reports to GSK Biologicals............................114
Table 22
Holding rules assessed by the investigator...........................................122
Table 23
Holding rules during the planned iSRC or IDMC evaluation .................122
 
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Table 24
Maximum allowed interval between study visits (Amended 1 
August 2019)........................................................................................131
Table 25
Pooled groups......................................................................................132
Table 26
GSK Biologicals’ laboratories ...............................................................151
Table 27
Outsourced laboratories.......................................................................151
Table 28
Toxicity grading scales for hematology and biochemistry 
parameters applicable for this study.....................................................152
 
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LIST OF FIGURES
PAGE
Figure 1
Study design ..........................................................................................56
Figure 2
Schematic overview of required additional hematology and 
biochemistry testing during the study .....................................................81
Figure 3
Decision tree for passive and active surveillance contacts ...................104
Figure 4
Evaluations based on 30 or 50 enrolled subjects - Risk 
assessment curve for one formulation based on the proposed 
safety holding rules assessed by the investigator and the 
sponsor................................................................................................123
Figure 5
Evaluations based on 50 subjects per group - Risk assessment 
curve for one formulation based on the proposed safety holding 
rules during the planned IDMC evaluation............................................123
Figure 6
Exact 95% confidence interval on the proportion of subjects with 
adverse events following vaccination based on 50 enrolled 
subjects................................................................................................129
 
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LIST OF APPENDICES
PAGE
APPENDIX A LABORATORY ASSAYS .....................................................................148
APPENDIX B CLINICAL LABORATORIES ................................................................151
APPENDIX C TOXICITY GRADING FOR HEMATOLOGY AND 
BIOCHEMISTRY PARAMETERS ........................................................152
APPENDIX D THE SYMPTOMS AND GRADING FOR ASSESSMENT VISITS 
AND WORSENING VISITS..................................................................153
APPENDIX E AMENDMENTS AND ADMINISTRATIVE CHANGES TO THE 
PROTOCOL.........................................................................................157
 
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LIST OF ABBREVIATIONS
AE:
Adverse Event
AESI:
Adverse Events of Special Interest
CD (CD4, CD8):
Cluster of Differentiation (4, 8)
ChAd155:
Chimpanzee Adenovirus Type 155
ChAd155-RSV:
Investigational recombinant chimpanzee adenovirus Type 
155-vectored RSV vaccine
CI:
Confidence Interval
CLS:
Clinical laboratory sciences
eCRF:
electronic case report form
ELISA:
Enzyme-Linked Immunosorbent Assay
EoS:
End of Study
ERD:
Enhanced RSV disease
ES:
Exposed Set 
F:
RSV fusion protein
FB:
Formulation buffer (S9b) 
FI-PIV:
Formalin-Inactivated Parainfluenza Virus vaccine
FI-RSV:
Formalin-Inactivated whole virus RSV vaccine
GCP:
Good Clinical Practice
GMC:
Geometric Mean Concentration
GMT:
Geometric Mean Titer
GSK:
Glaxosmithkline
HIV:
Human Immunodeficiency Virus
HR:
Heart Rate
HRP:
Horse-Radish Peroxidase 
IB:
Investigator Brochure
 
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ICF:
Informed Consent Form
ICH:
International Conference on Harmonization
ICS:
Intracellular Staining
IDMC:
Independent Data Monitoring Committee
IEC:
Independent Ethics Committee
IgG :
Immunoglobulin G
IM:
Intramuscular
IMP:
Investigational Medicinal Product
IND:
Investigational New Drug
IRB:
Institutional Review Board
iSRC:
Internal Safety Review Committee
LAR:
Legally Acceptable Representative
LRTI:
Lower Respiratory Tract Infection
LSLV:
Last subject last visit
M2-1:
RSV matrix protein
MedDRA:
Medical dictionary for regulatory activities
mm³:
cubic millimeter
N:
RSV nucleocapsid protein
PCD
Primary Completion Date
PCR:
Polymerase Chain Reaction
PPS:
Per-Protocol Set 
RNA:
Ribonucleic Acid
RR:
Respiratory Rate
RSV:
Respiratory Syncytial Virus
RSV-RTI:
Respiratory Tract Infection associated with RSV infection
 
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RTI:
Respiratory Tract Infection
RVP:
Respiratory Viral Panel
SAE:
Serious Adverse Event
SAP:
Statistical Analysis Plan 
SBIR:
Randomization system on internet
SDV:
Source Document Verification
SmPC:
Summary of Product Characteristics
SPM:
Study procedures manual
SpO2:
Blood oxygen saturation by pulse oximetry
TLR:
Toll-like receptor 
UK:
United Kingdom 
ULN:
Upper Limit Of Normal
vp:
Viral Particles
VSMB:
Vaccine Safety Monitoring Board
WHO:
World Health Organization
 
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GLOSSARY OF TERMS
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.
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 6.3 for 
details on observer-blinded studies). 
Child in care:
A child who has been placed under the control or 
protection of an agency, organization, institution or entity 
by the courts, the government or a government body, 
acting in accordance with powers conferred on them by 
law or regulation. The definition of a child in care can 
include a child cared for by foster parents or living in a 
care home or institution, provided that the arrangement 
falls within the definition above. The definition of a child 
in care does not include a child who is adopted or has an 
appointed legal guardian.
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).
 
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For studies with collection of Human Biologicals 
Samples or imaging data, study completion 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. Study completion 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.
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 7.6.2
and 11.5 for details on criteria for evaluability).
Exposed Set
All subjects who received at least 1 dose of the study 
treatment. The allocation in a group is done in function of 
the administered treatment.
Grade 1 abnormality 
with potential clinical 
relevance
Grade 1 laboratory parameters which cannot be explained 
or which are judged by the investigator to be potentially 
clinically relevant (refer to APPENDIX C).
Grade 1 abnormality 
without clinical relevance
Grade 1 laboratory parameters which can be explained by
a condition which is not related to vaccination and does 
not increase the risk for an adverse outcome of 
vaccination (refer to APPENDIX C).
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.
Infant:
As per US Food and Drug Administration’s definition an 
infant is aged one month to two years.
 
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Investigational vaccine:
(Synonym of 
Investigational Medicinal 
Product)
A pharmaceutical form of an active ingredient being 
tested in a clinical trial, including a product with a 
marketing authorization when used in a way different 
from the approved form, or when used for an unapproved 
indication, or when used to gain further information about 
an approved use.
Legally acceptable 
representative
(The terms legal 
representative or legally 
authorized 
representative are used 
in some settings.)
An individual or juridical or other body authorized under 
applicable law to consent, on behalf of a prospective 
subject, to the subject's participation in the clinical trial.
Per Protocol Set
Subset of subjects in the exposed set (ES) who have 
complied with eligibility criteria, study procedures up to 
the time point of analysis and who have availability of 
measurement(s) for the analysis variable(s) of interest
(Amended 1 August 2019).
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 Harmonization (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.
Site Monitor:
An individual assigned by the sponsor who is responsible 
for assuring proper conduct of clinical studies at one or 
more investigational sites.
 
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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 as a reference or 
administered concomitantly, in a clinical trial that 
evaluates the use of an investigational vaccine/product.
Subject:
Term used throughout the protocol to denote an 
individual who has been contacted in order to participate 
or participates in the clinical study, either as a recipient of 
the vaccine(s) 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) 
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 products 
will be written without the superscript symbol ™ or ® and in italics.
Trademarks of the GSK group of 
companies
Generic description
Bexsero
Meningococcal group B vaccine 
(recombinant, adsorbed)
Menveo
Meningococcal (Groups A, C, Y and W-135) 
Oligosaccharide Diphtheria CRM197 
Conjugate Vaccine
Nimenrix (licensed to Pfizer)
Meningococcal group A, C, W-135 and Y 
conjugate vaccine
Synflorix
Pneumococcal polysaccharide conjugate 
vaccine (adsorbed)
Trademarks not owned by the GSK group 
of companies
Generic description
Synagis (MedImmune)
Recombinant humanized monoclonal anti-
RSV antibodies
Allplex (Seegene)
Respiratory panel assay
TrueBlue (SeraCare)
Peroxidase substrate
 
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1.
INTRODUCTION
1.1.
Background
1.1.1.
RSV disease burden
Respiratory syncytial virus (RSV) is a ribonucleic acid virus of which two 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.
During the first year of life, 50-70% of infants are infected with RSV and essentially all 
children have had an RSV infection by their second birthday. The risk for severe 
RSV-associated lower respiratory tract infections (LRTI) is highest in infants below 
6 months of age and is a leading cause of hospitalization. It is estimated that on average 
31 per 1000 children below 6 months of age are hospitalized for RSV-associated LRTI 
Boyce, 2000; Deshpande, 2003; Hall, 2009; Holman, 2004; Iwane, 2004; Paramore, 
2004; Vicente, 2003. 50-70% of these hospitalized children do not have additional risk 
factors like preterm birth or cardiopulmonary disease Boyce, 2000; García, 2010; Hall, 
2009; Rietveld, 2004. For human immunodeficiency virus (HIV)-infected children, the 
incidence rate of hospitalization for RSV-associated LRTI was reported to be 2.5- to 5-
fold greater than in HIV-uninfected children Cohen, 2015; Madhi, 2006. Although RSV 
hospitalization rates substantially decrease after 6 months of age, a considerable number 
of RSV infections in children of 6-15 months of age, still lead to bronchiolitis or 
(broncho)pneumonia requiring medical attention [Fisher, 1997].
Previous infection with RSV does not prevent subsequent infections. Therefore, re-
infection with RSV occurs throughout an individual’s lifetime and is common in all age 
groups [Simoes, 1999; Krilov, 2011]. These re-infections generally go undiagnosed 
because they usually present as common acute upper respiratory tract infections. In more 
vulnerable persons (e.g., immunocompromized subjects or elderly), re-infections can 
however also lead to severe disease [Graham, 2011].
1.1.2.
Current management of RSV disease in infants
To date, no vaccine is available against RSV and treatment of RSV disease is largely 
symptomatic and supportive care [Murray, 2014].
The antiviral drug ribavirin is currently the only approved antiviral therapy for RSV 
treatment, but its use is restricted to severe hospitalized cases due to uncertainties 
regarding its efficacy, difficulty in administration (aerosol) and high cost American 
Academy of Pediatrics Subcommittee on Diagnosis and Management of Bronchiolitis, 
2006.
RSV-specific monoclonal antibodies (palivizumab, Synagis) are indicated for use in 
infants at highest risk for severe RSV disease. Synagis is only effective as prophylaxis 
and is not indicated or recommended in the general, healthy infant population.
 
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1.1.3.
History of enhanced RSV disease with formalin-inactivated RSV 
vaccines
In the late sixties, following initial encouraging results in small clinical trials, field 
evaluation trials of a formalin inactivated vaccine targeting RSV, called FI-RSV, were 
initiated in the United States. FI-RSV was cultured on monkey kidney cells, harvested, 
inactivated with formalin and aluminum-precipitated (FI-RSV lot 100). Four clinical 
studies in different age groups were conducted in parallel in 1965-1967 [Chin, 1969; 
Fulginiti, 1969; Kapikian, 1969; Kim, 1969]. The study results indicated that the FI-RSV 
vaccine did not protect against infection with the respective virus. In addition, children 
who had been vaccinated with the FI-RSV vaccine developed more severe clinical 
symptoms upon subsequent natural infection with RSV compared to the children who had 
not been vaccinated with the FI-RSV vaccine (resulting in 2 deaths in the study in which 
the youngest children were vaccinated [Kim, 1969]). This observation is referred to as 
“FI-RSV enhanced RSV disease” (ERD) in this document. 
1.1.3.1.
Clinical symptoms of FI-RSV enhanced RSV disease
The key clinical observations from the FI-RSV trials are summarized below. These need 
to be taken into consideration when defining potential safety signals during the clinical 
development of new RSV vaccine candidates.
Age at the time of FI-RSV vaccination
The four studies included children aged between 2 months and 9 years. When comparing 
the different age strata at which children were vaccinated in these studies (Young infants 
[0-5 months]; Older infants [6-11 months]; Toddlers [12-23 months]; Children [≥24 
months]), the most prominent increase in RSV-associated LRTI and hospitalization 
following FI-RSV vaccination was observed in children vaccinated at younger age. In the 
study where the youngest subjects were vaccinated [Kim, 1969], 2 of the vaccinated 
children died, one at the age of 14 months, the other at the age of 16 months. Each had 
received three vaccine doses, the first one beginning at the age of 2 months, the other one 
at the age of 5 months.
 
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Table 1
Overview of impact of FI-RSV vaccination on age-related RSV 
disease
Condition Source
Def 
0-5m*
6-11m*
12-23m*
≥24m*
FI-RSV Cont
FI-RSV
Cont
FI-RSV
Cont
FI-RSV
Cont
Severe 
RSV-LRTI 
[Kim, 1969] 
season 1
Hospitali-
sation
20% 
(4/20)
0%
(0/20)
[Kim, 1969] 
season 2 †
Hospitali-
sation
51% 
(16/31)
2.5% 
(1/40)
[Fulginiti, 
1969]l
Hospitali-
sation
13.7%
(7/54)
1.5% 
(1/65)
5% 
(3/60)
0.92% 
(1/108)
0.28% 
(1/353)
0% 
(0/364)
[Kapikian, 
1969]
Hospitali-
sation
FI-RSV: 33% (5/15)
Cont: 0% (0/48)
0% (0/22)
0% 
(0/61)
All RSV-
LRTI 
[Chin, 1969]
MAARI
30.2% 
(13/43)
11.6% 
(5/43)
FI-RSV: 1.3% (2/148)
Control: 2.6% (4/151)
[Kapikian, 
1969]
LRTI 
(crepitation)
100% 
(2/2)
14.3% 
(1/7)
53.8% 
(7/13)
7.3% 
(3/41)
18%§
(4/22)
11.4% 
(7/61)
m: months; MAARI : medically-attended acute respiratory infection (Emergency room)
* Age at time of vaccination – Age at time of disease can be several months later.
† During season 2, average age of the subjects was 12 months
§ All cases in subjects <36 months old.
Specific/ defining clinical symptoms
In the four studies an attempt was made to identify specific/ defining clinical symptoms 
of the “FI-RSV enhanced RSV disease” by comparing the clinical picture of these 
patients with unvaccinated matched control subjects diagnosed with severe RSV disease 
or with patients suffering from RSV-associated LRTI in the control group. However, 
apart from the unexpected severity, none of the observed symptoms were unique in FI-
RSV vaccinated patients. Therefore, no specific/ defining symptom can be monitored as a 
safety signal in order to detect a similar adverse effect of new RSV vaccine candidates 
during clinical development. Finally, no increased incidence of RSV-associated 
respiratory disease of the upper and/or large airways was observed.
Definition of “FI-RSV enhanced RSV disease”
Based on the original publications, it can be summarised that “FI-RSV enhanced RSV 
disease” was:
1.
Caused by vaccination with at least one dose of FI-RSV lot 100 (and not by similar 
vaccines [e.g., FI-PIV]) below 2 years of age.
2.
More severe if the vaccine was administered at a younger age.
3.
Initiated by RSV infection (and not by similar pathogens [e.g., PIV]).
4.
Associated with high viral replication and shedding of RSV.
5.
Defined by increased severity and potentially duration of typical symptoms of RSV-
associated LRTI (but not upper RTI): bronchiolitis/(broncho)pneumonia.
 
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Key characteristics of vaccinees

RSV priming status: risk very low in subjects that are primed for RSV (i.e., who 
have been naturally infected with RSV before) as vaccination of primed subjects is 
expected to amplify the (non-pathogenic) immune response induced by natural RSV 
infection.

Age at vaccination: risk very low in children vaccinated at 2 years or older and 
progressively increasing with younger age (highest risk in infants < 6 months of age, 
who have a more immature immune system).

Age at first exposure to RSV after vaccination: risk for severe RSV disease upon 
natural infection being higher in younger infants, who have smaller airways and a 
more immature immune system.
1.1.3.2.
Serum immune responses to the FI-RSV vaccine and to subsequent 
RSV infection
During the trials with the FI-RSV vaccine, serological assays were performed to monitor 
1) the immune response to vaccination 2) the immune response to natural infection post-
vaccination. In general, vaccinees developed high levels of total serum antibodies in 
response to vaccination (as measured by complement fixation). When the sera of these 
infants and children were later compared with those of infants and children with natural 
RSV infection, it could be observed that FI-RSV vaccination induced high total IgG 
antibody titers, but a relatively low level of neutralising antibody titers [Murphy, 1986]. 
1.1.3.3.
Pathological observations of RSV disease in FI-RSV vaccinated 
children
Post-mortem examinations of the 2 FI-RSV vaccinated children who died (aged 14 and 
16 months at time of death, vaccinated at 2 and 5 months of age, respectively) showed 
extensive bronchopneumonia in both children with patchy atelectasis, emphysema and 
pneumothorax in one of them [Kim, 1969]. Microscopically, there was an intense 
inflammatory infiltrate, with a predominance of neutrophils and macrophages in the lungs 
accompanied by the occasional presence of eosinophils in smaller bronchioles; a 
pathological picture consistent with primary RSV infection. Since eosinophils were also 
detected in the blood of some of the vaccinees, this finding gained a lot of attention in 
later investigations. Large quantities (104 plaque-forming units [pfu] per gram) of RSV 
were recovered from the lungs and bacteria could be cultured from the lungs of both 
children (Klebsiella from one and E. coli from the other).
Re-examination of the original autopsy report and of new histological preparations from 
the same tissues confirmed the observations, and re-emphasised the relatively small 
contribution of eosinophils (1-2%) compared to neutrophils. Gram stain did not detect 
bacteria in the lungs, suggesting that the positive cultures may have been due to small 
numbers of bacteria only (and making it less likely that the primary cause of the disease 
process could have been bacterial) [Prince, 2001]. During a second re-examination of the 
lung samples, evidence of immune complex deposition (arthus-like reaction) was 
detected in the small airways [Polack, 2007].
 
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In summary, the pathological observations indicate that 1) RSV viral replication was 
abundant, 2) the overall pathology was consistent with severe viral bronchopneumonia 
and 3) immune complexes were formed in the small airways.
1.1.3.4.
Animal models for “FI-RSV enhanced RSV disease”
In order to better understand the pathophysiology of “FI-RSV enhanced RSV disease”, 
several animal models have been developed to mimic this phenomenon. In general, 
animal models suggest that the immunopathology seen with the FI-RSV vaccine was a 
result of a poor functional antibody response [Graham, 2011; Openshaw, 2002] An 
unbalanced cellular immune response skewed towards Th2 (disturbed Th1/Th2 balance) 
could also be observed in mouse models [Connors, 1992; Connors, 1994; Waris, 1996], 
but is not consistently supported by data from other model animals [Antonis, 2003; 
Castilow, 2008; Phipps, 2007]. Note that the results of animal models of FI-RSV 
enhanced RSV disease should however be interpreted with caution due to the inherent 
differences between the animal model and humans per se and different replicative 
potential of RSV in the different species in particular.
1.1.3.5.
Pathophysiology of “FI-RSV enhanced RSV disease”
Based on the clinical and pathological observations in the vaccinated children in 
combination with a large body of data from animal models, two (non-mutually exclusive) 
hypotheses on the immunological factors that contributed to FI-RSV enhanced RSV 
disease have been proposed:

Induction of low-quality, non-neutralising antibodies. Murphy et al observed that 
upon natural RSV infection, the FI-RSV vaccinated subjects produced high amounts 
of poorly neutralising antibodies, indicating that natural infection boosted the low-
quality antibody response induced by the FI-RSV vaccine [Murphy, 1986]. These 
antibodies did not neutralise RSV replication and contributed to the formation of 
immune complexes that may have contributed to the severe clinical symptoms and 
potentially immunopathology [Polack, 2002].
Two (non-mutually exclusive) culprits for this poorly neutralising antibody response 
have been proposed 1) Formalin-induced disruption of neutralising epitopes on the 
inactivated virus vaccine, leading to an unusually large proportion of antibodies 
directed against non-protective epitopes [Murphy, 1986; Murphy, 1988; 
Moghaddam, 2006]. 2) Formalin-induced disruption of the Toll-like receptor (TLR)-
4 agonist activity of the F-protein (a major surface protein of RSV). F-protein in its 
native form is known to bind and stimulate TLR-4, which leads to antibody affinity 
maturation and high avidity antibodies. If this binding is disrupted, affinity 
maturation may not (sufficiently) occur and antibodies remain of low affinity and 
neutralising capacity [Delgado, 2009].

An unbalanced cellular immune response. Another potential explanation is the 
induction of an unbalanced cellular immune response skewed towards Th2 
(disturbed Th1/Th2 balance) [Connors, 1992; Connors, 1994; Waris, 1996]. This 
latter hypothesis is however mainly based on preclinical data in mouse models and is 
not consistently supported by data from other model animals [Antonis, 2003; 
 
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Castilow, 2008; Phipps, 2007] and more likely a cytokine storm (irrespective of Th 
balance) has been contributing to FI-RSV enhanced RSV disease [Boukhvalova, 
2006].
1.1.4.
Rationale for a viral vector-based RSV vaccine
Immunity induced by natural RSV infection is not able to fully prevent RSV re-infection, 
allowing re-infections to occur commonly throughout life. Both arms of the immune 
system are involved in protection from severe disease.
The humoral immune response is capable of neutralizing the virus and inhibiting viral 
replication, thereby playing a major role in protection against lower RSV infection and 
severe disease [Piedra, 2003]. Indeed, passive immunization with RSV-specific 
monoclonal antibodies (Synagis), when given prophylactically, has been shown to reduce 
RSV disease in premature infants and newborns with bronchopulmonary dysplasia or 
underlying cardiopulmonary disease [Cardenas, 2005].
T-cells are also involved in the control of RSV disease. Lethal RSV infections have been 
described in patients with low CD8 T-cells counts as in the case of severe combined 
immunodeficiency, bone marrow and lung transplant recipients [Hertz, 1989]. The 
histopathology of fatal cases of RSV infection of newborns shows that there is a relative 
paucity of CD8 T-cells in the lung infiltrate [Welliver, 2007]. Moreover, the presence of 
CD8 T-cells producing interferon gamma (IFN-) has been associated with diminished 
both Th2 responses and eosinophilia in animal models of RSV [Castilow, 2008; Stevens, 
2009].
A vaccine based on recombinant viral vectors carrying relevant RSV antigens, mobilizing 
both humoral and cellular arms of the immune response, is considered as an adequate 
solution to induce a balanced and more effective immune response against the RSV virus 
in a naïve population. Adenoviral vector-based vaccines have been shown to be potent 
inducers of CD8 T-cells producing IFN-and antibodies against expressed antigens 
[Liniger, 2007; Barnes, 2012].
Potent immunogenicity and lack of prolonged transgene expression have made 
replication incompetent adenoviruses attractive viral vectors for vaccine development. 
They possess a stable virion, allowing inserts of foreign genes not to be deleted and they 
can infect many different cell types; the transferred information remains epichromosomal 
thus avoiding the risk of insertional mutagenesis.
Chimpanzee-derived adenoviruses exhibit sequence homology to human adenoviruses 
within the hexon protein in particular, which is a major capsid protein used for subgroup 
classification of adenoviruses [Roy, 2011; Colloca, 2012]. They are not known to cause 
pathological illness in humans and antibodies against chimpanzee adenoviruses have low 
or no seroprevalence ranging from 0-4% in Europe and in the United States, up to 20% in 
the developing countries, which is far less than the most common human adenovirus 
serotype 5 (Ad5), with seroprevalence rates of 40–45% in the United States and up to 
90% in sub-Saharan Africa [Capone, 2013].
 
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In conclusion, the chimpanzee-derived adenovectors have the following important 
features:

Weak neutralization by human sera.

Potent immunogenicity, mainly Th1-directed.

Track record of good tolerability in human clinical trials.
1.1.5.
Antigens selected for the vaccine
The investigational vaccine is a recombinant viral vector manufactured using a synthetic 
deoxyribonucleic acid fragment that encodes three RSV proteins:

The fusion (F) protein deleted from the transmembrane and cytoplasmic regions 
(F0TM). The F protein is a major surface antigen of the RSV virus that is well 
conserved among RSV-A and RSV-B subgroups. In addition, it is the main target of 
the neutralizing antibody response to RSV, which is considered essential for 
protection against RSV-associated severe disease [Magro, 2012].

The nucleocapsid (N) protein is an internal (non-exposed) antigen, highly conserved 
between RSV strains and known to be a source of many T-cell epitopes [Anderson, 
2010; Townsend, 1984]. The N protein is essential for the replication and 
transcription of the RSV genome. Its primary function is to encapsidate the virus 
genome protecting it from ribonucleases.

The matrix (M2-1) protein is a transcription anti-termination factor that is important 
for the efficient synthesis of full-length messenger ribonucleic acid (RNA) as well as 
for the synthesis of polycistronic readthrough messenger RNA, which are 
characteristic of non-segmented negative-strand RNA viruses. M2-1 is an internal 
(non-exposed) antigen, highly conserved between RSV strains and known to be a 
source of many T-cell epitopes [Anderson, 2010; Townsend, 1984].
The N and M2-1 antigens were therefore included in the vaccine construct as source of T-
cell epitopes for the induction of cell-mediated immunity (CMI).
Please refer to the current Investigator Brochure (IB) for additional information.
1.1.6.
Pre-clinical experience
The candidate vaccine is based on the RSV viral proteins F, N and M2-1 encoded by a 
chimpanzee-derived adenovector (ChAd155-RSV). A number of pre-clinical studies were 
conducted to demonstrate immunogenicity, efficacy and safety of intramuscular (IM) 
injection of the ChAd155-RSV vaccine. Several animal models have been selected for 
such studies: mice, cotton rats and newborn calves. Importantly, vaccination has not 
induced hallmarks of enhanced pathology in these models.
Please refer to the current IB for information regarding the pre-clinical studies of GSK 
Biologicals’ investigational ChAd155-RSV vaccine.
 
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1.1.7.
Clinical experience
The immunogenicity, safety and reactogenicity of the pediatric candidate RSV vaccine 
(ChAd155-RSV vaccine) have been evaluated in healthy adults aged 18 to 45 years 
(study 201974 [RSV PED-001; NCT02491463]) There were no significant safety 
concerns identified up to Day 60 in study RSV PED-001. Overall, the ChAd155-RSV 
vaccine high dose (5x1010 viral particles [vp]) seems to be more reactogenic (local and 
general) than the ChAd155-RSV vaccine low dose (5x109 vp), however, the 
reactogenicity profile was less than that observed in the Bexsero group. No safety signal 
from the assessed hematology parameters (hemoglobin, platelet count, prothrombin time 
and APTT) was observed in subjects receiving the ChAd155-RSV vaccine. No 
significant reductions in platelet count or clinically significant changes in coagulation 
parameters were observed up to 30 days post Dose 2. An approximately 2.4-fold increase 
in RSV-A neutralizing antibody titers (geometric mean titer [GMT] from baseline) was 
observed in both RSV low dose and RSV high dose after Dose 1. No booster effect was 
evident after Dose 2. An anti-F IgA and IgG antibody secreting B-cells response and an 
RSV F, N and M2-1 specific IFN-γ secreting T-cells response in RSV high dose group 
after the first dose were observed with ELISpot. There was no booster response after the 
second vaccination. There was no specific vaccine-induced CD4 T-cellular response 
observed with intracellular staining (ICS). For CD8 T-cells only a weak CD8 IFN-γ 
response to N was shown with ICS for some subjects.
Please refer to the current IB for information regarding the clinical studies of 
GlaxoSmithKline (GSK) Biologicals’ investigational ChAd155-RSV vaccine.
1.2.
Rationale for the study and study design
1.2.1.
Rationale for the study
GSK Biologicals is developing the pediatric candidate RSV vaccine (ChAd155-RSV 
vaccine) to protect infants from RSV diseases.
The purpose of this study is to provide critical information on the safety, reactogenicity 
and immunogenicity profile of the ChAd155-RSV vaccine in infants likely to be 
unexposed to RSV before moving to a proof-of-concept trial in infants. An important 
aspect of this phase I/II study will be to compare a single lower dose of 1.5x1010 viral 
particles (vp) and two higher doses of 5x1010 vp according to a 0, 1 month schedule 
administered to infants aged 6 and 7 months likely to be unexposed to RSV, which is 
powered to statistically exclude a level of risk of ‘vaccine-induced enhanced RSV 
disease’, associated with historic FI-RSV vaccine trials [Kim, 1969].
This study is the first of a careful de-risking sequence of studies in a clinical development 
plan that will progressively exclude ERD as a potential risk prior to Phase III.
 
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1.2.2.
Rationale for the choice of study population
1.2.2.1.
Study population
The immunogenicity, safety and reactogenicity of the pediatric candidate RSV vaccine 
(ChAd155-RSV vaccine) has been evaluated in healthy adults aged 18 to 45 years (study 
201974 [RSV PED-001; NCT02491463]). A clinical study is currently being conducted 
in RSV-seropositive infants aged 12 to 23 months (study 204838 [RSV PED-002]). The 
safety profile of the ChAd155-RSV vaccine in adults (study 201974 [RSV PED-001; 
NCT02491463]) has been deemed satisfactory by GSK and an Independent Data 
Monitoring Committee (IDMC). Should there be a satisfactory safety profile of the 
ChAd155-RSV vaccine in RSV-seropositive infants, as evaluated by an IDMC on Day 60 
data (i.e., 30 days post-Dose 2 of the highest dose level) of the study RSV PED-002, the 
present study will be performed. This study will be conducted on infants aged 6 and 7 
months (having a low chance of natural exposure to RSV before inclusion in the study). 
Although potentially both RSV-exposed and RSV-unexposed subjects will be enrolled, 
the primary analysis for incidence of LRTI will be conducted in infants with a negative
RSV exposure status (at screening based on in-stream serological testing). This study will 
support the decision to age de-escalate to the targeted population (infants as from 6 weeks 
of age). 
1.2.2.2.
Choice of study population
Infants aged 6 and 7 months were selected to be vaccinated in this study because:

Infants of this age are more likely to be unexposed to RSV compared to older infants
[Dunn, 2013].

The natural course of RSV disease is generally less severe at this age. Their airways 
are relatively larger and they are therefore less at risk of serious RSV-RTI than 
younger infants.

Risk of adverse outcome of natural infection following FI-RSV vaccination was 
more pronounced when the vaccine was administered to younger infants.
For safety reasons, the population will have no predisposing risk factors for severe 
outcome following RSV disease (e.g., premature birth, past or current chronic lung 
disease, or cardiovascular disease).
1.2.2.3.
In-stream serological testing of baseline samples to determine 
exposure status (Amended 1 August 2019)
Subjects will not be screened for serostatus as criterion for enrolment in the study, due to 
the potential presence and detection of residual maternal antibodies (Refer to Section 
6.7.3 for more details on the determination of a negative RSV exposure status). The 
assumption is that the majority of infants are previously unexposed (see Section 1.2.2.2). 
Serological testing of baseline samples to determine exposure status will be performed in-
stream to ensure at least 50% of infants with a negative RSV exposure status (at 
screening based on in-stream baseline serological testing) and the sample size may be 
adjusted as needed through additional recruitment (Section 11.4). 
 
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1.2.3.
Rationale for regimen, dose and route of administration
This study will evaluate two regimens of the ChAd155-RSV vaccine; either one dose of 
1.5x1010 vp or two doses of 5x1010 vp will be administered. For the two dose schedule an 
interval of approximately one month between dosing will be used. A single dose arm was 
added in this 6-7 month-old study population before going to target population in 
subsequent studies.
The dose levels to be evaluated in this study have previously been administered to RSV-
seropositive infants aged 12 to 23 months (study RSV PED-002 [204838]) and will have 
been shown to have a satisfactory safety profile and reviewed by the IDMC. These doses 
might be modified following review by the IDMC of the safety data from study 
RSV PED-002 (204838). However if no significant safety concerns are identified with 
the highest ChAd155-RSV vaccine dose of 5x1010 vp administered in the RSV PED-002 
study, that dose will be the highest does level evaluated in this study.
In the bovine RSV challenge model in which seronegative, colostrum-restricted newborn 
calves, both a single and two dose regimen of 5x1010 vp ChAd155-RSV have been 
evaluated. The two dose regimen was given at an interval of four weeks apart. Both 
regimens showed a similar level of protection against challenge with bovine RSV, but the 
two dose regimen showed higher immunogenicity. Neither regimen was associated with 
pulmonary pathology. Low or potentially suboptimal dosing could be associated with 
lack of efficacy but is not likely to be associated with ERD. This is supported by animal 
data evaluating protection against a delayed challenge after a period of waning immunity. 
Non-clinical calf data showed that a challenge 4 months after the second dose or a 
challenge after a single dose did not induce any sign of ERD and demonstrated similar 
efficacy against LRTI. Despite waning immunity after 4 months, animals were fully 
protected upon challenge. 
Similarly, the selected one dose level of 1.5x1010 vp is the same as the mid-dose 
administered to RSV-seropositive infants in the RSV PED-002 study that will have been 
shown to have a satisfactory safety profile and reviewed by the IDMC. The rationale for 
using the mid-dose level is to collect safety and immunogenicity data on a lower dose and 
on the one-dose regimen in 6-7 months RSV-naïve infants before progressing to the 
target population i.e. infants as of 6 weeks of age. 
If tolerated, both candidate regimens would be evaluated in the target population to 
determine immune response and evaluate efficacy.
In this study, infants aged 6 to 7 months will be administered with the first dose of the 
ChAd155-RSV vaccine before the RSV season to increase the probability of enrolling 
infants unexposed to RSV, and then followed up through the RSV season. The second 
dose will be given one month after the first dose. RSV seasons will be determined for 
each country based on local epidemiological data (The RSV season is defined as the 
period of the year when 70% of the RSV cases have occurred in previous years. For the 
calculation, where available, data from up to the ten previous years should be applied. If 
the data permit calculation of the actual date of the beginning of the season, rather than 
approximation to the nearest month, this is desirable. Refer to the Study Procedures 
Manual [SPM] for RSV seasons per country).
 
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Please refer to the current IB for information regarding the pre-clinical, clinical and 
toxicology studies of GSK Biologicals’ investigational ChAd155-RSV vaccine.
Refer to Section 1.2.6 for the rationale for the use of active controls.
1.2.4.
Rationale for safety monitoring plan
During this study, safety evaluations will be performed by an internal safety review 
committee (iSRC) (refer to Section 9.10.2) and an independent data monitoring 
committee (IDMC) (refer to Section 9.10.3), with specific holding rules. Data of LRTI 
associated with RSV infection will be received by the IDMC within 48 hours upon GSK 
becoming aware (refer to Section 9.10.3 for more detailed information). Any holding 
rules met during the study will be escalated to the Vaccine Safety Monitoring Board 
(VSMB; refer to Sections 9.10.4 and 9.10.5).
1.2.4.1.
Rationale for RSV disease surveillance
ChAd155-RSV vaccine has been successfully tested in several preclinical models 
assessing the risk of vaccine-related ERD and it was associated with a profile that did not 
suggest disease enhancement. ChAd155-RSV vaccine induced an immune response 
associated to inhibition of viral replication in the lungs in all animal models tested and 
reduction of bovine RSV-LRTI signs in young calves. The ChAd155-RSV vaccine has 
been tested in young seronegative calves, which is a model that mimics natural RSV 
infection. Bovine RSV causes respiratory disease in young calves that is very similar to 
that observed in human infants. In addition, bovine RSV is genetically and antigenically 
close to human RSV. Exacerbation of respiratory disease has been reproduced in calves
vaccinated with FI-bovine RSV vaccine [Antonis, 2003]. The similarities of FI-RSV 
vaccine-induced ERD and the observed clinical signs make the newborn calve/bovine 
RSV model a relevant animal model for evaluation of safety of human RSV vaccines. In 
this model, vaccination with ChAd155-RSV vaccine was immunogenic, protected 
initially seronegative calves from bovine RSV infection and pulmonary pathology and 
did not induce ERD.
Although the risk of ERD is thought to be very low with an adenovirus-based vaccine, a 
cautious approach is taken and this is the first of a series of trials in potentially naïve 
infants. In this first step the minimum number of subjects is exposed to allow detection of 
a serious signal of ERD of the magnitude that occurred in association with the RSV-FI 
trials. For details of the sample size and assumptions refer to Section 11.4. Rates of RSV 
infection are highly variable by season and therefore a conservative rate of infection of 
20% in the first season is taken.
All subjects will be closely monitored for the occurrence of RSV-RTI and the early 
detection of ERD by IDMC and sponsor will comprise three complementary approaches: 
the detailed review of individual cases of RSV-LRTI, the monitoring of the disease 
severity of cases of RSV infection occurring in vaccinees and the comparison of RSV-
LRTI disease rates between vaccinees and control recipients.
 
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All subjects with symptoms of RTI detected by active or passive surveillance contacts 
will be reviewed by the investigator as soon as possible and those based on any suspicion 
of difficulty in breathing, wheezing or parental concern seen within 24 hours (refer to 
Section 9.2). This will ensure prompt assessment of need for medical care.
All cases of RSV-LRTI will be considered as adverse events (AEs) of special interest 
(refer to Section 9.1.5) and will have to be reported within 24 hours to the sponsor, and 
notified to the IDMC (which is not blinded), together with full case details, within 48 
hours upon sponsor becoming aware. In order to support this timely reporting, the 
investigator will make the diagnosis according to his/her medical judgment and locally-
available diagnostic tests of RSV infections. Criteria for hospitalization are not protocol 
defined but based on the attending clinicians’ judgment of medical need.
The IDMC will receive on a regular basis cumulative summary reports of the number of 
RSV infections (asymptomatic and symptomatic) and the proportion progressing to 
hospitalization in the vaccinees by group and the incidence of RSV-RTI, RSV-LRTI and 
severe RSV-LRTI according to standardized case definitions by group (refer to Section 
4.1). The frequency will be initially monthly from the beginning of the RSV season and 
will be adapted based on the instruction of the IDMC (refer to Section 9.10.3). The 
objective of this intense monitoring of cumulative RSV-RTI data by the IDMC is to 
ensure that, if it occurs, ERD is detected early in the course of the study allowing 
enrolment to be stopped and thereby minimizing the number of infants exposed to the 
ChAd155-RSV vaccine.
The final analysis of the incidence of RSV-LRTI by group will be performed according 
to the standardized case definitions for clinical symptomatology and diagnostic test at 
sponsor’s laboratory (refer to Table 6) ensuring consistency across sites.
1.2.4.2.
Rationale for monitoring for spontaneous or excessive bleeding
During a study carried out in adult subjects (RSV001), a mild non-clinically significant 
drop in hemoglobin was noted following vaccination with another adenoviral vector 
(PanAd3-RSV) without clinical signs and with a reversal towards baseline values over 
time [RSV001 Interim Study Report, 2014]. In the repeat dose toxicology study in rabbits 
using the ChAd155-RSV vaccine, a transient non-clinically significant drop in platelets 
was noted post IM vaccination (maximal drop of platelet observed 24 hours after 
vaccination; refer to the current IB for further details). In light of these data, subjects’ 
parent(s)/ legally acceptable representative(s) (LAR[s]) will be instructed to contact the 
investigator/study staff if their child presents symptoms of spontaneous bleeding or easy 
bruising or if their child develops a rash, within 30 days after either vaccination (Visit 1 
and Visit 3), in order to detect any thrombocytopenic petechiae or purpura. The 
investigator will, based on his/her medical judgment, measure the total blood count and 
appropriately investigate infants with clinical suspicion of low platelets.
 
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Note that a broad safety hematology and biochemistry evaluation was performed at each 
study visit in adults during study RSV PED-001 (201974; NCT02491463). In this study, 
blood samples for hematology/biochemistry were taken from all subjects at all study 
visits, i.e., at Screening, on the day of vaccination (Day 0 and Day 30), 1 day post 
vaccination (Day 1 and Day 31), 3 days post vaccination (Day 3 and 33), 7 days post 
vaccination (Day 7 and 37), 30 days post Dose 2 (Day 60), on Day 180 and on Day 360. 
The safety profile of the ChAd155-RSV vaccine was found to be satisfactory by an 
IDMC. No safety signal from the assessed hematology parameters (hemoglobin, platelet 
count, prothrombin time and APTT) was observed in subjects receiving the ChAd155-
RSV vaccine. No significant reductions in platelet count or clinically significant changes 
in coagulation parameters were observed up to 30 days post Dose 2.
1.2.5.
Rationale for study blinding
Given the different appearance and storage conditions of the investigational RSV vaccine 
and the active control comparator vaccines / Placebo, double blinding is not possible and 
the study will be conducted in an observer-blind manner.
When all data up to Day 61 are available, a statistical analysis will be performed. This 
analysis may lead to the unblinding of some subjects. As a consequence, after Day 61, the 
study cannot be considered as observer-blind, but will be conducted in a single blind 
manner, with subjects’ parent(s)/ legally acceptable representative(s) (LAR[s]) remaining 
blinded up to the last study visit (end of the second RSV transmission season*), while the 
investigator will still not have access to the treatment allocation up to the last study visit 
(end of the second RSV transmission season), except in case of emergency unblinding 
(see Section 9.8).
*Refer to the SPM for RSV seasons per country.
Please refer to the glossary of terms for the definition of observer-blind and single blind.
1.2.6.
Rationale for the use of controls
The comparator / Placebo groups are included as a control for the reactogenicity, safety 
and immunogenicity assessments. The choice of control between an active comparator or 
Placebo will be done at country level. Refer to the Informed Consent Form (ICF) for the 
local choice of comparator/Placebo.
Active comparators are included as a control for the reactogenicity, safety and 
immunogenicity assessments. The choice of one of four control vaccines, as active 
comparators has been driven by the fact that, in most countries at least one of these 
vaccines meet the criteria of being of medical benefit, and where possible licensed for 
infants and used with a similar dose and schedule as the investigational RSV vaccine, 
while not being part of a national immunization program. The choice of which active 
control comparator vaccine will be used will be done at the country level and will be used 
according to its approved label. 
 
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Since the immunization schedule for the active comparator vaccines for infants between 6 
and 18 months of age is slightly different, infants in the active control group will be 
administered FB at the time of administration of the first dose of the investigational RSV 
vaccine (for either Menveo or Synflorix) or the second dose of the investigational RSV 
vaccine (for either Bexsero or Nimenrix). To accommodate the various vaccination 
schedules of the active comparator vaccines across countries, FB may also be offered 
once during the two to three additional vaccinations given to complete the comparator 
vaccine schedule in the study (see Figure 1 and Table 2).
1.2.7.
Rationale for ChAd155 RSV vaccine recipients receiving active 
comparator vaccine
To provide potential benefit to all trial participants and to maintain the study blind until 
the end of follow up, the ChAd155-RSV vaccine recipients will also receive 
immunization with the selected active comparator vaccine.
1.3.
Benefit : Risk Assessment
Approximately two thirds of the infants (100) in this study will be exposed to the 
ChAd155-RSV vaccine, whereas all infants will receive either an active control 
comparator vaccine (Bexsero, or Nimenrix, or Synflorix, or Menveo), or Placebo (see 
Figure 1 and Table 2).
The choice of active comparator vaccine or Placebo is done at the country level.
Please refer to the current IB for the summary of potential risks and benefits of 
ChAd155-RSV vaccine.
Please refer to the local Prescribing Information for information regarding the summary
of potential risks and benefits of Bexsero, Nimenrix, Synflorix and Menveo.
The following section outlines the risk assessment and mitigation strategy for this study 
protocol:
1.3.1.
Risk Assessment
As with all injectable vaccines, immediate systemic allergic reactions to vaccination can 
occur. In order to be able to treat infants with an immediate systemic allergic reaction to 
vaccination, all infants across all groups will need to remain under observation (visual 
follow-up as well as measurement of vital signs) at the study site for at least 60 minutes 
after vaccination for Visit 1 and Visit 3 and 30 minutes for all remaining vaccination 
visits.
Intramuscular vaccination commonly precipitates a transient and self-limiting local 
inflammatory reaction. This may typically include pain at injection site, redness and 
swelling.
 
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Risks linked to the investigational RSV vaccine
Although the ChAd155-RSV vaccine is not a FI-RSV vaccine and the risk of ERD is 
thought to be very low (refer to Section 1.2), this is the first time that this vaccine will be 
administered to subjects likely to be unexposed to RSV. Consequently, all subjects will 
be closely monitored by active and passive surveillance for detection of RSV-RTI and 
wheezing (refer to Section 9.2). All cases of LRTI associated with RSV will be 
considered as AEs of special interest (refer to Section 9.1.5) and will have to be reported 
as SAEs (within 24 hours).
IM vaccination commonly precipitates a transient and self-limiting local inflammatory 
reaction. This may typically include redness, swelling and tenderness.
Most systemic symptoms observed in a clinical trial with a similar product carried out in 
healthy adults (chimpanzee adenovirus-based vaccine with ChAd3 as vector for 
vaccination against hepatitis C) at doses to be used in this trial did not exceed mild 
severity [HCV001 Clinical Study Report, 2011]. Fatigue, headache and malaise were the 
most commonly reported systemic AEs overall.
In a Phase I clinical trial with a similar simian adenoviral vector-based RSV vaccine with 
the same insert (PanAd3-RSV) carried out in healthy adults, the most commonly reported 
AEs concerned injection site reactions. However, a mild non-clinically significant drop in 
hemoglobin was noted following vaccination without clinical signs and with a reversal 
towards baseline values over time [RSV001 Interim Study Report, 2014].
A transient non-clinically significant drop in platelets was noted post IM vaccination in a 
preclinical study with the ChAd155-vector (refer to the current IB for further details). 
Furthermore, in Ebola Phase I studies in adults investigating a similar adenoviral 
vectored vaccine (ChAd3-EBO-Z), transient non-clinically significant decreases in 
thrombocyte counts were also observed (refer to the current IB of recombinant 
chimpanzee adenovirus Type 3-vectored Ebola Zaire vaccine for further details). A broad 
safety hematology and biochemistry evaluation was performed at each study visit in 
adults during study RSV PED-001 (201974). In this study, no significant safety concerns 
were identified up to 30 days post Dose 2 in healthy adults aged 18 to 45 years (refer to 
Section 1.1.7 and to the current IB). Hematology and biochemistry parameters are also 
being intensively evaluated in RSV-seropositive infants aged 12 to 23 months during 
study RSV PED-002 (204838).
Risks linked to the active control comparator vaccines
Refer to the local Prescribing Information for potential risks and contraindications related 
to Bexsero, Nimenrix, Synflorix or Menveo vaccines.
1.3.2.
Benefit Assessment
The infants receiving the investigational ChAd155-RSV vaccine may not directly benefit 
from vaccination since the efficacy of the investigational ChAd155-RSV vaccine has not 
been assessed yet and it is hence not known whether it is effective in protecting against 
RSV infection.
 
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The choice of active comparator vaccine (Bexsero, Nimenrix, Synflorix, or Menveo) for 
each participating country ensures that the vaccine may be given according to the local 
label and provides potential medical benefit in the country that chose active comparator. 
Within a given participating country, all infants in both groups of this study will receive 
the full locally recommended vaccination course of active comparator vaccine where 
possible and may be immunized against either invasive meningococcal disease caused by 
Neisseria meningitidis (with the meningococcal vaccines Bexsero, Nimenrix or Menveo);
or against invasive pneumococcal disease, pneumonia, and acute otitis media caused by 
Streptococcus pneumoniae (with the pneumococcal vaccine Synflorix)
Subjects’ parent(s)/ LAR(s) could gain medical advice about their infant’s general health 
status through the medical evaluations/assessments associated with this study (i.e., 
physical examination, blood testing [hematology and biochemistry data], surveillance for 
RTI and LRTI).
1.3.3.
Overall Benefit:Risk Conclusion
The investigational ChAd155-RSV vaccine is currently in Phase I/II stage of clinical 
development and no vaccine efficacy has been demonstrated. Taking into account the 
measures taken to minimize the risk to infants participating in this study, the potential 
risks to the subjects are justified by the potential benefits linked to the development of 
this pediatric RSV vaccine.
The four control vaccines administered to all participants in this study as active 
comparators, are licensed for infants in the particular country where possible, and 
therefore have demonstrated medical benefit in the prevention of invasive meningococcal 
disease caused by Neisseria meningitidis (for the meningococcal vaccines Bexsero,
Nimenrix, Menveo); or against invasive pneumococcal disease, pneumonia, and acute 
otitis media caused by Streptococcus pneumoniae (for the pneumococcal vaccine 
Synflorix
2.
OBJECTIVES
2.1.
Primary objective

To evaluate the safety and reactogenicity of the RSV investigational vaccine when 
administered IM as one (1.5x1010 vp) dose or as two (5x1010 vp) doses according to 
a 0, 1-month schedule, up to 60 days after Dose 1 (i.e., Day 61) in infants aged 6 and 
7 months.
Refer to Section 11.1 for the definition of the primary endpoints.
 
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2.2.
Secondary objectives

To evaluate the occurrence of RSV respiratory tract infections of any severity from 
Visit 1 (Day 1, after Dose 1) up to the end of the first RSV transmission season, in 
infants aged 6 and 7 months.

To evaluate the safety of the RSV investigational vaccine when administered IM as 
one (1.5x1010 vp) dose or as two (5x1010 vp) doses according to a 0, 1-month 
schedule, from study start (Day 1) up to the end of the second RSV transmission 
season in infants aged 6 and 7 months.

To evaluate the occurrence of RSV respiratory tract infections from Visit 1 (Day 1, 
after Dose 1) up to the end of the second RSV transmission season, in infants aged 6 
and 7 months.

To evaluate the occurrence of very severe RSV-LRTI from Visit 1 (Day 1, after 
Dose 1) up to the end of the first RSV transmission season in RSV infected infants 
aged 6 and 7 months with a negative RSV exposure status (at screening based on in-
stream baseline serological testing).

To evaluate the humoral immunogenicity induced by the RSV investigational 
vaccine when administered IM as one (1.5x1010 vp) dose or as two (5x1010 vp) doses 
according to a 0, 1-month schedule, from study start (Day 1) up to the end of the first 
RSV transmission season, in infants aged 6 and 7 months.
Refer to Section 11.2 for the definition of the secondary endpoints.
2.3.
Tertiary objectives

If deemed necessary, to further characterize the immune response of the RSV 
investigational vaccine when one (1.5x1010 vp) dose or two (5x1010 vp) doses are 
administered IM according to a 0, 1-month schedule to infants aged 6 and 7 months.
Refer to Section 11.3 for the definition of the tertiary endpoints and to Section 11.12.1 for 
the reporting of tertiary endpoint results.
 
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3.
STUDY DESIGN OVERVIEW
Figure 1
Study design
D: Day; FU: follow-up; IDMC: Independent Data Monitoring Committee; iSRC: internal Safety Review Committee; RSV: respiratory syncytial virus; RTI: respiratory tract infection; SE: 
solicited events; V: Visit 1D: 1 Dose (1.5x1010 vp/dose); 2D: 2 Dose (5x1010 vp/dose); FB: Formulation buffer S9b.
* Vaccine Dose 1 at Day 1 will be administered before the first RSV season (refer to Section 5.1 for definition of RSV season).
End of RSV 
season 2
SE to D8
= Blood sample for safety
BSS
BSS
Surveillance period for RSV RTI a
BSH
BSH
BSH
= Blood sample for humoral immunogenicity
BSH
Nasal swab, as applicable c
BSH
Vaccination phase
FU phase
Screening
Epoch 002
Epoch 003
Epoch 004
Epoch 001
D121
V6 ‡
D61
V5
End of RSV 
season 1
V7
V8 †
D1
D8
D31
D38
V1*
V2 †
V3
V4 †
Visit
Day
SCREENING
D-30 to D-1
IDMC/iSRC review b
SE to D8
2D RSV+Bexsero
2D RSV
Dose 1
Dose 2
Bexsero
Bexsero
Bexsero
Bexsero
Bexsero
FB
Bexsero
Bexsero
FB
2D RSV+Nimenrix
2D RSV
2D RSV
Nimenrix
Nimenrix
Nimenrix
Nimenrix
Nimenrix
FB
Nimenrix
Nimenrix
FB
2D RSV+Menveo
2D RSV
2D RSV
Menveo
Menveo
Menveo
FB
Menveo
FB
Menveo
2D RSV+Synflorix
2D RSV
2D RSV
Synflorix 
Synflorix
Synflorix
Synflorix
FB
Synflorix
Synflorix
Synflorix
FB
2D RSV
1D RSV+Bexsero
1D RSV
Bexsero
Bexsero
Bexsero
FB
1D RSV+Nimenrix
1D RSV
FB
Nimenrix
Nimenrix
Nimenrix
1D RSV+Menveo
1D RSV
FB
Menveo
Menveo
1D RSV+Synflorix
1D RSV
FB
Synflorix
Synflorix
Synflorix
IDMC review b
2D RSV+ Placebo
2D RSV
2D RSV
Placebo   
FB
FB
1D RSV+ Placebo
1D RSV
FB
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† Visit 2 (Day 8), Visit 4 (Day 38), and Visit 8 (no blood sampling for immune response and no vaccine administration) may take place in the subject’s home or at the investigators 
clinical facility as appropriate to the circumstances in the judgment of the investigator. For authorized sites only, Visit 5 (Day 61) and Visit 7 (both with blood sampling) may also 
take place in the subject’s home or at the investigators clinical facility as appropriate to the circumstances in the judgment of the investigator.
‡ In countries where Menveo or Placebo is used as a comparator, no administration will be performed at Day 121 and therefore in those countries there will be no Visit 6 and it will be 
administered at the end of the first RSV season at Visit 7 (refer to Table 2 and Table 7).
a Surveillance for RSV-RTI comprises monthly nasal swab collected to detect asymptomatic RSV infections during RSV season and active and passive surveillance contacts for RSV 
symptomatic RTI. Of note the swab may be omitted if a nasal swab has been taken at a symptomatic visit in the same month (see Section 9.2). Data about RSV–RTI incidence 
will be reviewed monthly by an IDMC.
b An iSRC will review all accumulating safety data monthly until the IDMC reviews has reviewed all safety data up to 30 days after administration of Dose 2 (i.e., Day 61). The IDMC will 
review all accumulating safety data monthly throughout the period of vaccination and accumulating SAEs until the end of the second RSV transmission season. Refer to Sections 
9.10.2 and 9.10.3.
c Refer to Section 6.6.12.3.
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Table 2
Vaccines administered and vaccination schedules 
Groups
Age* (Months) / (Visit, Day)
6-7 / (V1, D1)
7-8 / (V3, D31) 8-9 / (V5, D61)
10-11 / (V6, D121)**
14-18 / (V7)
1D RSV + Bexsero
1D RSV ChAd FB
Bexsero
Bexsero
Bexsero
2D RSV + Bexsero
2D RSV ChAd 2D RSV ChAd Bexsero
Bexsero
Bexsero
Bexsero
Bexsero
FB
Bexsero
FB
Bexsero
1D RSV + Nimenrix
1D RSV ChAd FB
Nimenrix
Nimenrix
Nimenrix
2D RSV + Nimenrix
2D RSV ChAd 2D RSV ChAd Nimenrix
Nimenrix
Nimenrix
Nimenrix
Nimenrix
FB
Nimenrix
FB
Nimenrix
1D RSV + Synflorix
1D RSV ChAd FB
Synflorix
Synflorix
Synflorix
2D RSV + Synflorix
2D RSV ChAd 2D RSV ChAd Synflorix
Synflorix
Synflorix
Synflorix
FB
Synflorix
Synflorix
FB
Synflorix
1D RSV + Menveo
1D RSV ChAd FB
Menveo
Menveo
2D RSV + Menveo
2D RSV ChAd 2D RSV ChAd Menveo
Menveo
Menveo
FB
Menveo
FB
Menveo
1D RSV + Placebo
1D RSV ChAd FB
2D RSV + Placebo
2D RSV ChAd 2D RSV ChAd
Placebo
FB
FB
V: Visit; D: Day; 1D: 1 Dose (1.5x1010 vp/dose); 2D: 2 Dose (5x1010 vp/dose); RSV ChAd: ChAd155-RSV vaccine;
FB: Formulation buffer S9b.
* Assumes enrolled at 6 and 7 months of age for the vaccine Dose 1 to be administered before the first RSV season; 
the second dose will be given one month after the first dose. (RSV seasons will be determined for each country 
based on local epidemiological data [The RSV season is defined as the period of the year when 70% of the RSV 
cases have occurred in previous years. For the calculation, where available, data from up to the ten previous 
years should be applied. If the data permit calculation of the actual date of the beginning of the season, rather 
than approximation to the nearest month, this is desirable. Refer to the SPM for RSV seasons per country.])
** In countries where Menveo or Placebo is used as a comparator, no administration will be performed at Day 121 and 
therefore in those countries there will be no Visit 6 and it will be administered at the end of the first RSV season at 
Visit 7.
Protocol waivers or exemptions are not allowed unless necessary for the management of 
immediate safety concerns. Therefore, adherence to the study design requirements, 
including those specified in the outline of study procedures (Section 6.5), are essential 
and required for study conduct.

Experimental design: Phase I/II, observer-blind, randomized, controlled, multi-
centric study with three parallel groups.

Duration of the study: approximately 24 months.

Epoch 001: Screening Visit starting up to 30 days before first vaccination and 
ending on Day -1).

Epoch 002: primary starting at Visit 1 (Day 1) and ending at Visit 5 (Day 61).

Epoch 003: follow-up starting after Visit 5 (Day 61)* and ending at Visit 7 (end 
of the first RSV transmission season).

Epoch 004: follow-up starting after Visit 7 (end of the first RSV transmission 
season)* and ending at Visit 8 (end of the second RSV transmission season).
 
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*Any safety, immunogenicity and disease surveillance data collected beyond
Visit 5 (Day 61) will be collected in Epoch 003. Any safety, immunogenicity 
and disease surveillance data collected beyond Visit 7 (end of the first RSV 
transmission season) will be collected in Epoch 004. Refer to the SPM for RSV 
transmission seasons per country.

Primary Completion Date (PCD): Visit 5 (Day 61).
Refer to glossary of terms for the definition of PCD.

End of Study (EoS): Last testing results released of samples collected at Visit 8 (end 
of the second RSV transmission season) related to primary and secondary 
endpoints.*
* Up to Visit 8 (end of the second RSV season), there will be monthly nasal swab to 
detect asymptomatic RSV infections during the RSV season or if following active or 
a passive surveillance contacts, a subject presents symptoms of respiratory tract 
infection (RTI), a nasal swab will be collected.
Refer to the glossary of terms for the definition of EoS.
Study groups:
Table 3
Study groups and epochs foreseen in the study
Study groups
Target Number 
of subjects
Age (Min/Max)
Epochs
Epoch 001
Epoch 002
Epoch 003
Epoch 004
1D RSV + Bexsero
50
6 – 7 months
N/A
x
x
x
1D RSV + Nimenrix
6 – 7 months
N/A
x
x
x
1D RSV + Synflorix
6 – 7 months
N/A
x
x
x
1D RSV + Menveo
6 – 7 months
N/A
x
x
x
1D RSV + Placebo
6 – 7 months
N/A
x
x
x
2D RSV + Bexsero
50
6 – 7 months
N/A
x
x
x
2D RSV + Nimenrix
6 – 7 months
N/A
x
x
x
2D RSV + Synflorix
6 – 7 months
N/A
x
x
x
2D RSV + Menveo
6 – 7 months
N/A
x
x
x
2D RSV + Placebo
6– 7 months
N/A
x
x
x
Bexsero
50
6 – 7 months
N/A
x
x
x
Nimenrix
6 – 7 months
N/A
x
x
x
Synflorix
6 – 7 months
N/A
x
x
x
Menveo
6 – 7 months
N/A
x
x
x
Placebo
6 – 7 months
N/A
x
x
x
1D: 1 Dose (1.5x1010 vp/dose); RSV: ChAd155-RSV vaccine; 2D: 2 Dose (5x1010 vp/dose); N/A: Not Applicable.
 
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Table 4
Study groups and treatment foreseen in the study
Treatment name
1D RSV ChAd
2D RSV ChAd
Bexsero
Nimenrix
Synflorix
Menveo
FB
Vaccine/ 
Product name
1D ChAd155-RSV 
1.5X1010vp/dose
2D ChAd155-RSV
5X1010 vp/dose
Bexsero
Nimenrix
Synflorix
Menveo
FB
Study Groups
1D RSV + Bexsero
x
x
x
1D RSV + Nimenrix
x
x
x
1D RSV + Synflorix
x
x
x
1D RSV + Menveo
x
x
x
1D RSV + Placebo
x
x
2D RSV + Bexsero
x
x
2D RSV + Nimenrix
x
x
2D RSV + Synflorix
x
x
2D RSV + Menveo
x
x
2D RSV + Placebo
x
Bexsero
x
x
Nimenrix
x
x
Synflorix
x
x
Menveo
x
x
Placebo
x
ChAd155-RSV: Chimpanzee Adenovirus Type 155 RSV vaccine; FB: Formulation buffer S9b; RSV ChAd: ChAd155-
RSV vaccine; 1D: 1 Dose (1.5x1010 vp/dose); 2D: 2 Dose (5x1010 vp/dose).

Controls: active comparator vaccines (Bexsero, or Nimenrix, or Synflorix, or
Menveo, or Placebo (FB)*.
* The choice of active comparator vaccine (Bexsero, Nimenrix, Synflorix, or 
Menveo) or Placebo is done at the country level. Refer to the ICF for the local choice 
of comparator/Placebo.

Vaccination schedules:
RSV investigational vaccine:

In the 1 Dose (1D) groups, a single lower dose of 1.5x1010 vp will be 
administered IM at Day 1 (Visit 1). Formulation buffer will be administered in 
the 1D groups at Day 31 (Visit 3). In the 2 Dose (2D) groups, two doses of 
5x1010 vp will be administered IM according to a 0, 1-month schedule, (i.e., at 
Day 1 [Visit 1] and Day 31 [Visit 3]) (see Figure 1 and Table 2). Dose 1 will be 
administered before the first RSV season and the second dose will be given one 
month after the first dose (RSV seasons will be determined for each country 
based on local epidemiological data and documented in the Study Procedures 
Manual [SPM]. The RSV season is defined as the period of the year when 70% 
of the RSV cases have occurred in previous years. For the calculation, where 
available, data from up to the ten previous years should be applied. If the data 
permit calculation of the actual date of the beginning of the season, rather than 
approximation to the nearest month, this is desirable..
 
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Comparator or Placebo:

In countries where Bexsero or Nimenrix is used as a control, two doses will be 
administered IM with at least a 2 month interval between these primary doses. A 
booster dose will be administered IM in the second year of life at Visit 7, with 
an interval of at least 2 months between the primary series and booster dose. The 
first Bexsero or Nimenrix dose will be administered at Day 1 (Visit 1) (in the 
groups receiving only Bexsero or Nimenrix, respectively). In the groups 
receiving only Bexsero or Nimenrix, the second dose will be at Day 61 (Visit 5). 
The first Bexsero or Nimenrix dose to be administered to the 1D and 2D RSV 
groups will be at Day 61 (Visit 5), following the 1 or 2 RSV vaccine doses, 
respectively. The second dose of Bexsero or Nimenrix in the 1D and 2D groups 
will be at Day 121 (Visit 6). Formulation buffer will be administered, when 
neither RSV vaccine nor comparator is scheduled, at the 5 vaccination visits (see 
Figure 1 and Table 2).

In countries where Synflorix is used as a control, two doses will be administered 
IM with at least a 1 month interval between these primary doses. A booster dose 
will be administered IM in the second year of life at Visit 7. The first Synflorix 
dose will be administered at Day 31 (Visit 3) (in the group receiving only 
Synflorix). In the group receiving only Synflorix, the second dose will be at 
Day 61 (Visit 5). The first Synflorix dose to be administered to the 1D and 2D 
RSV groups will be at Day 61 (Visit 5), following the 1 or 2 RSV vaccine doses, 
respectively. The second dose of Synflorix in the 1D and 2D groups will be at 
Day 121 (Visit 6). Formulation buffer will be administered, when neither RSV 
vaccine nor comparator is scheduled, at the 5 vaccination visits (see Figure 1
and Table 2). 

In countries where Menveo is used as a control, two doses will be administered 
IM at least 3 months apart with the second dose in the second year of life at 
Visit 7. The first Menveo dose will be administered at Day 31 (Visit 3) (in the 
group receiving only Menveo). The first Menveo dose to be administered to the 
1D and 2D RSV groups will be at Day 61 (Visit 5), following the 1 or 2 RSV 
vaccine doses, respectively. Since the second Menveo dose has to be 
administered in the second year of life at Visit 7, no administration will be 
performed at Day 121 (Visit 6). Formulation buffer will be administered, when 
neither RSV vaccine or comparator is scheduled, at the 4 vaccination visits (see 
Figure 1 and Table 2).

In countries where Placebo is used as a control, one dose will be administered 
IM at Day 31 (Visit 3) in the 1D RSV + Placebo group and two IM doses will be 
administered IM according to a 0, 1-month schedule at Day 1 (Visit 1) and 
Day 31 (Visit 3) in the Placebo group (see Figure 1 and Table 2). 

Treatment allocation: infants will be randomized using a centralized randomization 
system on internet (SBIR) before first vaccination and after assessment of eligibility 
(i.e., after screening conclusion) (refer to Section 6.2.2 for details about 
randomization of treatment). The randomization algorithm will use a minimization 
procedure accounting for country as a minimization factor and the grouping 
comparator/placebo as a stratification factor.
 
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
Blinding: not applicable for Epoch 001 (Screening Visit), observer-blind in Epoch 
002 and single-blind in Epoch 003 and Epoch 004. Refer to Section 6.3 for details of 
blinding procedure.
Table 5
Blinding of study epochs
Study Epochs
Blinding
Epoch 001
N/A
Epoch 002
observer-blind
Epoch 003
single-blind
Epoch 004
single-blind
N/A: Not applicable.

Sampling schedule:

Blood samples for hematology/biochemistry will be taken from all infants at 
Screening (up to 30 days before first vaccination to Day -1). Blood samples for 
hematology/biochemistry may be taken from infants at any timepoints, if 
deemed necessary by the investigator. Refer to Table 12 for the list of 
parameters to be tested.
Refer to Section 6.6.12.2 and Figure 2 for information about the re-testing of 
samples in case of any Grade 1 abnormality with potential clinical relevance 
(according to investigators judgment) or any ≥Grade 2 abnormality.

Blood samples for humoral immunogenicity will be taken from all subjects at 
Screening and on Day 31, Day 61, and at the visit occurring at the end of the 
first RSV transmission season.

Blood sample for assessment of mechanism of illness (potential ERD) will be 
taken from subjects hospitalized for LRTI (only for RSV-positive subjects using 
a locally available RSV test).

Nasal swab: there will be monthly nasal swab to detect asymptomatic RSV 
infections during the RSV season and if following active or a passive 
surveillance contacts, a subject presents symptoms of RTI, a nasal swab will be 
collected (as well as a sample for local testing i.e., the type of sample to be 
determined locally [e.g., swab, etc.]) (Refer to the SPM).

Study visits: Other than the screening visit and assessment visits for active/passive 
surveillance, there will be 8 study visits except in countries where Menveo or 
Placebo is used as a control where there will be 7 study visits. 

In countries where Menveo is used as a comparator, no administration will be 
performed at Day 121 and therefore in those countries there will be no Visit 6 
and it will be administered at the end of the first RSV season at Visit 7 (refer to 
Table 2 and Table 7).

In countries where Placebo is used as a control, no vaccine administration will 
be performed after Visit 3 and therefore in those countries there will be no Visit 
6. There will be a Visit 5 and Visit 7 for countries using Placebo and all other 
study procedures will occur at these visits except vaccination. 
 
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
Visit 2 (Day 8), Visit 4 (Day 38), and Visit 8 (no blood sampling for immune 
response and no vaccine administration) may take place in the subject’s home or 
at the investigators clinical facility as appropriate to the circumstances in the 
judgment of the investigator. 
o
For authorized sites only, Visit 5 (Day 61) and Visit 7 (both with blood 
sampling) may also take place in the subject’s home or at the investigators 
clinical facility as appropriate to the circumstances in the judgment of the 
investigator. 

Type of study: self-contained.

Data collection: electronic Case Report Form (eCRF).

Safety monitoring: internal safety review committee (iSRC) and IDMC (refer to 
Section 9.10).

Surveillance for RSV-RTI, difficulty in breathing, and wheezing episodes.
Surveillance period will be carried out from Visit 1 (after Dose 1) until the last study 
visit (end of the second RSV transmission season). In order to detect asymptomatic 
RSV-RTI, monthly nasal swabs for analysis at sponsor laboratory will be performed 
for all subjects during the RSV season. In order to timely detect RSV-RTI and to 
ensure cases are timely captured by the study sites, both active and passive 
surveillance will be conducted:

Passive surveillance: parent(s)/LAR(s) are instructed to contact the 
investigator/study staff as soon as the subject experiences new RTI symptoms 
(cough, runny nose or blocked nose) or worsening of RTI symptoms, or in case 
of difficulty in breathing or wheezing.

Active surveillance: parent(s)/LAR(s) of all the subjects will be contacted by 
the investigator/study staff on a regular basis (weekly during the RSV season 
and every month outside the RSV season) to identify any potential RSV-RTI 
and to remind the parent(s)/LAR(s) of the subjects to report any new occurrence 
of RTI symptoms (cough, runny nose or blocked nose), or in case of difficulty in 
breathing or wheezing as soon as possible.
Refer to Section 9.2 for more information about active and passive surveillance.

Surveillance for spontaneous or excessive bleeding.
Subjects’ parent(s)/LAR(s) will be instructed to contact the investigator/study staff if 
their child presents symptoms of spontaneous bleeding or easy bruising or if their child 
develops a rash, within 30 days after either vaccination (Visit 1 and Visit 3), in order to 
detect any thrombocytopenic petechiae or purpura. The investigator will, based on his/her 
medical judgment, measure the total blood count and appropriately investigate infants 
with clinical suspicion of low platelets.
 
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4.
CASE DEFINITION
It should be noted that for the reporting of safety (unsolicited AEs, AEs of special interest 
and SAEs), the investigator will use all available information and his/her medical 
judgment to make diagnoses. The case definitions presented below will be used for a 
safety analysis complementary to standard safety tabulations of events according to 
Medical Dictionary for Regulatory Activities (MedDRA) preferred terms.
4.1.
RTI case definitions
During the analysis of the study, all cases identified during the surveillance of RSV-RTI 
will be definitively classified as either RTI, LRTI, severe LRTI or very severe LRTI 
according to the standardized case definitions (see Table 6) based on the available World 
Health Organization (WHO) case definitions [Modjarrad, 2016].
Table 6
Case definitions for data analysis
Case
At sea level up to 2500 meters elevation
Above 2500 meters elevation
RSV-RTI
Runny nose OR blocked nose OR cough
AND 
Confirmed RSV infection 4
Same
RSV-LRTI
History of cough OR difficulty breathing 1
AND
SpO2 < 95% 2, OR RR increase 3
AND
Confirmed RSV infection 4
Same but with SpO2 <92%
severe RSV-LRTI
Meeting the case definition of RSV-LRTI 
AND
SpO2 < 93% 2, OR lower chest wall in-
drawing
Same but with SpO2 <90%
very severe RSV-LRTI
Meeting the case definition of RSV-LRTI 
AND 
SpO2 < 90% 2, OR inability to feed, OR 
failure to respond / unconscious
Same but with SpO2 <88%
RSV hospitalization
Confirmed RSV infection 5
AND
Hospitalized for acute medical condition 6
Same
All-cause LRTI
History of cough OR difficulty breathing 1
AND 
SpO2 < 95% 2, OR RR increase 3
Same but with SpO2 <92%
LRTI = lower respiratory tract infections; RR = respiratory rate; RTI = respiratory tract infections; SpO2 = blood oxygen 
saturation.
Based on [Modjarrad, 2016]
1 Based on history reported by parents. 
2 The lowest value during the course of illness will be used.
3 RR increase defined as:
50/minute (2 to 11 months of age)
40/minute (12 months of age or above)
The highest value during the course of the illness will be used.
4 RSV infection confirmed on nasal swab positive for RSV A or B by quantitative Reverse Transcription Polymerase 
Chain Reaction (qRT-PCR).
5 RSV sampling and testing is based on medical judgment of medical practitioner or driven by algorithm.
6 Hospitalization is defined as a medical decision that the infant requires admission for observation or treatment.
 
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5.
STUDY COHORT
5.1.
Number of subjects
The target will be to enroll approximately 150 infants likely to be previously unexposed 
to RSV with about 50 infants for each of three randomization groups. If necessary, the 
sample size may be increased through additional recruitment in order to achieve a 
sufficient number of RSV infected infants, with a negative RSV exposure status (at 
screening based on in-stream serological testing), in each RSV vaccine group. Dose 1 
administration should be completed before the first RSV season and second dose will be 
given one month after the first dose (RSV seasons will be determined for each country 
based on local epidemiological data and documented in the SPM). The RSV season is 
defined as the period of the year when 70% of the RSV cases have occurred in previous 
years. For the calculation, where available, data from up to the ten previous years should 
be applied. If the data permit calculation of the actual date of the beginning of the season, 
rather than approximation to the nearest month, this is desirable. Refer to the SPM for 
RSV seasons per country. Refer to Section 11.4 for the determination of sample size
(Amended 1 August 2019).
Overview of the screening plan:
Upon completion of all screening procedures (refer to Table 7), the investigator will 
review the inclusion/exclusion criteria for each infant. Infants meeting all eligibility 
criteria will be enrolled in the study. Their screening information will be recorded on the 
appropriate screen of eCRF.
If the investigator believes there is a reasonable reason to do so, screening procedures 
may be repeated once only. All screening procedures may be repeated except the blood 
sampling for humoral response (neutralizing antibody titers against RSV-A, RSV-F 
protein antibody concentrations and palivizumab-competing antibody concentrations).
5.2.
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’ parent(s)/LAR(s) who, in the opinion of the investigator, can and will 
comply with the requirements of the protocol (e.g., completion of the diary cards, 
return for follow-up visits).

Written informed consent obtained from the parent(s)/LAR(s) of the subject prior to 
performing any study specific procedure.

A male or female between and including 6 and 7 months of age (from the day the 
infant becomes 6 months of age until the day before the infant achieves 8 months of 
age) at the time of the first vaccination.
 
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
Healthy subjects as established by medical history and clinical examination before 
entering into the study.

Born full-term (i.e., after a gestation period of 37 to less than 42 completed weeks) 
with a minimum birth weight of 2.5 kg.

Subjects’ parent(s)/LAR(s) need to have access to a consistent mean of telephone 
contact (e.g., land line or mobile) or computer.
5.3.
Exclusion criteria for enrolment
Deviations from exclusion criteria are not allowed because they can potentially 
jeopardize the scientific integrity, regulatory acceptability of the study or subject safety. 
Therefore, adherence to the criteria as specified in the protocol is essential.
The following criteria should be checked at the time of study entry. If ANY exclusion 
criterion applies, the subject must not be included in the study:

Child in care
Please refer to the glossary of terms for the definition of child in care.

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.

Chronic administration (defined as more than 14 days in total) of 
immunosuppressants or other immune-modifying drugs during the period starting six 
months prior to the first vaccine. For corticosteroids, this will mean prednisone 0.5 
mg/kg/day (for pediatric subjects), or equivalent. Topical steroids are allowed.

Administration of long-acting immune-modifying drugs (e.g., infliximab) or planned 
administration at any time during the study period.

Administration of immunoglobulins and/or any blood products during the period 
starting three months before the first dose of study vaccine or planned administration 
during the study period.

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 vaccine administration, with the exception of scheduled routine 
pediatric vaccines. (For details of permitted concomitant vaccines refer to 
Section 7.6). Scheduled routine pediatric vaccines may be administered ≥7 days
before a dose of study vaccine or ≥7 days following a dose of study vaccine, with 
the exception of live viral vaccines which may be administered ≥14 days before a 
dose or ≥7 days after a dose.

Acute or chronic, clinically significant pulmonary, cardiovascular, hepatic or renal 
functional abnormality, as determined by physical examination or laboratory 
screening tests.

A history of, or on-going confirmed RSV disease or highly compatible clinical 
picture (e.g., bronchiolitis).
 
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
Serious chronic illness.

Major congenital defects.

History of any neurological disorders or seizures.

History of or current autoimmune disease.

History of recurrent wheezing. (“Recurrent wheezing” is defined as ≥ 2 episodes of 
wheezing in the subject´s lifetime). Wheezing should have been verified on 
auscultation by doctor.

History of chronic cough (4 weeks or more duration).

Previous hospitalization for lower respiratory illnesses.

Previous, current or planned administration of Synagis (palivizumab).

Neurological complications following any prior vaccination.

Born to a mother known or suspected to be HIV-positive (no laboratory testing 
required).

Any confirmed or suspected immunosuppressive or immunodeficient condition, 
based on medical history and physical examination (no laboratory testing required).

Family history of congenital or hereditary immunodeficiency.

Previous vaccination with a recombinant simian or human adenoviral vaccine.

History of any reaction or hypersensitivity to any component of the vaccines
(investigational or control) or placebo used in this study or any contraindication to 
them.

Hypersensitivity to latex.

Current severe eczema.

Acute disease and/or fever at the time of enrolment (Visit 1).

Fever is defined as temperature 38.0°C / 100.4°F. The preferred location for 
measuring temperature in this study will be the rectum for subjects < 12 months 
of age.

Clinically significant upper respiratory tract infection.

Subjects with a minor illness (such as mild diarrhea) without fever may be 
enrolled at the discretion of the investigator.

Any clinically significant Grade 1 or any Grade 2* hematological or biochemical 
laboratory abnormality detected at the last screening blood sampling.
* Refer to APPENDIX C. For Grade 1 laboratory abnormalities, the investigator 
should use his/her clinical judgment to decide which ones are clinically relevant. 
Infants with hematological/biochemical values out of normal range which are 
expected to be temporary, may be re-screened at a later date.

Any medical condition that in the judgment of the investigator would make IM 
injection unsafe.
 
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
Any other conditions that the investigator judges may interfere with study procedures 
(e.g., drawing blood), findings (e.g., immune response).

Any conditions that could constitute a risk for the subjects while participating to this 
study.

Weight below the fifth percentile according to the World Health Organization 
(WHO) weight-for-age tables 
(https://www.who.int/childgrowth/standards/weight_for_age/en/).

Participating in another clinical study, at any time during the study period, in which 
the subject or mother (if breastfeeding) has been or will be exposed to an 
investigational or a non-investigational vaccine/product (pharmaceutical product or 
device)

Planned move to a location that will prohibit participating in the trial until study end.

For Thailand only, subjects who have received Synflorix prior to enrolment.
6.
CONDUCT OF THE STUDY
6.1.
Regulatory and ethical considerations, including the 
informed consent process
The study will be conducted in accordance with all applicable regulatory requirements.
The study will be conducted in accordance with the ICH Guideline for GCP, all 
applicable subject privacy requirements and the guiding principles of the Declaration of 
Helsinki.
The study has been designed and will be conducted in accordance with the ICH 
Harmonized Tripartite Guideline for clinical investigation of medicinal products in the
pediatric population (ICH E11) and all other applicable ethical guidelines.
GSK will obtain favourable opinion/approval to conduct the study from the appropriate 
regulatory agency, in accordance with applicable regulatory requirements, prior to a site 
initiating the study in that country.
Conduct of the study includes, but is not limited to, the following:

Institutional Review Board (IRB)/Independent Ethics Committee (IEC) review and 
favourable opinion/approval of study protocol and any subsequent amendments.

Subject’s parent(s)/LAR(s) informed consent.

Investigator reporting requirements as stated in the protocol.
GSK will provide full details of the above procedures to the investigator, either verbally, 
in writing, or both.
Freely given and written or witnessed/ thumb printed informed consent must be obtained 
from each subject’s parent(s)/LAR(s), prior to participation in the study.
 
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GSK Biologicals will prepare a model 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.
6.2.
Subject identification and randomization
6.2.1.
Subject identification
Subject identification numbers will be assigned sequentially to the subjects who have 
consented to participate in the study, according to the range of subject identification 
numbers allocated to each study center.
6.2.2.
Randomization of treatment
6.2.2.1.
Randomization of supplies
The randomization of supplies within blocks will be performed at GSK Biologicals, using 
MATerial EXcellence (MATEX), a program developed for use in Statistical Analysis 
System (SAS®) (Cary, NC, USA) by GSK Biologicals. Entire blocks will be shipped to 
the study centers /warehouse(s).
6.2.2.2.
Treatment allocation to the subject
The treatment numbers will be allocated by components.
6.2.2.2.1.
Study group and treatment number allocation
The target will be to enroll approximately 150 infants. Approximately 50 infants likely to 
be previously unexposed to RSV will be randomly assigned to receive 2 doses at 0, 1 
month schedule of 0.5 mL of the ChAd155-RSV vaccine (5x1010 vp) [the 2D RSV + 
comparator group], approximately 50 infants likely to be previously unexposed to RSV 
will be randomly assigned to receive a single dose of 0.5 mL of ChAd155-RSV vaccine 
(1.5x1010 vp) [the 1D RSV + comparator group], and approximately 50 infants likely to 
be previously unexposed to RSV will be randomly assigned to receive 0.5 mL of the 
comparator/Placebo control vaccine [the comparator/Placebo control alone group].
 
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Allocation of the subject to a study group at the investigator site will be performed using 
a randomization system on internet (SBIR) operated at the study level.
The randomization algorithm will assign each subject to the 2 doses of RSV vaccine + 
comparator group, the single dose of RSV vaccine + comparator group, or its 
corresponding active control comparator group with the aim of keeping the ratio between 
the pooled 2 dose RSV + comparator group, the pooled single dose RSV + comparator 
group and the pooled comparator group at 1:1:1 in the entire study (see Table 25 for a 
description of pooled groups).
Countries will be grouped into five levels according to the choice of comparator vaccine 
or Placebo, the randomization algorithm will use a minimization procedure accounting 
for country as a minimization factor and the grouping comparator/placebo as a 
stratification factor to attempt to maintain a 1:1:1 ratio as well within each level in the 
assignment of RSV + comparator vaccine versus comparator/Placebo control vaccine 
alone.
The actual randomization assignment the subject received (to one of five 2 dose of RSV 
+ comparator vaccine groups, to one of five single dose of RSV + comparator vaccine 
groups, or to one of five comparator/Placebo control alone groups) will be able to be 
identified in SBIR.
After obtaining the signed and dated ICF from the subject’s parent(s)/LAR(s) and having 
checked the eligibility of the subject, the delegated study staff will access SBIR. Upon 
providing the subject identification number and the age, the randomization system will 
determine the study group and will provide the treatment number to be used for the first 
dose.
The number of each administered treatment must be recorded in the eCRF on the Vaccine 
Administration screen.
When SBIR is not available, please refer to the SBIR user guide or the SPM for specific 
instructions.
6.2.2.2.2.
Treatment number allocation for subsequent doses
For each dose subsequent to the first dose, the delegated study staff 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.
 
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6.3.
Method of blinding
Data will be collected in an observer-blind manner. By observer-blind, it is meant that 
during the course of the study, the vaccine recipient and those responsible for the 
evaluation of any study endpoint (e.g., safety, reactogenicity) will all be unaware of 
which vaccine was administered. To do so, vaccine preparation and administration will 
be done by authorized medical personnel who will not participate in any of the study 
clinical evaluation assays.
When all data up to Day 61 are available, a statistical analysis will be performed. This 
analysis may lead to the unblinding of some subjects. As a consequence, after Day 61, the 
study cannot be considered as observer-blind, but will be conducted in a single blind 
manner, with subjects’ parent(s)/ LAR(s) remaining blinded up to the last study visit (end 
of the second RSV transmission season), while the investigator will still not have access 
to the treatment allocation up to the last study visit (end of the second RSV transmission 
season), except in case of emergency unblinding (see Section 9.8).
The laboratory in charge of the laboratory testing will be blinded to the treatment, and 
codes will be used to link the subject and study (without any link to the treatment 
attributed to the subject) to each sample.
6.4.
General study aspects
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the accompanying SPM. The SPM provides the investigator and the site 
personnel with administrative and detailed technical information that does not impact the 
safety of the subjects.
In the same investigational center, infants will be vaccinated sequentially, separated by a 
minimum interval of 60 minutes.
Refer to Section 9.10 for information about limited vaccination, holding rules, safety
monitoring and safety evaluation by iSRC and IDMC.
 
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6.5.
Outline of study procedures
Table 7
List of study procedures
Epoch
Epoch 001
Epoch 002
Epoch 003
Epoch 004
Age
6-7 months
6-9 months
Type of contact
Screening Visit 1 Visit 2 b Visit 3 Visit 4 b Visit 5 Visit 6 c
Visit 7
Visit 8 b
Unscheduled 
visit for 
safety e
Contact for 
active/ 
passive 
surveillance f
Surveillance 
for 
asymptomatic 
RSV-RTI g
Assessment 
of potential 
RSV-RTI h
Timepoints
D -30 to
D-1 a
D1
D8
D31
D38
D61
D121
End of the 
1st RSV 
season d
End of the 
2nd RSV 
season d
Monthly or 
Weekly
Monthly
Informed consent
●
Check inclusion/exclusion criteria
●
O
Collect demographic data
●i
Medical history j
●
Physical examination k
●
O
O
O
O
O
O
O
O
O
●
Growth monitoring l
●
●
●
●
●
Check contraindications and 
warnings and precautions
O
O
O
O
O
(Pre-vaccination) body temperature
●
●
●
●
●
Randomization
O
Vaccine administration m
●
●
●
●c
●
Recording of administered treatment 
number
●
●
●
●
●
60 minutes post-vaccination 
observation n
O
O
30 minutes post-vaccination 
observation for additional 
comparator/FB vaccinations
O
O
O
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Epoch
Epoch 001
Epoch 002
Epoch 003
Epoch 004
Age
6-7 months
6-9 months
Type of contact
Screening Visit 1 Visit 2 b Visit 3 Visit 4 b Visit 5 Visit 6 c
Visit 7
Visit 8 b
Unscheduled 
visit for 
safety e
Contact for 
active/ 
passive 
surveillance f
Surveillance 
for 
asymptomatic 
RSV-RTI g
Assessment 
of potential 
RSV-RTI h
Timepoints
D -30 to
D-1 a
D1
D8
D31
D38
D61
D121
End of the 
1st RSV 
season d
End of the 
2nd RSV 
season d
Monthly or 
Weekly
Monthly
Blood sampling for assessment of 
mechanisms of illness (potential 
ERD; ~2.5 mL)
●o
Blood sampling for hematology and 
biochemistry (~2.3 mL)
●p
●q
Blood sampling for humoral response 
(~2.5 mL)
●r
●s
●
●
Surveillance for RSV-RTI, difficulty in 
breathing and wheezing
O
O
O
O
O
O
O
O
O
O
Documentation of symptoms and 
signs of RTI t
●
Nasal swab for central testing (RSV
and RVP)
●u
●v
Specimen for local testings (RSV and 
RVP)
●w
Distribution of RTI episode card x
O
O
O
O
O
O
O
Collection of RTI episode card x
O
O
O
O
O
O
O
O
O
O
Transcription of RTI episode card
●
●
●
●
●
●
●
O
●
●
Record any concomitant 
medications/vaccinations
●
●
●
●
●
●
●
●
●
●
●
Distribution of the subject card
O
Distribution of diary card
O
O
O
O
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Epoch
Epoch 001
Epoch 002
Epoch 003
Epoch 004
Age
6-7 months
6-9 months
Type of contact
Screening Visit 1 Visit 2 b Visit 3 Visit 4 b Visit 5 Visit 6 c
Visit 7
Visit 8 b
Unscheduled 
visit for 
safety e
Contact for 
active/ 
passive 
surveillance f
Surveillance 
for 
asymptomatic 
RSV-RTI g
Assessment 
of potential 
RSV-RTI h
Timepoints
D -30 to
D-1 a
D1
D8
D31
D38
D61
D121
End of the 
1st RSV 
season d
End of the 
2nd RSV 
season d
Monthly or 
Weekly
Monthly
Return of diary card
O
O
O
O
Diary card transcription by 
investigator
●
●
●
●
Recording of solicited AEs (Day 1–7)
●
●
●
●
●y
Recording of unsolicited AEs (Day 1-
30)
●
●
●
●
●
●y
Recording of AE leading to study 
withdrawal
●
●
●
●
●
●
●
●
●
●
●
●
Recording of AESI (RSV-LRTI)
●
●
●
●
●
●
●
●
●
●
●
●
Recording of AESI (spontaneous or 
excessive bleeding) z
●
●
●
●
●
●
Reporting of easy bruising, or 
rash/petechiae monitored by 
parent(s)/LAR(s) z
O
O
O
O
O
Recording of SAEs
●
●
●
●
●
●
●
●
●
●
●
●
Recording of SAEs related to study 
participation, or to a concurrent GSK 
medication/vaccine
●
●
●
●
●
●
●
●
●
●
●
●
●
Screening conclusion
●
Study conclusion
●
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Epoch
Epoch 001
Epoch 002
Epoch 003
Epoch 004
Age
6-7 months
6-9 months
Type of contact
Screening Visit 1 Visit 2 b Visit 3 Visit 4 b Visit 5 Visit 6 c
Visit 7
Visit 8 b
Unscheduled 
visit for 
safety e
Contact for 
active/ 
passive 
surveillance f
Surveillance 
for 
asymptomatic 
RSV-RTI g
Assessment 
of potential 
RSV-RTI h
Timepoints
D -30 to
D-1 a
D1
D8
D31
D38
D61
D121
End of the 
1st RSV 
season d
End of the 
2nd RSV 
season d
Monthly or 
Weekly
Monthly
Signing of investigator signature form 
by investigator after Screening and 
before each analysis
●
●
●
●
AE: adverse event; AESI: Adverse Events of Special Interest; FB: Formulation buffer S9b; LRTI: lower respiratory tract infection; RSV: respiratory syncytial virus; RTI: respiratory tract 
infection, RVP: respiratory viral panel SAE: serious adverse event.
● is used to indicate a study procedure that requires documentation in the individual eCRF.
O is used to indicate a study procedure that does not require documentation in the individual eCRF.
Note: the double-bordered lines following Visit 5 (Day 61), Visit 7 (end of the first RSV transmission season) and Visit 8 (end of the second RSV transmission season) indicate the 
statistical analyses which will be performed. After Visit 5 (Day 61) the study will be conducted in a single blind manner, with patients remaining blinded up to the last study visit 
(end of the second RSV transmission season). The investigator will not have access to the treatment allocation up to the last study visit (end of the second RSV transmission 
season), except in case of emergency unblinding.
a For vaccination done on the same day as screening, it must be ensured that screening procedures only begin after signing consent and that all the screening procedures confirming 
eligibility, including the laboratory results, are made available prior to vaccination (see Section 6.6.2).
bVisit 2 (Day 8), Visit 4 (Day 38), and Visit 8 (no blood sampling for immune response and no vaccine administration) may take place in the subject’s home or at the investigators 
clinical facility as appropriate to the circumstances in the judgment of the investigator. For authorized sites only; screening, Visit 5 (Day 61) and Visit 7 (both with blood sampling) 
may also take place in the subject’s home or at the investigators clinical facility as appropriate to the circumstances in the judgment of the investigator ￼￼
c In countries where Menveo or Placebo is used as a comparator, no administration will be performed at Day 121 and therefore in those countries there will be no Visit 6 and it will be 
administered at the end of the first RSV season at Visit 7 (refer to Figure 1 and Table 2).
d Refer to the SPM for RSV seasons per country.
e This visit is applicable for infants with hematological/biochemical values out of normal range or for further evaluation of clinical suspicion of low platelet count.
f Active contacts for surveillance of RSV-RTI will take place weekly during each RSV season and every month outside the RSV season. Passive phone contacts from the carers to the 
investigator will take place when symptoms occur.
gIn order to detect asymptomatic RSV infection, monthly visits will be performed during the RSV season.
hThis visit is only applicable for infants with potential RSV-RTI.
i Recording of demographic data includes date of birth, sex, race, ethnicity and comparator group.
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jMedical history is collected by interview and/or review of the subject’s medical records and includes recording the subject’s weight at birth and gestation in weeks at birth as well as 
any pre-existing conditions or signs and/or symptoms present in a subject prior to the first study vaccination in the eCRF.
kAt screening, perform a complete physical examination, including assessment of vital signs (body temperature, heart rate [HR], and RR). At subsequent study visits, perform a 
physical examination only if the subject’s parent(s)/LAR(s) indicate(s) during questioning that there might be some underlying pathology(ies) or if deemed necessary.
lGrowth monitoring includes weight and length (for infants < 24 months of age) or height (for subjects 24 months of age).
mRefer to Table 2 and to the SPM for the comparator vaccine selection for each country.
n Infants will need to remain under observation (visual follow-up as well as measurement of resting vital signs) at the study site for at least 60 minutes after vaccination. Vital signs are 
body temperature, HR and RR. Vital signs are measured preferably when the infant is calm.
oBlood sample collected for subjects hospitalized for LRTI (only for RSV-positive subjects using a locally available RSV test). Refer to Section 6.7.3.
p At Screening, for infants with hematological/biochemical values out of normal range which are expected to be temporary, a re-screening visit may be scheduled during which blood 
sample collection for hematology/biochemistry will be repeated (maximum one re-screening visit per infant is allowed).
q If any Grade 1 abnormality with potential clinical relevance (according to investigator judgment) or any ≥ Grade 2 abnormality is detected, or for further evaluation of clinical suspicion 
of low platelet count, refer to Section 6.6.12.2 and Figure 2 for re-test.
rIf no blood sample was collected for humoral immunogenicity at the screening visit, an additional blood sample will be taken at Visit 1 that must be taken before vaccination.
sSamples must be taken before vaccination.
t Signs and symptoms to be recorded in the eCRF are listed in the SPM.
u Nasal swab collected at the monthly surveillance for asymptomatic RSV-RTI will be tested by quantitative RT-PCR. This swab may be omitted upon investigator discretion if a swab 
has been taken for a symptomatic episode in the previous 4 weeks (see Section 6.6.12.3).
v If during passive or active surveillance contact, the investigator/study staff assesses that an infant presents a potential RSV-RTI (refer to Table 6 for definition), the potential RSV 
infection will be assessed by quantitative RT-PCR.
w At a local routine laboratory
x Subject’s parent(s)/LAR(s) will be instructed to record on the RTI episode card symptoms the start date and the end date of the following symptoms (cough, runny nose, blocked 
nose, difficulty in breathing, or wheezing) and to return it to the investigator at the next visit or by mail (e-mail or postal mail).
y Only when the unscheduled visit occurs within the AE reporting time frame, i.e., from Day 1 to Day 7 for solicited AEs and from Day 1 to Day 30 for unsolicited AEs.
zSubjects’ parent(s)/LAR(s) will be instructed to contact the investigator/study staff if their child presents symptoms of spontaneous bleeding or easy bruising or if their child develops a 
rash, within 30 days after either vaccination, in order to detect any thrombocytopenic petechiae or purpura (see Table 19).
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Whenever possible, the investigator should arrange study visits within the interval 
described in Table 8.
Table 8
Target intervals between study visits
Interval
Length of interval
Screening Visit 1 (Day 1)
30 days 1
Visit 1 (Day 1) Visit 2 (Day 8)
7 days
Visit 1 (Day 1) Visit 3 (Day 31)
30 days
Visit 1 (Day 1) Visit 5 (Day 61)
60 days
Visit 3 (Day 31) Visit 4 (Day 38)
7 days
Visit 3 (Day 31) Visit 5 (Day 61)
30 days
Visit 5 (Day 61) Visit 6 (Day 121) 2
60 days
Visit 7 (end of the first RSV transmission season)
From vaccination to the defined end of the first RSV 
transmission season
Visit 8 (end of the second RSV transmission season)
From vaccination to the defined end of the second RSV 
transmission season
1 Visit 1 should take place no longer than 30 days after the Screening visit. When applicable, a re-screening visit may 
be scheduled at any time (but only once to assess eligibility). All screening procedures need to be performed 
within 30 days of Visit 1.
2 In countries where Menveo or Placebo is used as a comparator, no administration will be performed at Day 121 and 
therefore in those countries there will be no Visit 6 and if applicable it will be administered at the end of the first 
RSV season at Visit 7 (refer to Figure 1 and Table 2).
Refer to Table 24 for intervals between study visits that determine subjects’ eligibility for 
inclusion in the per-protocol (PP) analysis.
6.6.
Detailed description of study procedures
6.6.1.
Informed consent
The signed/witnessed/thumb printed informed consent of the subject’s parent(s)/LAR(s) 
must be obtained before study participation. Refer to Section 6.1 for the requirements on 
how to obtain informed consent.
6.6.2.
Screening visit
Following the signing of the informed consent, the screening procedures must be done 
within 30 days prior to vaccination.
For vaccination done on the same day as screening, all the screening procedures 
confirming eligibility including the laboratory results must be made available prior to 
vaccination.
6.6.3.
Check inclusion and exclusion criteria
Check all inclusion and exclusion criteria as described in Sections 5.2 and 5.3 before 
enrolment.
 
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6.6.4.
Collect demographic data
Record demographic data such as date of birth (day, month and year), sex, race, ethnicity 
and comparator group in the subject’s eCRF.
6.6.5.
Medical history
Obtain the subject’s medical history by interview and/or review of the subject’s medical 
records and record weight at birth and gestation in weeks at birth as well as any pre-
existing conditions or signs and/or symptoms present in a subject prior to the first study 
vaccination in the eCRF. For World Health Organization (WHO) weight percentile 
standards for girls and boys, refer to the following link:
https://www.who.int/childgrowth/standards/weight_for_age/en/.
6.6.6.
Physical examination
At screening, perform a physical examination of the subject, including assessment of vital 
signs preferably when the infant is calm. Vital signs are body temperature, heart rate 
(HR) and RR. Collected information needs to be recorded in the eCRF.
At subsequent study visits, perform a physical examination only if the subject’s 
parent(s)/LAR(s) indicates during questioning that there might be some underlying 
pathology(ies) or if deemed necessary.
Treatment of any abnormality observed during physical examination should be performed 
according to local medical practice outside this study or by referral to an appropriate 
health care provider.
6.6.7.
Growth monitoring
Growth monitoring includes weight and length (for infants < 24 months of age) or height 
(for subjects 24 months of age; [United Nations, 1986]). Collected information needs to 
be recorded in the eCRF.
6.6.8.
Check contraindications, warnings and precautions to 
vaccination
Contraindications, warnings and precautions to vaccination must be checked at the 
beginning of each vaccination visit. Refer to Sections 7.5 for more details.
6.6.9.
Assess pre-vaccination body temperature
The rectal (preferred route) body temperature of each subject needs to be measured prior 
to any study vaccines administration. If the subject has fever (fever is defined as 
temperature 38.0°C/100.4°F regardless the location of measurement) on the day of 
vaccination, the vaccination visit will be rescheduled within the allowed interval for this 
visit (see Table 8).
 
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6.6.10.
Randomization
Study group and treatment number allocation will be performed as described in Section 
6.2.2. The number of each administered treatment must be recorded in the eCRF.
6.6.11.
Study vaccines administration

In the same investigational center, infants will be vaccinated sequentially, separated 
by a minimum interval of 60 minutes (Refer to Section 9.10.1).

After completing all prerequisite procedures prior to vaccination, one dose of study 
vaccine will be administered via IM injection in the anterolateral thigh. Refer to 
Section 7.3 for detailed description of the vaccines administration procedure. If the
investigator or delegate determines that the infant’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).

The subjects will be observed closely (visual follow-up as well as measurement of 
resting vital signs) for at least 60 minutes following the administration of the 
vaccines at Visit 1 and Visit 3, with appropriate medical treatment readily available 
in case of anaphylaxis. Vital signs are body temperature, HR and RR. Vital signs are 
preferably measured when the infant is calm. After administration of comparator 
vaccines or FB at Visit 5, Visit 6 and Visit 7, the subjects will be observed closely 
(visual follow-up as well as measurement of resting vital signs) for at least 30 
minutes following the administration of the vaccines, with appropriate medical 
treatment readily available in case of anaphylaxis.
6.6.12.
Sampling
Refer to the Module on Biospecimen Management in the SPM for detailed instructions 
for the collection, handling and processing of the samples.
To minimize any development of needle aversion, pain relief by means of a topical local 
anesthetic may be offered to infants prior to any blood sampling requested by the 
protocol at the discretion of the investigator and in line with prescribing information.
6.6.12.1.
Blood sampling for humoral immunity
Blood samples will be taken during certain study visits as specified in Section 6.5 List of 
Study Procedures.

A volume of 2.5 mL of whole blood (to provide at least 800 L of serum) should be 
drawn from all infants for analysis of humoral response at each pre-defined 
timepoint. After centrifugation, serum samples should be kept at –20°C/ –4°F or 
below until shipment. Refer to the SPM for more details on sample storage 
conditions.

Blood sampling for humoral response will not be repeated in case of insufficient 
volume, at any timepoint except if no blood sample for humoral immunogenicity 
was collected at the screening visit. In that case an additional blood sample will 
be taken at Visit 1 that must be taken before vaccination.
 
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6.6.12.2.
Blood sampling for hematology and biochemistry

A volume of maximum 2.3 mL of whole blood should be drawn from all infants for 
analysis of the hematology and biochemistry parameters (refer to Table 12) at each 
pre-defined timepoint.
Hematology and biochemistry parameters measurement will be performed according 
to laboratory practices.
If any Grade 1 abnormality with potential clinical relevance (according to 
investigators judgment, refer to the glossary of terms) or any ≥Grade 2 abnormality 
is detected (refer to Figure 2 and APPENDIX C):

at Screening, for infants with hematological/biochemical values out of normal
range which are expected to be temporary, a re-screening visit may be scheduled 
during which blood sample collection for hematology/biochemistry will be 
repeated (maximum one re-screening visit per infant is allowed within the 
interval planned in Table 8; blood for humoral response will not be re-sampled 
at the re-screening visit).
Note: Blood may be re-sampled for hematology and biochemistry assessment during a re-
screening visit (as described above) or during an Unscheduled Visit where there is 
clinical indication for additional testing.
 
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Figure 2
Schematic overview of required additional hematology and biochemistry testing during the study
Note: Blood can be re-sampled for hematology and biochemistry assessment where there is clinical indication for additional testing.
Re-testing at screening
Grade 1 abnormality with 
potential clinical 
relevance  or ≥ Grade 2 
abnormality, expected to 
be temporary 
Subject may be 
enrolled in the study 
Testing may be repeated at 
any time (but only once to 
assess eligibility). 
To be performed within 
screening visit window
Grade 1 with potential clinical 
relevance  or ≥ Grade 2
Values within normal range or 
Grade 1 without clinical 
relevance
Subject not 
eligible
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6.6.12.3.
Nasal swab or other specimen for PCR assay
Nasal swab or other specimen for PCR assay collected during assessment visit
Real time assessment of potential RSV-LRTI cases is important for the timely monitoring 
of safety.
If during passive or active surveillance contact, the investigator/study staff assesses that 
an infant presents a potential RSV-RTI (refer to Section 9.2), a nasal swab or another 
specimen for assay will be collected during an assessment visit:

The nasal swab will allow assessing the potential RSV infection by quantitative RT-
PCR and respiratory viral panel (RVP) at sponsor laboratory.

The specimen for local assay will allow assessing the potential RSV infection and 
RVP at a local routine laboratory, where available. The specimen type will depend 
on the assay run locally.
Nasal swab collected for PCR assay to detect asymptomatic RSV infections
During RSV season, there will be monthly nasal swabs to detect asymptomatic RSV 
infections. These nasal swabs will allow assessing the potential RSV infection by 
quantitative RT-PCR performed centrally at the sponsor laboratory. This swab may be 
omitted upon investigator discretion if a swab has been taken for a symptomatic episode 
in the previous 4 weeks.
Refer to the SPM for more details about nasal swab.
6.6.13.
Surveillance for RSV-RTI and wheezing
Surveillance period for RSV-RTI and wheezing will start at Visit 1 (after Dose 1) until 
the final visit (Visit 8 [end of the second RSV transmission season]). In order to timely 
detect RSV-RTI and to ensure cases are timely captured by the study sites, both active 
and passive surveillance will be conducted as described in Section 9.2. Contacts for 
active and passive surveillance will be recorded in the eCRF.
If an assessment visit is performed (refer to Section 9.2.4), this visit will be recorded in 
the eCRF, as well as signs and symptoms. Signs and symptoms to be recorded in the 
eCRF are listed in the SPM.
At the first vaccination visit (Visit 1 [Day 1]), RTI episode cards will be provided to the 
subject's parent(s)/LAR(s). At subsequent study visits, new RTI episode card(s) will be 
distributed as needed. The subject's parent(s)/LAR(s) will record the start date and the 
end date of the following symptoms: cough, runny nose, blocked nose, difficulty in 
breathing, or wheezing. The subject's parent(s)/LAR(s) will be instructed to return the 
completed RTI episode card to the investigator at the next visit or by mail (e-mail or 
postal mail). The investigator will transcribe the collected information into the eCRF. 
Any unreturned RTI episode cards will be sought from the subject's parent(s)/LAR(s) 
through telephone call(s) or any other convenient procedure.
 
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6.6.14.
Check and record concomitant medication/vaccination
Concomitant medication/vaccination must be checked and recorded in the eCRF as 
described in Section 7.6.
6.6.15.
Recording of AEs, AEs of special interest and SAEs

Refer to Section 9.3 for procedures for the investigator to record AEs, AEs of special 
interest (RSV-LRTI) and SAEs. Refer to Section 9.4 for guidelines and how to report 
AEs of special interest and SAE reports to GSK Biologicals.

The subjects’ parent(s)/LAR(s) will be instructed to contact the investigator 
immediately should the subjects manifest any signs or symptoms they perceive as 
serious.

Subjects’ parent(s)/LAR(s) will be instructed to contact the investigator/study staff if 
their child presents symptoms of spontaneous bleeding or easy bruising or if their 
child develops a rash, within 30 days after either vaccination (Visit 1 and Visit 3), in 
order to detect any thrombocytopenic petechiae or purpura after each vaccination 
from Visit 1 [Day 1] to Visit 5 Day 61.

At each vaccination visit of the RSV investigational vaccine (Visit 1 [Day 1] and 
Visit 3 [Day 31]), a diary card will be provided to the subject’s parent(s)/LAR(s). 
The subject’s parent(s)/LAR(s) will be instructed to measure and record the rectal 
body temperature (preferred route), any solicited local/general AEs, any unsolicited 
AEs, and concomitant medications/products/vaccinations on the day of vaccination 
and 6 subsequent days. The subject’s parent(s)/LAR(s) will be instructed to return 
the completed diary card to the investigator at Visit 2 (Day 8) and Visit 4 (Day 38).
The subject’s parent(s)/LAR(s) will record on the same diary card any unsolicited 
AEs and concomitant medications/products/vaccinations from 7 to 29 days after each 
vaccination. The subject’s parent(s)/LAR(s) will be instructed to return the 
completed diary card to the investigator at Visit 3 (Day 31) and Visit 5 (Day 61).
The investigator will collect and verify completed diary cards during discussion with 
the subject’s parent(s)/LAR(s) on Visit 2 (Day 8), Visit 3 (Day 31), Visit 4 (Day 38), 
and Visit 5 (Day 61). The investigator will transcribe the collected information into 
the eCRF in English.
Any unreturned diary cards will be sought from the subject’s parent(s)/LAR(s) 
through telephone call(s) or any other convenient procedure.
6.6.16.
Screening conclusion
At the end of the screening visit, the investigator will:

Review data collected.

Complete the Screening Conclusion screen in the eCRF.
 
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6.6.17.
Signing of investigator signature form by investigator
At the end of the screening visit, Visit 5 (Day 61), Visit 7 (end of the first RSV 
transmission season) and Visit 8 (end of the second RSV transmission season), the 
investigator will sign the investigator signature form in the eCRF.
6.6.18.
Study conclusion
At the last visit (Visit 8 [end of the second RSV transmission season]), the investigator 
will:

Review data collected to ensure accuracy and completeness.

Complete the Study Conclusion screen in the eCRF.
6.7.
Biological sample handling and analysis
Please refer to the SPM for details on biospecimen management (handling, storage and 
shipment).
Samples will not be labelled with information that directly identifies the subject but will 
be coded with the identification number for the subject (subject number).

Collected samples will be used for protocol mandated research and purposes related 
to the improvement, development and quality assurance of the laboratory tests 
described in this protocol. This may include the management of the quality of these 
tests, the maintenance or improvement of these tests, the development of new test 
methods, as well as making sure that new tests are comparable to previous methods 
and work reliably.

It is also possible that future findings may make it desirable to use the samples 
acquired in this study for future research, not described in this protocol. Therefore, 
all subjects in countries where this is allowed will be asked to give a specific consent 
to allow GSK or a contracted partner to use the samples for future research. Future 
research will be subject to the laws and regulations in the respective countries and 
will only be performed once an independent Ethics Committee or Review Board has 
approved this research.
Information on further investigations and their rationale can be obtained from GSK 
Biologicals. 
Any sample testing will be done in line with the consent of the individual subject’s 
parent(s)/LAR(s).
Refer also to the Investigator Agreement, where it is noted that the investigator cannot 
perform any other biological assays except those described in the protocol or its 
amendment(s). 
 
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If additional testing is performed, the marker priority ranking given in Section 6.7.4 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.
6.7.1.
Use of specified study materials
When materials are provided by GSK Biologicals, it is MANDATORY that all clinical 
samples (including serum samples) be collected and stored exclusively using those 
materials in the appropriate manner. The use of other materials could result in the 
exclusion of the subject from the per-protocol analysis (See Section 11.5 for the 
definition of cohorts to be analysed). The investigator must ensure that his/her personnel 
and the laboratory(ies) under his/her supervision comply with this requirement. However, 
when GSK Biologicals does not provide material for collecting and storing clinical 
samples, appropriate materials from the investigator’s site must be used. Refer to the 
Module on Clinical Trial Supplies in the SPM.
 
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6.7.2.
Biological samples
Table 9
Biological samples
Sample
Timepoint
Type of sample†
Subject
Number of 
subjects
Quantity
Blood
Screening
Blood sample for hematology and biochemistry
All infants
150
2.3 mL
Blood sample for humoral response 
All infants
150
2.5 mL
Total volume of blood collected for each subject
4.8 mL
Visit 3 (Day 31)
Blood sample for humoral response
All infants
150
2.5 mL
Visit 5 (Day 61)
Blood sample for humoral response
All infants
150
2.5 mL
Total volume of blood collected for each subject from Screening to Visit 5 (Day 61)*
9.8 mL
Visit 7 (end of the 
first RSV 
transmission 
season)
Blood sample for humoral response
All infants
150
2.5 mL
Assessment of 
potential RSV-RTI
Blood sampling for assessment of mechanisms 
of illness (potential ERD)
Hospitalization 
for RSV-LRTI 
(only for RSV-
positive 
subjects using 
a locally 
available RSV 
test)
Hospitalization 
for RSV-LRTI 
(only for RSV-
positive 
subjects using 
a locally 
available RSV 
test)
2.5 mL
Unscheduled visit 
for safety
Blood sample for hematology and biochemistry
Event-driven Event-driven
2.3 mL
Total volume of blood collected for each subject from Screening to Visit 8 (end of the 
second RSV transmission season)*
12.3 mL
Nasal 
swab
Assessment of 
potential RSV-RTI
Nasal swab**
Event-driven Event-driven
-
Surveillance for 
asymptomatic 
RSV-RTI
Nasal swab***
All infants
150
-
† The priority ranking in blood sampling is hematology > biochemistry > humoral response.
Venipuncture will not be repeated for humoral response in case of insufficient volume, at any timepoint except if no 
blood sample for humoral immunogenicity was collected at the screening visit. In that case an additional blood 
sample will be taken at Visit 1 that must be taken before vaccination.
* Total quantity of blood for each subject excludes any optional or unscheduled hematology and biochemistry blood 
sampling or blood sample for assessment of mechanism of illness collected if a subject has been hospitalized for 
RSV-LRTI.
** If during passive or active surveillance contact, the investigator/study staff assesses that an infant presents a 
potential RSV-RTI (refer to Table 6 for definition), the potential RSV infection will be assessed by quantitative RT-
PCR of nasal swab specimens taken at an assessment visit.
*** During RSV season, there will be monthly nasal swabs to detect asymptomatic RSV infections. These swabs will be 
tested by quantitative RT-PCR at sponsor laboratory.
These assays will be performed only on enrolled infants and samples from non-enrolled subjects will be discarded.
6.7.3.
Laboratory assays
Please refer to APPENDIX A for a detailed description of the assays performed in the 
study. Please refer to APPENDIX B for the address of the clinical laboratories for sample 
analysis.
 
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Determination of a negative RSV exposure status in infants at 6 to 7 months of age will 
be based on RSV A and/or B neutralizing antibody titers present in serum at screening 
(before vaccination with the RSV vaccine) based on in-stream baseline serological 
testing. At birth, newborns do show positive for neutralizing antibodies due to maternal 
transfer during gestation. The titer of these antibodies declines over time. At the age of 6 
to 7 months a cut-off can be defined below which infants are considered to have a 
negative RSV exposure status. Infants that show neutralizing antibody titers above this 
cut-off are suspected to have experienced a recent RSV infection. This cut-off will thus 
allow the discrimination between a negative RSV exposure status versus RSV infected 
infants before start of vaccination. 
The following laboratory assays are planned:

Functional (neutralizing) antibody titers against RSV-A will be measured by a 
neutralization assay on serum samples (Table 10).

RTI will be assessed by:

Quantitative RT-PCR that is able to discriminate RSV-A and RSV-B subtypes 
(Table 11).

Qualitative multiplex PCR for detection of a panel of viruses (Table 11).

Local RSV assay, and/or local RVP where available (Table 11) (Amended 1 
August 2019).
Final confirmation of RSV presence will be obtained through the definitive results from 
the central test. 
These assays will be performed at the investigator’s laboratory, at GSK Biologicals’ 
laboratory or at laboratory designated by GSK Biologicals (refer to Table 10 and Table
11).
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 ED60
GSK Biologicals1
SERUM Respiratory 
Syncytial 
Virus F 
protein 
Ab.IgG
(Anti-RSV 
PreF 
antibody)
ELISA
In-house
EU/ml
To be defined
NÉOMED-LABS1
Ab: antibody; ELISA: enzyme-linked immunosorbent assay; IgG: immunoglobulin G; RSV: respiratory syncytial virus
* Assay cut-off and unit might be subject to change (e.g., in case of requalification, revalidation or standardization). In 
this case, this will be documented in the clinical report.
**Refer to APPENDIX B for the laboratory addresses.
1 GSK Biologicals laboratory refers to the CLS in Rixensart, Belgium; Wavre, Belgium.
 
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Table 11
Molecular Biology (PCR tests)
System
Component
Kit / 
Manufacturer
Method
Unit
Laboratory*
Nasal swab
RSV A RNA
RSV B RNA
In-house
Quantitative
RT-PCR 
Copies/ml
GSK Biologicals1 
Nasal swab
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 
(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) 2
Allplex
Respiratory 
Panel 
(Seegene) or 
equivalent 2
Multiplex PCR 
(Luminex)
Qualitative assay 
(positive/ 
negative)
GSK Biologicals1 
Other 
specimen
RSV
Not applicable
Locally 
available RSV 
assay
Not applicable
Routine local 
laboratory
Other 
specimen
RVP
Not applicable
Locally 
available RVP 
assay
Not applicable
Routine local 
laboratory
PCR: polymerase chain reaction; PIV: parainfluenza virus; RSV: respiratory syncytial virus; RT: Reverse Transcription; 
RVP: respiratory viral panel.
*Refer to APPENDIX B for the laboratory addresses.
1 GSK Biologicals laboratory refers to the CLS in Rixensart, Belgium; Wavre, Belgium.
2 The list of components might be subject to change in case equivalent kit is used for multiplex RVP testing.
 
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Additional exploratory testing on the vaccine and/or on the disease under study may be 
performed within the framework of the study if deemed necessary for accurate 
interpretation of the data or should such assay(s) become available at GSK. These assays 
may not be represented in the objectives/endpoints of the study protocol
Additional viral diagnosis testing on the nasal swabs, such as (but not limited to) 
multiplex PCR and/or high-throughput sequencing, may be done, if deemed necessary, 
provided specific 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:

Anti-vector immunity: neutralization.

RSV F protein antibody concentrations and palivizumab-competing antibody 
concentrations will be determined by in-house ELISA on serum sample.
For subjects hospitalized for LRTI and RSV-positive using a locally available RSV test, 
an additional blood sample will be collected (refer to Section 9.2.5). The corresponding 
serum sample will be stored at GSK Biologicals’ laboratory to further characterize the 
mechanisms of illness (potential ERD), if deemed necessary. In this event, the serum 
samples could be tested by RSV neutralization assay and also by ELISA (or alternative 
method) for measurement of protein F antibodies and cytokines.
Hematology and biochemistry assessments will be performed in the investigator’s 
laboratory as per local practice using standardized and validated procedures (Table 12).
Table 12
Hematology and biochemistry tests
System
Discipline
Component
Timepoint
Method
Scale
Laboratory
Whole blood Hematology
Hemoglobin
Screening
As per 
local 
practice
Quantitative
Local 
laboratory
Leukocytes (White Blood Cells)
Lymphocytes
Neutrophils
Platelets
Serum
Biochemistry
Alanine Aminotransferase
Screening
As per 
local 
practice
Quantitative
Aspartate Aminotransferase
Creatinine
At screening repeat testing may be performed once according to Figure 2. At any time 
during the trial additional hematology and/or biochemistry testing may be performed for 
the further investigation of a potential AE.
The GSK Biologicals’ clinical laboratories have established a Quality System supported 
by procedures. The activities of GSK Biologicals’ clinical laboratories are audited 
regularly for quality assessment by an internal (sponsor-dependent) but laboratory-
independent Quality Department.
 
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6.7.4.
Biological samples evaluation
6.7.4.1.
Immunological read-outs
Table 13
Immunological read-outs
Blood sampling timepoint
No. 
subjects
Component
Components 
priority rank
Type of contact and 
timepoint
Sampling 
timepoint
System
Screening
(Day -30 to Day -1)
Pre-Vaccination
Serum 
~ 150
Anti-RSV A Neutralizing Antibody
1
Respiratory Syncytial Virus F protein 
Ab.IgG (Anti-RSV PreF antibody)
2
Visit 3 (Day 31)
Post-Vaccination 1
Serum
~ 150
Anti-RSV A Neutralizing Antibody
1
Respiratory Syncytial Virus F protein 
Ab.IgG (Anti-RSV PreF antibody)
2
Visit 5 (Day 61)
Post-Vaccination 2
Serum
~ 150
Anti-RSV A Neutralizing Antibody
1
Respiratory Syncytial Virus F protein 
Ab.IgG (Anti-RSV PreF antibody)
2
Visit 7 (end of the first 
RSV transmission 
season)
Post-Vaccination 2
Serum
~ 150
Anti-RSV A Neutralizing Antibody
1
Respiratory Syncytial Virus F protein 
Ab.IgG (Anti-RSV PreF antibody)
2
Ab: Antibody; IgG: immunoglobulin G; RSV: respiratory syncytial virus.
In case of insufficient blood sample volume to perform assays for all antibodies, the 
samples will be analysed according to priority ranking provided in Table 13.
The RVP (Multiplex PCR) on specimens from all RSV-A/B positive and confirmed LRTI 
cases, according to case definition presented in Table 6 (Figure 3), will qualitatively 
assess the potential co-infections occurring in these subjects. The panel of viruses 
profiled is presented in Table 14.
 
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Table 14
Molecular biology for nasal swab and specimen analysis
Sampling timepoint
No. 
subjects
Component
Components 
priority rank
Type of contact and 
timepoint
Sampling 
timepoint
System
Surveillance for 
asymptomatic RSV-
RTI
Monthly contact 
during the RSV 
season
Nasal swab
~ 150
Quantitative RT-PCR
(RSV A RNA and RSV B RNA)
Not 
applicable
Assessment of 
potential RSV-RTI
All subjects 
attending 
assessment visit
Nasal swab
Event-
driven
Quantitative RT-PCR
(RSV A RNA and RSV B RNA)
Not 
applicable
Assessment of 
potential RSV-RTI
All subjects 
attending 
assessment visit 
with positive 
Quantitative RSV 
A/B RT-PCR 
results
Nasal swab
Event-
driven
Qualitative multiplex PCR 
(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 (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)
Not 
applicable
Assessment of 
potential RSV-RTI
All subjects 
presenting 
confirmed LRTI* 
(with negative 
Quantitative RSV 
A and B RT-PCR 
results)
Nasal swab
Event-
driven
Qualitative multiplex PCR 
(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 (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)
Not 
applicable
 
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Sampling timepoint
No. 
subjects
Component
Components 
priority rank
Type of contact and 
timepoint
Sampling 
timepoint
System
Human rhinovirus A/B/C (HRV)
Human coronavirus 229E (229E)
Human coronavirus NL63 (NL63)
Human coronavirus OC43 (OC43)
Assessment of 
potential RSV-RTI
All subjects 
attending 
assessment visit
Other 
specimen
Event-
driven
Locally available RSV assay
Not 
applicable
Assessment of 
potential RSV-RTI
All subjects 
attending 
assessment visit
Other 
specimen
Event-
driven
Locally available RVP assay
Not 
applicable
* Refer to Table 6 for the case definitions.
2 The list of components might be subject to change in case equivalent kit is used for multiplex RVP testing.
PCR: polymerase chain reaction; RSV: respiratory syncytial virus; RTI: respiratory tract infection; RVP: respiratory viral 
panel.
6.7.5.
Immunological correlates of protection
No generally accepted immunological correlate of protection has been established so far 
for the antigens used in the candidate ChAd155-RSV vaccine.
7.
STUDY VACCINES AND ADMINISTRATION
7.1.
Description of study vaccines
The investigational ChAd155-RSV vaccine has been developed and manufactured by 
GSK Biologicals.
The Quality Control Standards and Requirements for the 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.
Commercial vaccines are assumed to comply with the specifications given in the 
manufacturer’s Summary of Product Characteristics.
 
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Table 15
Study vaccines
Treatment 
name
Vaccine name
Formulation
Presentation
Volume to be 
administered
Number of 
doses
1D RSV ChAd 1D ChAd155-RSV
ChAd155-RSV=3*10¹⁰vp/mL
Liquid in 
monodose vial †
0.5 ml
1
2D RSV ChAd 2D ChAd155-RSV
ChAd155-RSV=1*10¹¹vp/mL
Liquid in 
monodose vial †
0.5 ml
2
Formulation 
buffer (FB)
Formulation buffer 
S9b
Na₂HPO₄=1.3mg; 
KH₂PO₄=186µg; NaCl=3.85mg; 
KCl=100µg; MgCl₂=50µg
Clear liquid
0.5 ml
0, 1 or 2 ‡
Placebo
Formulation buffer 
S9b
Na₂HPO₄=1.3mg; 
KH₂PO₄=186µg; NaCl=3.85mg; 
KCl=100µg; MgCl₂=50µg
Clear liquid
0.5 ml
2
Bexsero
Bexsero
Recombinant Neisseria 
meningitidis group B NHBA fusion 
protein=50µg; Recombinant 
Neisseria meningitidis group B 
NadA protein=50µg; Recombinant 
Neisseria meningitidis group B 
fHbp fusion protein=50µg; Outer 
membrane vesicles (OMV) from 
Neisseria meningitidis group B 
strain NZ98/254=25µg; 
Al(OH)₃=500µg Al3+
White opalescent 
liquid suspension 
for injection in 
pre-filled syringe
0.5 ml
3
Nimenrix
Nimenrix §
MenACWY-TT
PSA=5µg TT; PSC=5µg TT; 
PSW₁₃₅=5µg TT; PsY=5µg TT; 
TT~=44µg
White powder or 
cake in a single 
dose glass vial
0.5 ml
3
Nimenrix §
NaCl
NaCl=150mM
Sodium chloride 
as a clear liquid 
for suspension
Menveo
Menveo ¥
MenA lyo
MenA=10µg,CRM197=16.7-
33.3µg; KH₂PO₄=5mM; 
Sucrose=12.5mg
Lyophilized 
component in a 
vial
0.5 ml
2
Menveo ¥
MenCWY liquid
MenC=5µg,CRM197=7.1-12.5µg; 
MenW=5µg,CRM197=3.3-8.3µg; 
MenY=5µg,CRM197=5.6-10µg; 
NaCl=4.5mg; Na3PO4=10mM; 
NaH2PO4=2.5mM; 
Na₂HPO₄=7.5mM; water=0.5ml
Liquid 
component in a 
vial
Synflorix
Synflorix
10Pn-PD-DiT
PS1=1µg PD; PS4=3µg PD; 
PS5=1µg PD; PS6B=1µg PD; 
PS7F=1µg PD; PS9V=1µg PD; 
PS14=1µg PD; PS18C=3µg TT; 
PS19F=3µg DT; PS23F=1µg PD; 
PD=9-16µg; DT=3-6µg; TT=5-
10µg; AlPO₄=500µg Al3+
Turbid white 
suspension
0.5 ml
3
† Clear, colorless solution free from visible particles.
‡ The number of Formulation buffer doses depends on the study arm and study country (see Table 2).
§ MenACWY-TT, a white powder or cake, is resuspended with a NaCl solution, to make Nimenrix.
¥ MenA lyo, a lyophilized component, is resuspended with MenCWY liquid, to make Menveo.
* Formulation buffer will be administered, when neither RSV vaccine nor comparator is scheduled, at the vaccination 
visits (see Figure 1, Table 2 and Table 16).
 
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7.2.
Storage and handling of study vaccines
The study vaccines 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 vaccines.
Temperature excursions must be reported in degree Celsius.
For the Placebo [Saline] (Formulation buffer S9b) and for the active control comparator 
vaccines (Bexsero, Nimenrix, Synflorix and Menveo) any temperature excursion outside 
the range of 2.0 to +8.0C (for +2 to +8°C/+36 to +46°F label storage condition) and for 
the ChAd155-RSV vaccine any temperature excursion above -60°C (for -60°C/-76°F
label storage condition) must be reported in the appropriate (electronic) temperature 
excursion decision form. The impacted investigational medicinal products (IMPs) must 
not be used and must be stored in quarantine at label temperature conditions until usage 
approval has been obtained from the sponsor.
Refer to the Module on Clinical Trial Supplies in the SPM for details and instructions on 
the temperature excursion reporting and usage decision process, packaging and 
accountability of the study vaccines.
Refer to the SPM for more details on aspects vaccine handling including disposal of 
waste and management of accidental spills.
7.3.
Dosage and administration of study vaccines
The first IM dose of ChAd155-RSV vaccine must be administered before the first RSV 
season while the second dose (when applicable) will be given one month after the first 
dose. The volume to be administered for each IM vaccination will be 0.5 mL in the 
anterolateral thigh. The preferable side for administration is the left side. If for some 
reason the left side cannot be used, please ensure the subsequent doses are administered 
on the same side as the first dose. In the second year of life at Visit 7 if the muscle size is 
adequate, the site of administration can be the deltoid on the left side. 
 
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Table 16
Dosage and administration
Type of 
contact and 
timepoint
Study group
Treatment name1
Volume to be 
administered
(0.5 mL)
Route2
(IM)
Site
Location
(Anterolateral 
Thigh) 3
Laterality 4
(Left)
Visit 1
(Day 1)
1D RSV + Bexsero
1D RSV ChAd
0.5 mL
IM
Anterolateral 
Thigh
Left
1D RSV + Nimenrix
1D RSV ChAd
1D RSV + Synflorix
1D RSV ChAd
1D RSV + Menveo
1D RSV ChAd
1D RSV + Placebo
1D RSV ChAd
2D RSV + Bexsero
2D RSV ChAd
2D RSV + Nimenrix
2D RSV ChAd
2D RSV + Synflorix
2D RSV ChAd
2D RSV + Menveo
2D RSV ChAd
2D RSV + Placebo
2D RSV ChAd
Bexsero
Bexsero
Nimenrix
Nimenrix
Synflorix
FB
Menveo
FB
Placebo
FB
Visit 3
(Day 31)
1D RSV + Bexsero
FB
1D RSV + Nimenrix
FB
1D RSV + Synflorix
FB
1D RSV + Menveo
FB
1D RSV + Placebo
FB
2D RSV + Bexsero
2D RSV ChAd
2D RSV + Nimenrix
2D RSV ChAd
2D RSV + Synflorix
2D RSV ChAd
2D RSV + Menveo
2D RSV ChAd
2D RSV + Placebo
2D RSV ChAd
Bexsero
FB
Nimenrix
FB
Synflorix
Synflorix
Menveo
Menveo
Placebo
FB
Visit 5
(Day 61)
1D RSV + Bexsero
Bexsero
1D RSV + Nimenrix
Nimenrix
1D RSV + Synflorix
Synflorix
1D RSV + Menveo
Menveo
2D RSV + Bexsero
Bexsero
2D RSV + Nimenrix
Nimenrix
2D RSV + Synflorix
Synflorix
2D RSV + Menveo
Menveo
Bexsero
Bexsero
Nimenrix
Nimenrix
Synflorix
Synflorix
Menveo
FB
 
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Type of 
contact and 
timepoint
Study group
Treatment name1
Volume to be 
administered
(0.5 mL)
Route2
(IM)
Site
Location
(Anterolateral 
Thigh) 3
Laterality 4
(Left)
Visit 6
(Day 121) 5
1D RSV + Bexsero
Bexsero
0.5 mL
IM
Anterolateral 
Thigh
Left
1D RSV + Nimenrix
Nimenrix
1D RSV + Synflorix
Synflorix
2D RSV + Bexsero
Bexsero
2D RSV + Nimenrix
Nimenrix
2D RSV + Synflorix
Synflorix
Bexsero
FB
Nimenrix
FB
Synflorix
FB
Visit 7 (end 
of the first 
RSV 
transmission 
season)
1D RSV + Bexsero
Bexsero
1D RSV + Nimenrix
Nimenrix
1D RSV + Synflorix
Synflorix
1D RSV + Menveo
Menveo
2D RSV + Bexsero
Bexsero
2D RSV + Nimenrix
Nimenrix
2D RSV + Synflorix
Synflorix
2D RSV + Menveo
Menveo
Bexsero
Bexsero
Nimenrix
Nimenrix
Synflorix
Synflorix
Menveo
Menveo
1D: 1 Dose (1.5x1010 vp/dose); 2D: 2 Dose (5x1010 vp/dose); RSV ChAd: Chimpanzee Adenovirus Type 155 RSV 
vaccine; NA: not applicable; FB: Formulation buffer S9b.
1 The choice of active comparator vaccine or Placebo control is done at the country level (see Table 2).
2 IM: Intramuscular.
3 In the second year of lifeon Visit 7 if the muscle size is adequate, the site of administration can be the deltoid on the 
left side.
4The preferable side for administration is the left side. If for some reason the left side cannot be used, please ensure 
the subsequent doses are administered on the same side as the first dose.
5 In countries where Menveo or Placebo is used as a comparator, no administration will be performed at Day 121 and 
therefore in those countries there will be no Visit 6 and it will be administered at the end of the first RSV season at 
Visit 7 (refer to Figure 1, Table 2 and Table 7).
7.4.
Replacement of unusable vaccine doses
In addition to the vaccine doses provided for the planned number of subjects (including 
over-randomization when applicable), at least 10% additional vaccine doses will be 
supplied to replace those that are unusable.
The investigator will use SBIR to obtain the replacement vial number. The replacement 
numbers will be allocated by dose. The system will ensure, in a blinded manner, that the 
replacement vial matches the formulation the subject was assigned to by randomization.
 
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7.5.
Contraindications to subsequent vaccination
The following events constitute absolute contraindications to further administration of 
ChAd155-RSV. If any of these events occur during the study, the subject must not 
receive additional doses of vaccine but may continue other study procedures at the 
discretion of the investigator (see Section 9.5).

Anaphylaxis following the administration of vaccines.

Any confirmed or suspected immunosuppressive or immunodeficient condition, 
including HIV infection.

Any condition that in the judgment of the investigator would make IM injection 
unsafe.

Current autoimmune disease.

Acute or chronic, clinically significant pulmonary, cardiovascular, hepatic or renal 
functional abnormality, as determined by physical examination or laboratory tests.

Failure to thrive.
The following events constitute contraindications to administration of ChAd155-RSV at 
that point in time; if any of these events occur at the time scheduled for vaccination, the 
subject may be vaccinated at a later date, within the time window specified in the 
protocol (see Section 6.5), or the subject may be withdrawn at the discretion of the 
investigator (see Section 9.5).

Acute disease and/or fever at the time of vaccination.

Fever is defined as temperature 38.0°C / 100.4°F. The preferred location for 
measuring temperature in this study will be the axilla for subjects 1 and < 5 
years of age and the rectum for subjects < 12 months of age.

Subjects with a minor illness (such as mild diarrhea, mild upper respiratory tract 
infections) without fever can be administered all vaccines.

Receipt of a routine pediatric vaccine within the previous 7 days, with the 
exception of live viral vaccines, for which an interval of 14 days should be 
respected.
7.6.
Concomitant medications/products and concomitant 
vaccinations
At each study visit, the investigator or delegate should question the subject’s 
parent(s)/LAR(s) about any medications/products taken and vaccinations received by the 
subject.
Scheduled routine pediatric vaccines may be administered 7 days before a dose of study 
vaccine or 7 days following a dose of study vaccine, with the exception of live viral 
vaccines which may be administered 14 days before a dose or 7 days after a dose. 
Vaccines needed for urgent individual medical need (e.g., rabies prophylaxis) may be 
administered at any time.
 
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In case an emergency mass vaccination for an unforeseen public health threat (e.g., a 
pandemic) is organized by the public health authorities, outside the routine immunization 
program, the time period described above can be reduced if necessary for that vaccine 
provided it is licensed and used according to its Summary of Product Characteristics 
(SmPC) or Prescribing Information and according to the local governmental 
recommendations and provided a written approval of the Sponsor is obtained.
7.6.1.
Recording of concomitant medications/products and 
concomitant vaccinations
The following concomitant medication(s)/product(s)/vaccine(s) must be recorded in the 
eCRF.

All concomitant medications/products, except vitamins and dietary supplements, 
administered in the 30 day follow-up period after the administration of each dose of 
study vaccines (Day 1 to Day 30).

Any concomitant vaccination administered in the period starting 30 days before the 
first dose of study vaccines and ending at the last study visit (Day -29 to end of the 
second RSV transmission season).

Prophylactic medication (i.e., medication administered in the absence of ANY 
symptom and in anticipation of a reaction to the vaccination or blood sampling).

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 axilla for subjects 1 and < 5 years of age and the rectum for 
subjects < 12 months of age.

E.g. a topical local anesthetic used prior to a blood sampling is considered to be 
prophylactic.

Any concomitant medications/products/vaccines listed in Section 7.6.2.

Any concomitant medications/products/vaccines relevant to a SAE to be reported as 
per protocol or administered at any time during the study period for the treatment of 
a SAE. In addition, concomitant medications relevant to SAEs need to be recorded 
on the expedited Adverse Event report.

Any antipyretic administered in the period starting 6 hours before vaccination and 
ending 12 hours after vaccination need to be recorded on the specific page of the 
eCRF.
 
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7.6.2.
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 11.5 for cohorts to be analysed.

Any investigational or non-registered product (drug or vaccine) other than the study 
vaccines used during the study period. 

Immunosuppressants or other immune-modifying drugs administered chronically 
(i.e., more than 14 days in total) during the study period. For corticosteroids, this will 
mean prednisone 0.5 mg/kg/day (for pediatric subjects), 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 dose of vaccine*, with 
the exception of:

Scheduled routine pediatric vaccines which may be administered 7 days before 
a dose and 7 days after a dose of study vaccines, with the exception of live 
viral vaccines which may be administered 14 days before a dose or 7 days 
after a dose.

Vaccines needed for urgent individual medical need (e.g., rabies prophylaxis).
*In case an emergency mass vaccination for an unforeseen public health threat (e.g.: 
a pandemic) is organized by the public health authorities, outside the routine 
immunization program, the time period described above can be reduced if necessary 
for that vaccine provided it is licensed and used according to its Summary of Product 
Characteristics (SmPC) or 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.
8.
HEALTH ECONOMICS
Not applicable.
9.
SAFETY
The investigator or site staff is/are responsible for the detection, documentation and 
reporting of events meeting the criteria and definition of an AE or SAE as provided in 
this protocol. 
Each subject’s parent(s)/LAR(s) will be instructed to contact the investigator immediately 
should they/the subject manifest any signs or symptoms they perceive as serious.
 
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9.1.
Safety definitions
9.1.1.
Definition of an adverse event
An AE is any untoward medical occurrence in a clinical investigation subject, temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with 
the use of a medicinal product. For marketed medicinal products, this also includes 
failure to produce expected benefits (i.e., lack of efficacy), abuse or misuse.
Examples of an AE include:

Significant or unexpected worsening or exacerbation of the condition/indication 
under study.

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study vaccines 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 
vaccines or a concurrent medication (overdose per se should not be reported as an 
AE/SAE).

Signs, symptoms temporally associated with study vaccines 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 9.1.3. 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).

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.
 
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9.1.2.
Definition of a serious adverse event
A SAE is any untoward medical occurrence that:
a.
Results in death,
b.
Is life-threatening,
Note: The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in 
which the subject was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, had it been more severe.
c.
Requires 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,
Note: The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions. This definition is not intended to include experiences 
of relatively minor medical significance such as uncomplicated headache, nausea, 
vomiting, diarrhea, influenza like illness, and accidental trauma (e.g., sprained ankle) 
which may interfere or prevent everyday life functions but do not constitute a 
substantial disruption.
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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9.1.3.
Solicited adverse events
9.1.3.1.
Solicited local (injection-site) adverse events
The following local (injection-site) AEs will be solicited:
Table 17
Solicited local adverse events
All age groups
Pain at injection site
Redness at injection site
Swelling at injection site
9.1.3.2.
Solicited general adverse events
The following general AEs will be solicited:
Table 18
Solicited general adverse events
Infant
Drowsiness
Fever
Irritability/Fussiness
Loss of appetite
Note: parent(s)/LAR(s) will be instructed to measure and record the rectal body 
temperature in the evening. Should additional temperature measurements be performed at 
other times of day, parent(s)/LAR(s) will be instructed to record the highest temperature 
in the diary card.
9.1.4.
Clinical laboratory parameters and other abnormal assessments 
qualifying as adverse events or serious adverse events 
In absence of diagnosis, abnormal laboratory findings (e.g., clinical chemistry, 
hematology, urinalysis) or other abnormal assessments (e.g., physical examination) that 
are judged by the investigator to be clinically significant will be recorded as AE or SAE 
if they meet the definition of an AE or SAE (refer to Sections 9.1.1 and 9.1.2). Clinically 
significant abnormal laboratory findings or other abnormal assessments that are present at 
baseline and significantly worsen following the start of the study will also be reported as 
AEs or SAEs. 
The investigator will exercise his or her medical and scientific judgement in deciding 
whether an abnormal laboratory finding or other abnormal assessment is clinically 
significant.
 
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9.1.5.
Adverse events of special interest
9.1.5.1.
Spontaneous or excessive bleeding
Subjects’ parent(s)/ legally acceptable representative(s) (LAR[s]) will be instructed to 
contact the investigator/study staff if their child presents symptoms of spontaneous 
bleeding or easy bruising or if their child develops a rash, within 30 days after either 
vaccination (Visit 1 and Visit 3), in order to detect any thrombocytopenic petechiae or 
purpura. The investigator will, based on his/her medical judgment, measure the total 
blood count and appropriately investigate infants with clinical suspicion of low platelets.
Any episode of spontaneous or excessive bleeding occurring within 30 days after each 
vaccination should be fully investigated with a full range of hematological tests to 
identify the underlying cause and reported as an AE of special interest.
9.1.5.2.
RSV-LRTI
LRTI associated with RSV infection will be reported as an adverse event of special 
interest in an expedited manner. These will be detected through the surveillance for RSV-
RTI (refer to Section 9.2).
To identify RSV-LRTI for the purpose of AE of special interest, the diagnosis should be 
based on the investigators’ clinical judgment taking into account the clinical history, the 
examination, relevant medical investigations and within 24 hours of results of a locally-
available diagnostic test for RSV. Of note the case definition presented in Table 6 is 
based on a limited set of symptoms and signs and is designed for protocol specified 
analyses pooled across sites at study conclusion and should not be used for the purpose of 
reporting RSV-LRTI as an AE of special interest during the trial conduct.
In addition to report these cases as AE of special interest, the investigator should 
investigate the case according to the procedures for the surveillance of RSV-RTI (refer to 
Section 9.2) and document it in the eCRF. Of note a nasal swab should be taken for 
confirmatory and quantitative testing of RSV infection by the sponsor.
9.2.
Surveillance for RSV-RTI, difficulty in breathing and 
wheezing episodes
Each subject will be under surveillance for RSV-RTI, difficulty in breathing, and 
wheezing episodes from the administration of Dose 1 (Visit 1) and will continue until the 
final visit (Visit 8). Surveillance will be performed via phone or e-mail contacts and 
assessment visits (refer to Figure 3). The passive and active surveillance contacts can also 
be made by/with the person designated by the parent(s)/LAR(s) (e.g., grandparents, 
nanny) as long as the parent(s)/LAR(s) have given approval.
The safety of the infant is paramount and for any reported illness, the 
investigator/study staff should assess the need for any intervention and provide this 
as part of regular healthcare or instruct/advise the parent(s)/LAR(s) where to 
obtain this care.
 
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Figure 3
Decision tree for passive and active surveillance contacts
1 Active contacts will take place weekly during each RSV season and every month outside the RSV season. Passive 
phone contacts from the parents/LARs to the investigator will take place when symptoms occur.
2 Refer to the SPM for signs and symptoms to be collected.
3 RSV-A/B quantitative PCR on all specimens.
4 RVP (Multiplex PCR) on all specimens RSV-A/B positive and on all cases of confirmed LRTI according to case 
definition presented in Table 6.
5 For example, in the event that the subject requires urgent medical evaluation and care or has travelled to another 
location.
6 In case of worsening of symptoms, optional sample if the previous specimen was RSV-positive, and mandatory if the 
previous sample was RSV-negative.
Refer to APPENDIX D for the symptoms and grading for assessment visits and 
worsening visits.
Active or Passive surveillance 
contact1
Yes
Yes
No
Yes
No
No
Perform Assessment visit within 72 hours
•
Document signs and symptoms2
•
Record SpO2 and RR
•
Take a specimen (for analysis of RSV and 
RVP at a local routine laboratory)
•
Take a nasal swab (for analysis at sponsor 
laboratory)3,4
Perform Assessment visit within 24 hours
•
Document signs and symptoms2
•
Record SpO2 and RR
•
Take a specimen (for analysis of RSV and RVP at a local routine 
laboratory)6
•
Take a nasal swab (for analysis at sponsor laboratory)3,4
•
Give medical advice as appropriate
OR in the event the Assessment visit within 24 hours is not possible5
•
Advise to seek medical care
•
Record clinical details from medical records2
•
Request a specimen (for analysis of RSV and RVP at a local 
routine laboratory)
•
Take a nasal swab within 72 hours (for analysis at sponsor 
laboratory)3,4
Note: Report all RSV-LRTI as AE of specific interest within 24 
hours (Expedited AE report)
Suspicion of difficulty in 
breathing, wheezing or 
parental concern?
RTI Symptoms
(cough, runny nose, blocked
nose), difficulty in breathing
or wheezing?
Remind to report any worsening 
of symptoms
Remind to report any future 
symptoms
Worsening of 
symptoms or parental 
concern?
 
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9.2.1.
Passive surveillance
All subjects’ parent(s)/LAR(s) will be instructed to contact investigator/study staff in 
case of any new or worsened RTI symptoms (cough, runny nose or blocked nose) or in 
case of any new difficulty in breathing or wheezing. They will be also reminded to record 
the start date and the end date of the RTI symptoms on the RTI episode card.

If there is any new difficulty in breathing, wheezing or parental concern, the 
investigator/study staff will schedule an assessment visit as soon as possible (refer to 
Section 9.2.4), but no later than 24 hours after the phone contact to ensure prompt 
assessment of the need for medical care.

If there is no suspicion of difficulty in breathing, nor wheezing, nor parental 
concern, but there are any new symptoms of an RTI (cough, runny nose or blocked 
nose), the investigator/study staff will schedule an assessment visit as soon as 
possible (refer to Section 9.2.4), but no later than 72 hours after the phone contact. 
Performing the visit as soon as possible is important to assess the need for medical 
care, to ensure that early symptoms are captured, and also to collect an optimal nasal 
swab for the detection of RSV.

All passive surveillance contacts will be documented in the eCRF.

In the event that it is not possible to schedule an assessment visit, which may arise if 
the family has travelled, then the assessment visit page of the eCRF should be filled 
in as completely as possible using available medical records.
9.2.2.
Surveillance for asymptomatic RSV-RTI

In order to detect asymptomatic RSV-RTI, monthly nasal swabs for analysis at 
sponsor laboratory will be performed for all subjects during the RSV season who are 
‘RTI symptom free’ within an approximate 30 day period. Upon investigators 
discretion, the asymptomatic visit may be omitted if a nasal swab has been taken for 
a potential disease episode in the previous 4 weeks (please refer to the SPM for an 
example of when to schedule the visit). The asymptomatic nasal swab will be tested 
by quantitative PCR.

These nasal swabs may be performed in the subject’s home or the investigators 
clinical facility as appropriate to the circumstances in the judgment of the 
investigator.

All surveillance visits for asymptomatic RSV-RTI will be documented in the eCRF.
 
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9.2.3.
Active surveillance
There will be contact between the investigator/study staff and subject’s parent(s)/LAR(s) 
on a regular basis (weekly during the RSV season and every month outside the RSV 
season). If there has not been a contact through a clinic visit (i.e., Visits 1, 2, 3, 4, 5, 6*, 
7, 8), a passive surveillance contact (refer to Section 9.2.1), an assessment visit (refer to 
Section 9.2.4) or a surveillance for asymptomatic RSV infection (refer to Section 9.2.2), 
then the investigator/study staff will contact the subject’s parent(s)/LAR(s). The active 
surveillance will be performed by phone, mobile phone or e-mail.
* In countries where Menveo or Placebo is used as a comparator, no administration will 
be performed at Day 121 and therefore in those countries there will be no Visit 6 and it 
will be administered at the end of the first RSV season at Visit 7 (refer to Table 2 and 
Table 7).
During each active follow-up contact, the investigator/study staff will:

Confirm with the subjects’ parent(s)/LAR(s), if the subject has developed new RTI 
symptoms (cough, runny nose or blocked nose) and if he/she has developed any 
symptoms of difficulty in breathing or wheezing (during and between contacts).

If there is any new or on-going difficulty in breathing, wheezing or parental 
concern, the investigator/study staff will schedule an assessment visit as soon as 
possible (refer to Section 9.2.4), but no later than 24 hours after the contact to 
ensure prompt assessment of the need for medical care.

If there is no suspicion of difficulty in breathing, nor wheezing, nor parental 
concern, but any new symptoms of an RTI (cough, runny nose or blocked nose) 
are present, the investigator/study staff will schedule an assessment visit as soon 
as possible (refer to Section 9.2.4), but no later than 72 hours after the contact.

Performing the visit as soon as possible is important to assess the need for medical 
care, to ensure that early symptoms are captured, and also to collect a nasal swab for 
the detection of RSV. 

The investigator/study staff will remind subjects’ parent(s)/LAR(s) to record the start 
date and the end date of the RTI symptoms on the RTI episode card. 

All active surveillance contacts will be documented in the eCRF.

In the event that it is not possible to schedule an assessment visit, which may arise if 
the family has travelled, then the assessment visit page of the eCRF should be filled 
in as completely as possible using available medical records.
 
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9.2.4.
Assessment visit
The purpose of the assessment visit is to objectively document signs and symptoms by an 
appropriately qualified person (i.e., medical or nursing), provide medical advice and to 
take a nasal swab for detection of RSV infection.

Assessment visits may take place in the subject’s home, the investigators 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 parent(s)/LAR(s) 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.

During the assessment visit, the investigator/study staff will evaluate the clinical 
signs and symptoms of the RTI. Signs and symptoms to be recorded in the eCRF are 
listed in the SPM.

Oxygen saturation will be measured by pulse oximetry in room air using 
standardized equipment in preference.

Specimen for testing of RSV and RVP at a local routine laboratory will be collected 
for all the subjects who have symptoms of an RTI.

Nasal swabs for analysis at sponsor laboratory will be collected for all the subjects 
who have symptoms of an RTI. Note: all subjects experiencing an RSV-LRTI must 
be reported as an SAE in an expedited manner (refer to Section 9.4).

Parent(s)/LAR(s) will be instructed to contact the study staff if the severity of the 
already existing symptoms increases or if the subject develops difficulty in breathing 
or wheezing and this may lead to a repeat assessment visit upon the judgment of the 
investigator.

During subsequent surveillance contacts after an assessment visit, the status and 
evolution of the case will be followed until case resolution.

Each assessment visit will be encoded in the eCRF.
9.2.5.
Subject hospitalized for LRTI
Subjects admitted to hospital and treated for an LRTI will be documented fully as SAEs. 
In addition, to establish the severity of the illness, the eCRF screen corresponding to the 
assessment visit will be completed as fully as possible from medical records. Signs and 
symptoms to be recorded in the eCRF are listed in the SPM, and include where available 
oxygen saturation in air. Study staff will collect a nasal swab for all the subjects who 
have been hospitalized with a RTI for analysis at sponsor laboratory. All subjects with 
clinical suspicion of LRTI must be tested for RSV and RVP using locally available test.
Study staff will also collect a blood sample to be stored at sponsor’s laboratory for future 
assessment of mechanism of illness (potential ERD). This will be required to be done 
only for RSV-positive subjects using a locally available RSV test.
 
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9.3.
Detecting and recording adverse events, adverse events of 
special interest and serious adverse events
9.3.1.
Time period for detecting and recording adverse events, adverse 
events of special interest and serious adverse events
All AEs starting within 30 days following administration of each dose of study vaccine 
(Day 1 to Day 30) must be recorded into the appropriate section of the eCRF, irrespective 
of intensity or whether or not they are considered vaccination-related.
The time period for collecting and recording SAEs will begin at the first receipt of study 
vaccine and will end at study conclusion. See Section 9.4 for instructions on reporting of 
SAEs.
All AEs/SAEs leading to withdrawal from the study will be collected and recorded from 
the time of the first receipt of study vaccine.
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.
The time period for collecting AEs of special interest (RSV-LRTI) will begin at the first 
receipt of study vaccine and will end at study conclusion. The time period for collecting 
AEs of special interest (spontaneous or excessive bleeding) will begin at the first receipt 
of study vaccine and will end 30 days after the last vaccination on Day 61. See Section 
9.4 for instructions on reporting of AEs of special interest.
An overview of the protocol-required reporting periods for AEs, AEs of special interest 
and SAEs is given in Table 19.
 
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Table 19
Reporting periods for collecting safety information (Amended 1 August 2019)
Visit
SCR
V1
V2
V3
V4
V5
V6
V7
V8
Days
-30 to -1
1
7
8
30
31
37
38
60
61
121
end of 
the 1st
RSV 
season
end of 
the 2nd
RSV 
season
Solicited local and general AEs
Unsolicited AEs
AEs/SAEs leading to withdrawal from 
the study
AE of special interest (RSV-LRTI)
AE of special interest (spontaneous 
or excessive bleeding)*
SAEs**
SAEs related to study participation 
(start at signature of informed 
consent form) or concurrent GSK 
medication/ vaccine
AE: Adverse Event; RSV-LRTI: Respiratory Syncytial Virus-Lower Respiratory Tract Infection; SAE: Serious Adverse Event; SCR: Screening; V: Visit.
* Subjects’ parent(s)/LAR(s) will be instructed to contact the investigator/study staff if their child presents symptoms of spontaneous bleeding or easy bruising or if their child develops a 
rash, within 30 days after either vaccination, in order to detect any thrombocytopenic petechiae or purpura.
** Each subject’s parent(s)/LAR(s) will be instructed to contact the investigator immediately should they/the subject manifest any signs or symptoms they perceive as serious.
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9.3.2.
Post-Study adverse events and serious adverse events
A post-study AE/SAE is defined as any event that occurs outside of the AE/SAE 
reporting period defined in Table 19.
Investigators are not obligated to actively seek AEs or SAEs in former study participants. 
However, if the investigator learns of any SAE at any time after a subject has been 
discharged from the study, and he/she considers the event reasonably related to the study 
vaccine the investigator will promptly notify the Study Contact for Reporting SAEs.
9.3.3.
Evaluation of adverse events and serious adverse events
9.3.3.1.
Active questioning to detect adverse events and serious adverse 
events
As a consistent method of collecting AEs, the subject’s parent(s)/LAR(s) should be asked 
a non-leading question such as:
‘Has your child acted differently or felt different in any way since receiving the vaccine 
or since the last 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. For 
countries where it is not acceptable to provide copies of medical records to the sponsor, 
the required information will be transcribed by the investigator and provided to GSK 
respecting the subject’s anonymization (Amended 1 August 2019).
The investigator will attempt to establish a diagnosis pertaining to the event based on 
signs, symptoms, and/or other clinical information. In such cases, the diagnosis should be 
documented as the AE/SAE and not the individual signs/symptoms.
 
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9.3.3.2.
Assessment of adverse events
9.3.3.2.1.
Assessment of intensity
The intensity of the following solicited AEs will be assessed as described:
Table 20
Intensity scales for solicited symptoms in infants
Infant 
Adverse Event
Intensity grade
Parameter
Pain at injection site
0
None
1
Mild: Minor reaction to touch
2
Moderate: Cries/protests on touch
3
Severe: Cries when limb is moved/spontaneously painful
Redness at injection site
Record greatest surface diameter in mm
Swelling at injection site
Record greatest surface diameter in mm
Fever*
Record temperature in °C/°F
Irritability/Fussiness
0
Behaviour as usual
1
Mild: Crying more than usual/no effect on normal activity
2
Moderate: Crying more than usual/interferes with normal activity
3
Severe: Crying that cannot be comforted/prevents normal
activity
Drowsiness
0
Behaviour as usual
1
Mild: Drowsiness easily tolerated
2
Moderate: Drowsiness that interferes with normal activity
3
Severe: Drowsiness that prevents normal activity
Loss of appetite
0
Appetite as usual
1
Mild: Eating less than usual/no effect on normal activity
2
Moderate: Eating less than usual/interferes with normal activity
3
Severe: Not eating at all
* Fever is defined as temperature 38.0°C / 100.4° F by any route. The preferred location for measuring temperature 
in this study will be the axilla for subjects 1 and < 5 years of age and the rectum for subjects < 12 months of 
age. 
The maximum intensity of local injection site redness and swelling will be scored at GSK 
Biologicals as follows:
0
:
None
1
:
< 5 mm
2
:
5 to 20 mm
3
:
> 20 mm
The maximum intensity of fever will be scored at GSK Biologicals as follows:
0
:
< 38.0°C/100.4°F
1
:
38.0°C/100.4°F to 39.0°C/102.2°F
2
:
> 39.0°C/102.2°F to 40.0°C/104.0°F
3
:
> 40.0°C/104.0°F
 
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The investigator will assess the maximum intensity that occurred over the duration of the 
event for all unsolicited AEs (including SAEs) recorded during the study. The assessment 
will be based on the investigator’s clinical judgement.
The intensity should be assigned to one of the following categories:
1 (mild)
=
An AE which is easily tolerated by the subject, causing minimal 
discomfort and not interfering with everyday activities.
2 (moderate)
=
An AE which is sufficiently discomforting to interfere with 
normal everyday activities.
3 (severe)
=
An AE which prevents normal, everyday activities. Such an AE 
would, for example, prevent attendance at school/kindergarten/a 
day-care centre and would cause the parent(s)/LAR(s) to seek 
medical advice. 
An AE that is assessed as Grade 3 (severe) should not be confused with a SAE. Grade 
3 is a category used for rating the intensity of an event; and both AEs and SAEs can be 
assessed as Grade 3. An event is defined as ‘serious’ when it meets one of the pre-
defined outcomes as described in Section 9.1.2.
9.3.3.2.2.
Assessment of causality
The investigator is obligated to assess the relationship between study vaccines 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 vaccines will be considered and investigated. The investigator will also consult the 
IB to determine his/her assessment.
There may be situations when a SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK Biologicals. However, it is very 
important that the investigator always makes an assessment of causality for every event 
prior to submission of the Expedited Adverse Events Report to GSK Biologicals. The 
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:
 
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Is there a reasonable possibility that the AE may have been caused by the study vaccine?
YES
:
There is a reasonable possibility that the study vaccine contributed to 
the AE. 
NO
:
There is no reasonable possibility that the AE is causally related to the 
administration of the study vaccine. There are other, more likely causes 
and administration of the study vaccine is not suspected to have 
contributed to the AE.
If an event meets the criteria to be determined as ‘serious’ (see Section 9.1.2), additional 
examinations/tests will be performed by the investigator in order to determine ALL 
possible contributing factors for each SAE.
Possible contributing factors include:

Medical history.

Other medication.

Protocol required procedure.

Other procedure not required by the protocol.

Lack of efficacy of the vaccine, if applicable.

Erroneous administration.

Other cause (specify).
9.3.3.3.
Assessment of outcomes
The investigator will assess the outcome of all unsolicited AEs (including SAEs) 
recorded during the study as:

Recovered/resolved.

Recovering/resolving.

Not recovered/not resolved.

Recovered with sequelae/resolved with sequelae.

Fatal (SAEs only).
9.3.3.4.
Medically attended visits
For each solicited and unsolicited symptom the subject experiences, the subject’s 
parent(s)/LAR(s) will be asked if the subject received medical attention defined as 
hospitalization, or an otherwise unscheduled visit to or from medical personnel for any 
reason, including emergency room visits. This information will be recorded in the eCRF.
 
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9.4.
Reporting of serious adverse events and adverse events of 
special interest
9.4.1.
Prompt reporting of serious adverse events and adverse events 
of special interest to GSK Biologicals
SAEs that occur in the time period defined in Section 9.3 will be reported promptly to 
GSK within the timeframes described in Table 21, once the investigator determines that 
the event meets the protocol definition of a SAE.
AEs of special interest (RSV-LRTI and spontaneous or excessive bleeding) that occur in 
the time period defined in Section 9.3 will be reported promptly to GSK within the
timeframes described in Table 21.
Table 21
Timeframes for submitting serious adverse event and adverse 
events of special interest reports to GSK Biologicals
Type of Event
Initial Reports
Follow-up of Relevant Information on a 
Previous Report
Timeframe
Documents
Timeframe
Documents
SAEs
24 hours* †
electronic Expedited 
Adverse Events Report
24 hours*
electronic Expedited 
Adverse Events Report
AEs of special interest 
(RSV-LRTI)
24 hours*†
electronic Expedited 
Adverse Events Report
24 hours*‡
electronic Expedited 
Adverse Events Report
AE of special interest 
(spontaneous or 
excessive bleeding)
24 hours*†
electronic Expedited 
Adverse Events Report
24 hours*
electronic Expedited 
Adverse Events Report
* Timeframe allowed after receipt or awareness of the information.
† The investigator will be required to confirm review of the SAE/ AE of special interest causality by ticking the ‘reviewed’ 
box in the electronic Expedited Adverse Events Report within 72 hours of submission of the SAE/ AE of special 
interest.
‡ In the timeframe of awareness for the local RSV test result.
9.4.2.
Contact information for reporting serious adverse events and 
adverse events of special interest
Study Contact for Reporting SAEs and AEs of special interest
Refer to the local study contact information document.
Back-up Study Contact for Reporting SAEs and AEs of special interest
24/24 hour and 7/7 day availability:
GSK Biologicals Clinical Safety & Pharmacovigilance
Worldwide except US & Canada sites:
Fax: 
or 
Email address:
US sites only:
Fax: 
Canadian sites only:
Fax:
 
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PPD
PPD
PPD
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9.4.3.
Completion and transmission of SAE reports to GSK Biologicals
Once an investigator becomes aware that a SAE has occurred in a study subject, the 
investigator (or designate) must complete the information in the electronic Expedited 
Adverse Events Report WITHIN 24 HOURS. The report will always be completed as 
thoroughly as possible with all available details of the event. Even if the investigator does 
not have all information regarding a SAE, the report should still be completed within 24 
hours. Once additional relevant information is received, the report should be updated 
WITHIN 24 HOURS.
The investigator will always provide an assessment of causality at the time of the initial 
report. The investigator will be required to confirm the review of the SAE causality by 
ticking the ‘reviewed’ box in the electronic Expedited Adverse Events Report within 72 
hours of submission of the SAE.
9.4.3.1.
Back-up system in case the electronic reporting system does not work
If the electronic reporting system does not work, the investigator (or designate) must 
complete, then date and sign a paper Expedited Adverse Events Report and fax it to the 
Study Contact for Reporting SAEs (refer to the Sponsor Information) or to GSK 
Biologicals Clinical Safety and Pharmacovigilance department within 24 hours.
This back-up system should only be used if the electronic reporting system is not working 
and NOT if the system is slow. As soon as the electronic reporting system is working 
again, the investigator (or designate) must complete the electronic Expedited Adverse 
Events Report within 24 hours. The final valid information for regulatory reporting will 
be the information reported through the electronic SAE reporting system.
9.4.4.
Reporting of adverse events of special interest to GSK 
Biologicals
9.4.4.1.
RSV-LRTI
Note that ALL LRTI meeting the criteria of an SAE should be reported as SAEs 
with the timing of SAE reports.
In addition, once an investigator becomes aware that an episode of LRTI not meeting the 
criteria of an SAE, but which has been confirmed on local testing to be due to RSV has 
occurred in a study subject, the investigator (or designate) must complete the information 
in the electronic Expedited Adverse Events Report WITHIN 24 HOURS. The report will 
always be completed as thoroughly as possible with all available details of the event. 
Later 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 causality by ticking the 
‘reviewed’ box in the electronic Expedited Adverse Events Report within 72 hours of 
submission of the AE of special interest.
 
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Refer to Section 9.4.3.1 for back-up system in case the electronic reporting system does 
not work.
9.4.4.2.
Spontaneous or excessive bleeding
Once an investigator becomes aware that an episode of spontaneous or excessive 
bleeding has occurred in a study subject, the investigator (or designate) must complete 
the information in the electronic Expedited Adverse Events Report WITHIN 24 HOURS. 
The report will always be completed as thoroughly as possible with all available details 
of the event. Even if the investigator does not have all information regarding the event of 
spontaneous or excessive bleeding 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 causality by ticking the 
‘reviewed’ box in the electronic Expedited Adverse Events Report within 72 hours of 
submission of the AE of special interest.
Refer to Section 9.4.3.1 for back-up system in case the electronic reporting system does 
not work.
9.4.5.
Updating of serious adverse event and adverse event of special 
interest information after removal of write access to the subject’s 
eCRF
When additional SAE or AE of special interest 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 21.
9.4.6.
Regulatory reporting requirements for serious adverse events
The investigator will promptly report all SAEs to GSK in accordance with the procedures 
detailed in Section 9.4.1. GSK Biologicals has a legal responsibility to promptly notify, 
as appropriate, both the local regulatory authority and other regulatory agencies about the 
safety of a product under clinical investigation. Prompt notification of SAEs by the 
investigator to the Study Contact for Reporting SAEs is essential so that legal obligations 
and ethical responsibilities towards the safety of other subjects are met.
Investigator safety reports are prepared according to the current GSK policy and are 
forwarded to investigators as necessary. An investigator safety report is prepared for a 
SAE(s) that is both attributable to the study vaccines and unexpected. The purpose of the 
report is to fulfil specific regulatory and GCP requirements, regarding the product under 
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9.5.
Follow-up of adverse events, serious adverse events and 
adverse events of special interest
9.5.1.
Follow-up during the study
After the initial AE, AE of special interest or 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 AEs of special interest and 
SAEs; refer to Table 21).
All AEs of special interest (RSV-LRTI) and SAEs 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 AE of special interest (spontaneous or excessive bleeding) 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.
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.
9.5.1.1.
Follow-up after the subject is discharged from the study
The investigator will follow subjects:

with SAEs, with AEs of special interest 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 a paper/ electronic 
Expedited Adverse Events Report and/or pregnancy report as applicable.
GSK Biologicals may request that the investigator performs or arranges the conduct of 
additional clinical examinations/tests and/or evaluations to elucidate as fully as possible 
the nature and/or causality of the AE or SAE. The investigator is obliged to assist. If a 
subject dies during participation in the study or during a recognised follow-up period, 
GSK Biologicals will be provided with any available post-mortem findings, including 
histopathology.
9.6.
Treatment of adverse events
Treatment of any AE is at the sole discretion of the investigator and according to current 
good medical practice. Any medication administered for the treatment of a SAE and AE 
of special interest should be recorded in Expedited Adverse Event Report of the subject’s 
eCRF (refer to Section 7.6).
 
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9.7.
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 vaccines, 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 9.4.1).
9.8.
Emergency unblinding
Unblinding of a subject’s individual treatment code should occur only in the case of a 
medical emergency, or in the event of a serious medical condition, when knowledge of 
the treatment is essential for the clinical management or welfare of the subject, as judged 
by the investigator.
The emergency unblinding process consists of the automated system SBIR that allows the 
investigator to have unrestricted, immediate and direct access to the subject’s individual 
study treatment.
The investigator has the option of contacting a GSK Biologicals’ On-call Central Safety 
Physician (or Backup) if he/she needs medical advice or needs the support of GSK to 
perform the unblinding (i.e., he/she cannot access SBIR).
Any emergency unblinding must be fully documented by using the Emergency 
Unblinding Documentation Form, which must be appropriately completed by the 
investigator and sent within 24 hours to GSK Biologicals.
GSK Biologicals’ Contact information for Emergency Unblinding
24/24 hour and 7/7 day availability
GSK Biologicals’ Central Safety Physician: 
Worldwide except US/Canada:
(GSK Biologicals Central Safety Physician on-call)
For US/Canada only:
(GSK Biologicals Central Safety Physician on-call)
GSK Biologicals’ Central Safety Physician Back-up:
Worldwide except US/Canada:
US/Canada only:
Emergency Unblinding Documentation Form transmission:
Worldwide except US & Canada:
Fax:
or
US/Canada only:
Fax:
 
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9.9.
Subject card
Study subjects’ parent(s)/LAR(s) must be provided with the address and telephone 
number of the main contact for information about the clinical study.
The investigator (or designate) must therefore provide a “subject card” to each subject’s 
parent(s)/LAR(s). 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’ parent(s)/LAR(s) must be instructed to keep subject cards in their possession at 
all times during the study duration.
9.10.
Holding rules and safety monitoring
The investigational ChAd155-RSV vaccine has never been administered to RSV-
potentially naïve infants. Safety precautions such as limited vaccination, safety 
evaluations by an iSRC and an IDMC, and study holding rules have therefore been 
defined.
9.10.1.
Limited vaccination
In the same investigational center, all the infants should be vaccinated sequentially and at 
least 60 minutes apart to allow monitoring of any acute events (e.g., hypersensitivity 
reaction). All infants should be closely observed (visual follow-up as well as 
measurement of vital signs) for at least 60 minutes after vaccination. Vital signs are body 
temperature, HR and RR. Vital signs are preferably measured when the infant is calm.
9.10.2.
Internal safety review committee (iSRC) oversight
This study will be overseen by an iSRC operating under a charter. An iSRC was already 
involved in study RSV PED-002 (204838). Core members of the iSRC will include a 
GSK Biologicals’ safety physician, a CRDL, and a biostatistician who are not otherwise 
involved in the conduct of the project. The iSRC safety reviews will be conducted using 
unblinded data. The iSRC has access to the subject randomization and reviews unblinded 
data.
The iSRC will review all accumulating safety and reactogenicity data four weeks after 
the start of vaccination and then every 4 weeks until all dosing with ChAd155-RSV 
vaccine is complete on the study. The iSRC members will determine if a safety signal 
should be escalated to the VSMB. The iSRC members will determine whether any of the 
predefined holding rules are met (refer to Section 9.10.4) or if there is any other safety 
signal. In this case, vaccination in the study will be immediately put on hold (refer to 
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The iSRC will receive the following safety data within 48 hours upon GSK becoming 
aware of:

Fatal SAEs.

Life-threatening SAEs.

Related SAEs.

SAEs occurring within 30 days of vaccination.

LRTI associated with RSV infection (AE of special interest) occurring from Day 1 to 
the end of the second RSV transmission season.

Spontaneous or excessive bleeding (AE of special interest) occurring within 30 days 
after each vaccination.
In addition, the iSRC will receive:

Unblinded summary reports of accumulated solicited AEs and unsolicited AEs.

New information that may adversely affect the safety of the subjects or the conduct 
of the study.

All subsequent protocol amendments or administrative changes (for information).
9.10.3.
Independent Data Monitoring Committee (IDMC) oversight
This study will be overseen by an IDMC operating under a charter. The IDMC involved 
in the present study was already involved in study RSV PED-002 (204838). Overall, the 
role of the IDMC includes the review and protection of data integrity and rights and 
safety of study participants throughout the study period. It will provide initial, regular, 
and closing advice to GSK Biologicals on medical, ethical, scientific and safety-related 
issues. Its advice will be based on the interpretation of study data with reference to the 
study protocol.
The IDMC will review the protocol and statistical analysis plan. 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 the principal investigators and GSK Biologicals’ designated 
project representatives at any stage of the study.
The IDMC may recommend to the sponsor to suspend the enrolment to the study and/or 
vaccination based on their review of safety data arising in this study (refer to Section 
9.10.4).
The IDMC safety reviews will be conducted using unblinded data. The IDMC will 
review all available safety data while taking into account any other findings that could 
have an impact on the safety of the subjects.
The IDMC members will determine whether any of the predefined study holding rules 
are met (refer to Section 9.10.4) or if there is any other safety signal. If this is the case, 
vaccination in the study will be immediately put on hold. If no safety signal is observed, 
 
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the favorable outcome of the safety evaluation authorizing the investigator to proceed 
with vaccination of infants as outlined in Figure 1 will be also documented and provided 
in writing.

The IDMC will receive the following safety data within 48 hours upon GSK 
becoming aware of:

Fatal SAEs occurring from Day 1 to the end of the second RSV transmission 
season.

Life-threatening SAEs occurring from Day 1 to the end of the second RSV 
transmission season.

Related SAEs occurring from Day 1 to the end of the second RSV transmission 
season.

SAEs occurring within 30 days of vaccination.

LRTI associated with RSV infection (AE of special interest) occurring from Day 
1 to the end of the second RSV transmission season.

Spontaneous or excessive bleeding (AE of special interest) occurring within 30 
days after each vaccination.

The IDMC will receive the following safety data monthly:

Summary reports of solicited and unsolicited AEs. (during the period of 
vaccination).

Cumulative reports of the incidence of RSV RTI, RSV-LRTI, severe RSV-
LRTI, very severe RSV-LRTI and RSV-RTI leading to hospitalization based on 
Table 6 by using local test results until the quantitative PCR results are 
available.

Cumulative tables of incidence of all SAEs.
Additionally, an analysis on occurrence of the progression from infection to very severe 
RSV-LRTI from first vaccination (Day 1) up to the end of the first RSV transmission 
season will be conducted on all subjects who have completed Visit 7 (end of the first 
RSV transmission season) by independent Data Analysis Center if there are minimum of 
5 infections among subjects with a negative RSV exposure status (at screening which will 
be assessed by in-stream serological testing of baseline samples) in each randomized 
group.
In addition, the IDMC will receive from GSK Biologicals:

New information that may adversely affect the safety of the subjects or the conduct 
of the study.

All subsequent protocol amendments, informed consent changes or revisions or other 
documents originally submitted for review.

All subsequent protocol administrative changes (for information).
 
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9.10.4.
Holding rules
The safety holding rules which will be assessed by the investigator are defined in Table
22 and the safety holding rules which will be assessed by the iSRC or IDMC during the 
safety evaluation are defined in Table 23.
Table 22
Holding rules assessed by the investigator
Holding Rule Event
Number of 
infants/group
1a
Death or any life-threatening serious adverse event (SAE) that can be causally 
related to vaccination, according to investigator’s assessment.
≥ 1
1b
Any withdrawal from the study (by investigator or parent(s)/LAR(s) of the subject 
request) following a Grade 3 AE that cannot reasonably be attributed to a cause 
other than vaccination.
≥ 1
1c
Any local or general solicited AE leading to hospitalization that cannot reasonably 
be attributed to a cause other than vaccination.
≥ 1
1d
Within 30 days post-vaccination (Visit 1 and Visit 3),
Any spontaneous local or general bleeding
AND Thrombocytopenia < 50000/mm3
≥ 1
If an investigator detects one of the holding rules mentioned above, he/she will 
immediately put the enrolment or the vaccination on hold (refer to Section 9.10.4) and 
he/she will immediately inform the sponsor and enter the data in the eCRF. It is sponsor’s 
responsibility to put the enrolment or the vaccination on hold at all sites.
Table 23
Holding rules during the planned iSRC or IDMC evaluation 
Holding Rule Event
Number of infants
2a
Any Grade 3 solicited local AE lasting 48 hours or more 
following administration of an investigational RSV vaccine, 
within the 7-day (Days 1-7) post-vaccination period.
≥ 25% &
≥ 2 infants in any of two pooled RSV 
vaccine groups
2b
Any Grade 3 solicited general AE lasting 48 hours or more 
following administration of an investigational RSV vaccine, that 
cannot reasonably be attributed to a cause other than 
vaccination, within the 7-day (Days 1-7) post-vaccination period.
≥ 25% & 
≥ 2 infants in any of two pooled RSV 
vaccine groups
2c
Any Grade 3 unsolicited AE following administration of an 
investigational RSV vaccine, that cannot reasonably be 
attributed to a cause other than vaccination, within the 7-day 
(Days 1-7) post-vaccination period
≥ 25% &
≥ 2 infants in any of two pooled RSV 
vaccine groups
2d
Infants hospitalized for RSV-LRTI
≥ 6 (in the combination of two 
pooled RSV vaccine and the pooled 
comparator/Placebo groups)
Of note, no formal holding rules will be applied for other safety data collected. However, 
these data will also be reviewed by the iSRC and the IDMC in order to allow for an 
overall assessment of the benefit/risk ratio of vaccination.
Risk assessment
Figure 4 gives the probability of not meeting holding rule assessed by the investigator 
and the sponsor when 30 or 50 subjects are enrolled per study group.
 
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Figure 4
Evaluations based on 30 or 50 enrolled subjects - Risk assessment 
curve for one formulation based on the proposed safety holding 
rules assessed by the investigator and the sponsor
Figure 5 gives the probability of not meeting holding rule assessed during the planned 
IDMC evaluation when 50 subjects are enrolled per study group and 150 subjects in the 
whole trial.
Figure 5
Evaluations based on 50 subjects per group - Risk assessment 
curve for one formulation based on the proposed safety holding 
rules during the planned IDMC evaluation 
 
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9.10.5.
Procedure if the trial is put on hold
If the trial is put on hold by the investigator or iSRC or IDMC because a pre-defined 
holding rule is met or because of a safety concern, then all enrolment in the study and all 
vaccination will cease immediately, but all other procedures relating to safety, 
immunology and disease monitoring will continue. The iSRC/IDMC will review all 
available safety information and may ask for additional information to be provided by the 
investigators or the study team. The iSRC/IDMC will make a recommendation to the 
study team whether the study should be stopped permanently, modified or continued 
unchanged.
The VSMB will review all data and iSRC/IDMC recommendation and will decide 
whether to stop permanently, modify or continue the conduct of the study. The decision 
of the VSMB regarding the further conduct of the study will be documented and provided 
in writing to the investigators.
10.
SUBJECT COMPLETION AND WITHDRAWAL
10.1.
Subject completion
A subject who returns for the concluding visit foreseen in the protocol is considered to 
have completed the study.
10.2.
Subject withdrawal
Withdrawals will not be replaced.
10.2.1.
Subject withdrawal from the study
From an analysis perspective, a ‘withdrawal’ from the study refers to any subject who did 
not come back for the concluding visit 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 (e.g., three telephone calls and a certified letter to the 
last known address) to contact those subjects who do not return for scheduled visits or 
follow-up. 
 
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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’s parent(s)/LAR(s), 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/the subject’s 
parent(s)/LAR(s) has withdrawn consent, the investigator will document the reason for 
withdrawal of consent, if specified by the subject/subject’s parent(s)/LAR(s), in the 
eCRF.
Subjects who are withdrawn from the study because of SAEs/AEs must be clearly 
distinguished from subjects who are withdrawn for other reasons. Investigators will 
follow subjects who are withdrawn from the study as result of a SAE/AE until resolution 
of the event (see Section 9.5.1.1).
10.2.2.
Subject withdrawal from study vaccine
A ‘withdrawal’ from the study vaccine refers to any subject who does not receive the 
complete treatment, i.e., when no further planned dose is administered from the date of 
withdrawal. A subject withdrawn from the study vaccine may not necessarily be 
withdrawn from the study as further study procedures or follow-up may be performed 
(safety or immunogenicity) if planned in the study protocol. The investigator should 
make all efforts to ensure that the subjects remain in the study to ensure a proper safety 
follow-up and medical care if needed.
Information relative to premature discontinuation of the study vaccine will be 
documented on the Vaccine Administration page/screen of the /eCRF. The investigator 
will document whether the decision to discontinue further vaccination/treatment was 
made by the subject’s parent(s)/LAR(s) 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

Not willing to be vaccinated

Other (specify).
 
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10.3.
Extension study
During the study conclusion visit, the investigator will ask each subject’s 
parent(s)/LAR(s) if they are interested to allow the subject to participate in a booster 
study/long-term study. If subject’s parent(s)/LAR(s) is/are not interested in participating 
in the booster study/long-term study the reason for refusal will be documented in the 
subject’s eCRF.
10.4.
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.

Medical history.

Physical examination.

Growth monitoring.

Blood samples for hematology and biochemistry and humoral response.

SAEs related to study participation, to concomitant use of GSK products or any fatal 
SAEs.

Screening conclusion.
11.
STATISTICAL METHODS
11.1.
Primary endpoints

Occurrence of adverse events (AEs) from first vaccination (Day 1) up to Day 61.

Occurrence of each solicited local and general AE, during a 7-day follow-up 
period after each vaccination (i.e., the day of vaccination and 6 subsequent 
days).

Occurrence of any unsolicited AE, during a 30-day follow-up period after each 
vaccination (i.e., the day of vaccination and 29 subsequent days).

Occurrence of any serious adverse event (SAE) from Day 1 up to Day 61.

Occurrence of episode of spontaneous or excessive bleeding (AE of special 
interest), during a 30-day follow-up period after each vaccination.
 
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11.2.
Secondary endpoints

Occurrence of RSV-RTI, RSV-LRTI, severe RSV-LRTI and very severe RSV-LRTI 
(according to standardized case definitions) as from first vaccination (Day 1) up to 
the end of the first RSV transmission season.

Occurrence of RSV-RTI, RSV-LRTI, severe RSV-LRTI and very severe RSV-LRTI 
(according to standardized case definitions) as from first vaccination (Day 1) up to 
the end of the second RSV transmission season.

Occurrence of SAEs from first vaccination (Day 1) up to the end of the second RSV 
transmission season.

Occurrence of RSV-LRTI (AE of special interest) as from first vaccination (Day 1) 
up to the end of the first RSV transmission season, and up to the end of the second 
RSV transmission season.

Occurrence of very severe RSV-LRTI (according to standardized case definitions) 
among RSV infected infants with a negative RSV exposure status (at screening 
based on in-stream baseline serological testing) from first vaccination (Day 1) up to 
the end of the first RSV transmission season.

Humoral response to the investigational RSV vaccine, pre-vaccination (Screening), 
post-Dose 1 (Day 31) and post-Dose 2 (Day 61 and at the end of the first RSV 
transmission season):

Neutralizing antibody titers against RSV-A.

RSV F antibody concentrations.
11.3.
Tertiary endpoints

Humoral response to the investigational RSV vaccine, pre-vaccination (Screening), 
post-Dose 1 (Day 31) and post-Dose 2 (Day 61).

Palivizumab-competing antibody concentrations.

Any further exploratory immunology to detect disease-related or vaccine-related 
immune responses, such as but not limited to:

Anti-vector immunity: neutralization.
11.4.
Determination of sample size 
The sample size determination is based on the minimum number of subjects needed to 
allow detection of a serious ERD signal having a magnitude similar to that of the historic
FI-RSV vaccine trials [Kim, 1969]. A total of 150 infants will be enrolled and 
randomized with 1:1:1 ratio to receive either 1 dose of the 1.5x1010 vp/dose ChAd-155 
RSV vaccine [the 1D RSV + comparator group], 2 doses of the 5x1010 vp/dose ChAd-
155 RSV vaccine [the 2D RSV + comparator group], or no ChAd-155 RSV vaccine [the 
comparator/Placebo control alone group].
 
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An effect of vaccination on ERD will be monitored very closely. It is anticipated that at 
least 50% of subjects [Dunn, 2013] will have a negative RSV exposure status (at 
screening which will be assessed by in-stream serological testing of baseline samples). 
While the rate of RSV infection could be highly variable by season, a conservative rate of 
infection of 20% in the first season is assumed [Kutsaya, 2016]. Therefore, with 50 
infants in each RSV vaccine group, it is anticipated to observe at least 5 infected infants 
with a negative RSV exposure status (at screening based on in-stream baseline 
serological testing) in each RSV vaccine group [50×0.5×0.2=5].
With a one-sided type I error of 0.05, and the assumption of a 10% rate of infection 
progressing to very severe RSV-LRTI (which is a conservative assumption based on the 
rate in the natural history of disease), 5 infections can provide at least 90% statistical 
power to demonstrate the progression rate from infection to very severe RSV-LRTI is 
less than 80%. That is less extreme than that observed in the historic FI-RSV vaccine trial 
where 80% of RSV RTI cases progressed to hospitalization [Kim, 1969]. During the 
course of the study, since the actual negative RSV exposure status (at screening based on 
in-stream baseline serological testing) and infection rates may be lower than 50% and 
20%, respectively, the sample size may be adjusted as needed through additional 
recruitment in order to achieve a sufficient number of RSV infected infants with a
negative RSV exposure status (at screening based on in-stream baseline serological 
testing) in each RSV vaccine group (Amended 1 August 2019). 
If a maximum of 1 out of 5 infections in infants receiving ChAd-155 RSV vaccine 
progress to very severe RSV-LRTI, then it can be concluded with 95% confidence that 
the expected progression rate of infection is less than the effect reported in previous FI-
RSV trials; if a minimum of 3 out of 5 infections progress to very severe RSV-LRTI then 
it can be concluded with 95% confidence that the expected progression rate of infection is 
more than the 10% observed in natural history of infection. The above power analysis is 
based on the procedure of inequality of one proportion in PASS 12. 
With 50 subjects in each RSV vaccine group, the probability of observing at least one 
SAE would be about 92% if the true incidence rate of SAE is 5%. For estimating the 
proportion of subjects with AEs, the maximum width of exact 95% confidence interval 
(CI) would be under 30%, and it could be as large as 35% if attrition rate is 30%.
Figure 6 illustrates the precision on the estimate for the proportion of subjects with AEs 
following vaccination with each RSV formulation based on the number of subjects with
AEs observed from 50 subjects.
 
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Figure 6
Exact 95% confidence interval on the proportion of subjects with 
adverse events following vaccination based on 50 enrolled subjects
11.5.
Cohorts for Analyses
11.5.1.
Exposed Set 
The Exposed Set (ES) will include all subjects with at least one study vaccine 
administration documented.
A safety analysis based on the ES will include all vaccinated subjects.
An immunogenicity analysis will be conducted on the ES and will include all vaccinated 
subjects for whom immunogenicity data are available.
The ES analysis will be performed per treatment actually administered at Dose 1.
 
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11.5.2.
Exposed Set of subjects with a negative RSV exposure status
The Exposed Set of subjects with a negative RSV exposure status will include all 
vaccinated subjects assessed as RSV unexposed at screening based on in-stream baseline 
serological testing.
The safety analysis of incidence of RSV-LRTI will be conducted on the cohort of 
subjects with a negative RSV exposure status (at screening based on in-stream baseline 
serological testing) as well as on the entire ES.
11.5.3.
Per-protocol Set for analysis of immunogenicity
The per-protocol set (PPS) cohort for analysis of immunogenicity will be defined by 
timepoint and will consist of all subjects from the ES who complied with eligibility 
criteria, study procedures up to the end of the study and had immunogenicity results in 
the epoch as described below.
More specifically, the PPS cohort for analysis of immunogenicity up to Day 61 (Visit 5) 
/at Visit 7 (end of the first RSV transmission season) will include all evaluable subjects:

Who met all eligibility criteria (i.e., no protocol violation linked to the 
inclusion/exclusion criteria, including age).

Who received study vaccine as scheduled per protocol. 

For whom the administration route and site of the vaccine was as according to 
protocol.

Who received the vaccine according to protocol procedures.

Who complied with the vaccination schedule, as specified in Table 7.

Who did not receive a concomitant medication/product/vaccine leading to exclusion 
from a PPS analysis, as described in Section 7.6.2, up to Day 61 (Visit 5) /at Visit 7
(end of the first RSV transmission season).

Who complied with the timings of the post vaccination blood sampling for immune 
response evaluation, up to Day 61 (Visit 5) /at Visit 7 (end of the first RSV 
transmission season), as specified in Table 7.

For whom post-vaccination immunogenicity results are available for at least one 
assay up to Day 61 (Visit 5) /at Visit 7 (end of the first RSV transmission season).
 
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Table 24 presents the intervals between study visits that determine subjects’ eligibility 
for inclusion in the PPS analysis. 
Table 24
Maximum allowed interval between study visits (Amended 1 August
2019)
Interval
Allowed length of interval
Screening Visit 1 (Day 1)
0 - 30 days
Visit 1 (Day 1) Visit 2 (Day 8)
7 - 10 days
Visit 1 (Day 1) Visit 3 (Day 31)
23 - 44 days1
Visit 1 (Day 1) Visit 5 (Day 61)
60 - 81 days1
Visit 3 (Day 31) Visit 4 (Day 38)
7 - 10 days
Visit 3 (Day 31) Visit 5 (Day 61) 2
30 - 37 days 1,3
Visit 5 (Day 61) Visit 6 (Day 121)4
60 - 81 days
Visit 7
(end of the first RSV transmission season)
Defined end of first RSV transmission season5
Visit 8
(end of the second RSV transmission season)
Defined end of second RSV transmission season5
1 Subjects will not be eligible for inclusion in the PP cohort for analysis of immunogenicity if they make the study visit 
outside this interval.
2 Where Synflorix is used as the comparator, a minimum of 30 days between Visit 3 and Visit 5 must be 
maintained to align with the active comparator vaccination schedule.
3 The interval between Visit 1 and Visit 5 must be a minimum of 60 days to be in line with the active comparator 
vaccination schedules as per the respective approved labels.
4 In countries where Menveo or Placebo is used as a comparator, no administration will be performed at Day 121 and 
therefore in those countries there will be no Visit 6 and Menveo will be administered at the end of the first RSV 
season at Visit 7 (refer to Table 2 and Table 7).
5 As soon as possible after the end of the RSV season (approximately within 4 weeks) and in accordance with 
the active comparator vaccination schedule if applicable. If the active comparator dosing for V7 is later 
than 4 weeks after the end of the first RSV transmission season, then the recommended timing of the 
active comparator takes precedence.
 
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11.5.4.
Pooled groups in the study
All subjects in the single dose (1D, 1.5x1010 vp) RSV + comparator vaccine groups will 
be pooled together as the pooled 1D RSV group, similarly, all subjects in the two dose 
(2D, 5x1010 vp) RSV + comparator vaccine groups will be pooled together as the pooled 
2D RSV group, and all subjects in the comparator/Placebo control vaccine alone groups 
will be pooled together as the pooled comparator group (Table 25).
Table 25
Pooled groups
Study groups
Pooled groups
1D RSV + Bexsero
Pooled 1D RSV
1D RSV + Nimenrix
1D RSV + Synflorix
1D RSV + Menveo
1D RSV + Placebo
2D RSV + Bexsero
Pooled 2D RSV
2D RSV + Nimenrix
2D RSV + Synflorix
2D RSV + Menveo
2D RSV + Placebo
Bexsero
Pooled comparator
Nimenrix
Synflorix
Menveo
Placebo
1D: 1 Dose (1.5x1010 vp/dose); RSV: ChAd155-RSV vaccine; 2D: 2 Dose (5x1010 vp/dose)
11.6.
Derived and transformed data
11.6.1.
Demography
For a given subject and a given demographic variable, missing measurements will not be 
replaced.
11.6.2.
Safety
For a given subject and the analysis of solicited AEs 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., symptom screen completed).
For analysis of unsolicited AEs, SAEs and for the analysis of 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.
 
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11.6.3.
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 timepoint will exclude subjects with a missing or non-evaluable measurement. 
Kinetics will be plotted on subjects with results available at all timepoints.
The geometric mean titers/concentrations (GMTs/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.
Determination of a negative RSV exposure status in infants at 6 to 7 months of age will 
be based on RSV A and/or B neutralizing antibody titers present in serum at screening 
(before vaccination with the RSV vaccine) based on in-stream baseline serological 
testing. At birth, newborns do show positive for neutralizing antibodies due to maternal 
transfer during gestation. The titer of these antibodies declines over time. At the age of 6 
to 7 months a cut-off can be defined below which infants are considered to have a 
negative RSV exposure status. Infants that show neutralizing antibody titers above this 
cut-off are suspected to have experienced a recent RSV infection. This cut-off will thus 
allow the discrimination between a negative RSV exposure status versus RSV infected 
infants before start of vaccination. 
The description of the handling of data below the lower limit of quantification for GMC 
calculation and fold increase will be described in the statistical analysis plan.
11.6.4.
RTI and LRTI
For the analysis of RTI and LRTI, all cases will be definitively classified as either RSV-
RTI, RSV-LRTI, severe RSV-LRTI or very severe RSV-LRTI according to the case 
definitions presented in Table 6, and the association to RSV infection will be assessed by 
quantitative PCR as primary analysis.
All confirmed LRTI will also be investigated for a panel of respiratory viruses (multiplex 
PCR; refer to Table 11), as a supplementary analysis of the occurrence of RSV-LRTI 
diagnosed upon the multiplex PCR.
For the analysis of RTI episode, a new RTI episode will be defined as any occurrence of 
cough, runny nose, blocked nose with an interval of at least 7 symptom free days since 
the last episode of RTI that was diagnosed. For the analysis of LRTI episode, a new 
LRTI episode will be defined as a history of cough or difficulty breathing and blood 
oxygen saturation < 95%, or respiratory rate increase and confirmed RSV infection 
with an interval of at least 7 symptom free days since the last episode of LRTI that was 
diagnosed (Amended 1 August 2019).
 
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11.7.
Analysis of demographics
The analysis of demographics will be performed on the ES and on the PPS cohort for 
immunogenicity for each RSV + comparator vaccine group and each active control 
comparator group and also for the pooled RSV vaccine and pooled comparator groups.
Demographic characteristics (age at vaccination in months, sex, country and race and 
vital signs), cohort description will be summarized by group using descriptive statistics:

Frequency tables will be generated for categorical variables 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.
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.
11.8.
Analysis of safety
11.8.1.
Within groups assessment
The safety will be descriptively summarized based on the ES. The analysis of local AEs, 
general AEs and fever will be reported for each RSV + comparator vaccine group and 
each active control comparator group and also for the pooled RSV vaccine and pooled 
comparator groups. For the analysis of SAEs and AE of specific interest, the analysis will 
be performed only on the pooled RSV and pooled comparator groups.
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 vaccine dose and overall. The percentage of doses followed by at least one local AE 
(solicited and unsolicited), by at least one general AE (solicited and unsolicited) and by 
any AE during the 7-day or 30-day follow-up period will be tabulated, overall 
vaccination course, with exact 95% CI. The same computations will be done for Grade 3 
AEs, for any AEs considered related to vaccination for any Grade 3 AEs considered 
related to vaccination and AEs resulting in a medically attended visit.
The percentage of subjects reporting each individual solicited local AE (any grade, Grade 
2, Grade 3, resulting in a medically attended visit) and solicited general AE (any grade, 
Grade 2, Grade 3, any related, Grade 2 related, Grade 3 related, resulting in medically 
attended visit) during the 7-day follow-up period (Day 1-7) will be tabulated for each 
RSV + comparator vaccine group and each active control comparator group and also for 
the pooled RSV vaccine and pooled comparator groups after each vaccine dose and 
 
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overall. Similarly, the percentage of doses followed by each individual solicited local and 
general AE and their sub-categories, will be tabulated, overall vaccination course, with 
exact 95% CI.
For fever, the number and percentage of subjects reporting fever by half degree (°C) 
cumulative increments during the 7-day follow-up period (Day 1-7) will be tabulated for 
each RSV + comparator vaccine group and each active control comparator group and also 
for the pooled RSV vaccine and pooled comparator groups after each vaccine dose and 
overall. Similar tabulations will be performed for any fever with a causal relationship to 
vaccination, Grade 3 (> 40.0°C) causally related fever and for any fever resulting in a 
medically attended visit. In addition, the prevalence of any and Grade 3 fever will be 
presented graphically over time after vaccination.
For clinical safety laboratory parameters: a listing of laboratory value outside the normal 
range for the unscheduled visits will be provided as per the toxicity scale. The maximum 
grading during the study will be tabulated (Refer to APPENDIX C) Laboratory values 
will be classified according to toxicity criteria. Laboratory values that are outside the 
normal range will also be flagged in the data listings, along with corresponding normal 
ranges and assessment of clinical significance (Amended 1 August 2019).
The percentage of subjects with unsolicited AEs within 30 days (Day 1-30) after each 
vaccine dose (overall doses) with its exact 95% CI will be tabulated RSV + comparator 
vaccine group and each active control comparator group and also for the pooled RSV 
vaccine and pooled comparator groups and by 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 AEs 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 subject with episode of spontaneous or 
excessive bleeding (AE of specific interest), during a 30-day follow-up period after each 
vaccination will be tabulated according to associated Preferred Term code (to be 
identified in the Statistical Analysis Plan [SAP]). 
The percentage of subjects with RSV-LRTI (AE of specific interest) from Dose 1 up to 
end of the first RSV transmission season and from Dose 1 up to end of second RSV 
season will be tabulated according to associated Preferred Term code presented in the 
SAP. 
The percentage of subjects with SAE within 30 days (Day 1-30) after each vaccine dose 
with its exact 95% CI will be tabulated and by MedDRA preferred term. Similar tables 
will be generated for SAEs from Dose 1 to end of first RSV season and from Dose 1 to 
end of the second RSV season.
SAEs reported throughout the study and AE of special interest will be described in detail.
The percentage of subjects using concomitant medication (any medication, any 
antipyretic and any antipyretic taken prophylactically, respectively) during the 7-day 
follow-up period (Day 1-7) and during the 30-day follow-up period (Day 1-30) will be 
 
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summarized by the pooled RSV vaccine and pooled comparator groups after each vaccine 
dose and overall.
11.8.2.
Between groups assessment
Exploratory comparisons between the pooled RSV vaccine group and the pooled 
comparator group will be done in terms of the percentage of subjects, overall doses, 
reporting any Grade 2/3 AE during the 7-day follow-up period (Day 1-7) after 
vaccination, and/ or any fever >39.0°C during the 7-day follow-up period (Day 1-7) after 
vaccination, and/ or any vaccine-related SAE during the 7-day follow-up period (Day 1-
7) after vaccination.
The standardized asymptotic 95% CI for the difference between the pooled RSV group 
and (minus) the pooled comparator group will be computed.
11.9.
Analysis of immunogenicity
The primary analysis will be performed on the PPS for immunogenicity and, if in any 
pooled group the percentage of vaccinated subjects with serological results excluded 
from the PPS for immunogenicity is more than 10%, a second analysis will be performed 
on the ES. The results from immunogenicity analysis will be reported by the pooled RSV 
vaccine group and the pooled comparator group.
For the final analysis, the Adapted PPS for immunogenicity analysis will be used which 
allows the summary of immunogenicity results by time point. In summary table on the 
Adapted PPS for immunogenicity, PPS for immunogenicity at Day 61 will be used for 
Pre, Day 31 and Day 61 immunogenicity summary and PPS for immunogenicity at Day 
365 for Day 365 immunogenicity summary.
The infants are monitored for RSV infection starting from dose 1 and therefore 
immunogenicity analyses can be adjusted to exclude those infants with an infection prior 
to sampling. 
11.9.1.
Within groups assessment
11.9.1.1.
Analysis of secondary objectives
For three pooled groups, at each timepoint that blood samples are collected for humoral 
immune response against the investigational RSV vaccine (neutralizing antibody titers 
against RSV-A, RSV F antibody concentrations). 

Geometric mean titers/concentrations (GMTs/GMCs) will be tabulated with 95% CI 
and represented graphically.

Percentage of subjects above the seropositivity threshold will be tabulated with exact 
95% CI.

Antibody titers/concentrations will be displayed using reverse cumulative curves.
 
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
The distributions of neutralizing antibody titers/concentrations will be tabulated.

Percentage of responders in terms of neutralizing antibody titers will be tabulated 
with exact 95% CI.

Individual post-vaccination versus pre-vaccination results will be plotted using 
scatter plots. Results of the comparator group will be used as a reference.

Geometric mean of ratios of antibody titers/concentrations at each post-vaccination 
timepoint over pre-vaccination will be tabulated with 95% CI.

Distribution of the fold increase of the neutralizing antibody titers will be tabulated 
by pre-vaccination titer category.

The kinetics of individual antibody titers/antibody concentrations results will be 
plotted as a function of time for subjects with results available at all timepoints.
An immunogenicity analysis will also be performed on the ES with a negative RSV 
exposure status (at screening based on in-stream baseline serological testing) for whom 
immunogenicity data are available. 
At study end a sensitivity analysis of immunogenicity will be performed on infants by 
baseline values.
11.9.1.2.
Analysis of tertiary objective
If available, any further exploratory immunology results (including, but not limited to 
anti-vector immunity and palivizumab-competing antibody concentrations) will be 
reported by timepoint for the two pooled RSV vaccine groups and the pooled comparator 
group using descriptive summary statistics.
11.10.
Analysis of RTI and LRTI
The primary analysis will be performed on the ES of subjects with a negative RSV 
exposure status (at screening based on in-stream baseline serological testing) in the 
pooled single dose RSV vaccine group, the pooled two dose RSV vaccine group, and the 
pooled comparator group separately for first and second RSV seasons and overall. A 
similar analysis will be performed on the entire ES. As primary analysis, the assessment 
of RSV infection will be performed using the quantitative RT-PCR according to 
standardized case definitions (see Table 6) based on the available WHO case definitions.
The number of RSV infections within each group and the maximum disease severity of 
the event will be tabulated. The rate (with 95% CI) of RSV-RTI and RSV-LRTI and 
infections progressing to hospitalization will be evaluated for each of the three pooled 
groups.
The incidence rate of very severe RSV-LRTI among RSV infected infants with a
negative RSV exposure status (at screening based on in-stream baseline serological 
testing) from first vaccination (Day 1) up to the end of the first RSV transmission season
will be estimated as well as 95% one-sided lower CI.
 
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The incidence rate and the relative risk of subjects with RSV-associated RTI (with 95% 
CI) between each of two pooled RSV vaccine groups and the pooled control group will 
be calculated for both the cohort of subjects with a negative RSV exposure status (at 
screening based on in-stream baseline serological testing) on the ES and on the entire ES. 
The same descriptive analysis will be performed for RSV-associated LRTI and RSV-
associated severe LRTI (Amended 1 August 2019).
Descriptive analyses (mean, median, min, max) of viral load assessed by the quantitative 
RT-PCR (RSV-A/B) of all cases as listed in Table 6 will be tabulated by case category. 
This analysis will also be done on the three pooled groups.
The incidence rate of all cases as listed in Table 6 (with 95% CI) will be calculated by the 
three pooled groups. The same descriptive analysis will be performed for all cause LRTI 
and all cause severe LRTI. These will also be presented for each viral etiology identified 
by the multiplex PCR. 
The incidence rate of asymptomatic RSV infections (with 95% CI) detected by the 
quantitative PCR (RSV-A/B), will be tabulated by the three pooled groups. Descriptive 
analyses (mean, median, min, max) of viral load assessed by the quantitative RT-PCR 
(RSV-A/B) of those asymptomatic RSV infections will also be done on the three pooled 
groups.
The RVP (Multiplex PCR) on specimens from all RSV-A/B positive and confirmed LRTI 
cases, according to case definition presented in Table 6 (Figure 3), will be tabulated as a 
qualitative assessment profiling the potential co-infections occurring in these subjects.
11.11.
Interpretation of analyses
For the occurrence of very severe RSV-LRTI among RSV infected infants with a
negative RSV exposure status (at screening based on in-stream baseline serological 
testing) from first vaccination (Day 1) up to the end of the first RSV transmission season, 
if the upper boundary of the 95% one-sided lower CI of the rate is under 80%, it indicates 
that the very severe RSV-LRTI rate is less than that of the historic RSV-FI trials [Kim, 
1969].
Comparative analyses will be exploratory and should be interpreted with caution 
considering that there is no adjustment for multiplicity and that group sizes are small for 
these comparisons.
11.12.
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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11.12.1.
Sequence of analyses
In preparation of the planned iSRC and IDMC evaluations, analyses of all available 
safety data (i.e., data that are as clean as possible) will be performed (see Section 9.10 for 
more information). These analyses will be done by an independent data analysis center
to maintain the blinding of the study, and will be documented in a statistical analysis 
report. Only the outcome of the iSRC and IDMC reviews will be communicated to the 
RSV study team (no safety signal or safety signal). No clinical study report will be 
written (Amended 1 August 2019).
The statistical analyses will be performed in 3 steps:

An analysis will be performed when all data up to Day 61 are available. Additional 
safety data available at the time of this analysis will be described. At this point, the 
statistician will be unblinded (i.e., individual subject treatment assignments will be 
available) and the study will be conducted in a single blind manner, with patients 
remaining blinded up to the last study visit (end of the second RSV transmission 
season). Summary results may unblind some specific subjects but no individual 
listings will be provided and the investigator will not have access to the treatment 
allocation up to the last study visit (end of the second RSV transmission season), 
except in case of emergency unblinding (see Section 9.8).

An analysis will be performed when all data up to Visit 7 (end of the first RSV 
transmission season) are available. No individual listings will be provided.

The final analysis will be performed when all data up to study conclusion (end of the 
second RSV transmission season) are available. An integrated clinical study report 
containing all data will be written and made available to the investigators at that 
time.
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.
11.12.2.
Statistical considerations for interim analyses
No interim analyses are planned.
12.
ADMINISTRATIVE MATTERS
To comply with ICH GCP administrative obligations relating to data collection, 
monitoring, archiving data, audits, confidentiality, public disclosure requirements and 
publications must be fulfilled. 
12.1.
electronic Case Report Form instructions
A validated GSK defined electronic data collection tool will be used as the method for 
data collection. 
 
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In all cases, subject initials will not be collected nor transmitted to GSK. Subject data 
necessary for analysis and reporting will be entered/transmitted into a validated database 
or data system. Clinical data management will be performed in accordance with 
applicable GSK standards and data cleaning procedures.
While completed eCRFs are reviewed by a GSK Biologicals’ Site Monitor at the study 
site, omissions or inconsistencies detected by subsequent eCRF review may necessitate 
clarification or correction by the investigator or appropriately qualified designee. In all
cases, the investigator remains accountable for the study data. 
The investigator will be provided with a storage device containing the final version of the 
data generated at the investigational site once the database is archived and the study 
report is complete and approved by all parties.
12.2.
Study Monitoring by GSK Biologicals
GSK will monitor the study to verify that, amongst 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 a eCRF review and a Source Document 
Verification (SDV). By SDV we understand verifying eCRF entries by comparing them 
with the source data that will be made available by the investigator for this purpose. 
The Source Documentation Agreement Form describes the source data for the different 
data in the eCRF. This document should be completed and signed by the site monitor and 
investigator and should be filed in the 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.
 
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12.3.
Record retention
Following closure of the study, the investigator must maintain all site study records 
(except for those required by local regulations to be maintained elsewhere) in a safe and 
secure location. The records must be easily accessible, when needed (e.g., audit or 
inspection), and must be available for review in conjunction with assessment of the 
facility, supporting systems, and staff. Where permitted by applicable laws/regulations or 
institutional policy, some or all of these records can be maintained in a validated format 
other than hard copy (e.g., microfiche, scanned, electronic); however, caution needs to be 
exercised before such action is taken. The investigator must ensure that all reproductions 
are legible and are a true and accurate copy of the original and meet accessibility and 
retrieval standards, including re-generating a hard copy, if required. Furthermore, the 
investigator must ensure that an acceptable back-up of the reproductions exists and that 
there is an acceptable quality control procedure in place for making these reproductions.
GSK will inform the investigator/institution of the time period for retaining these records 
to comply with all applicable regulatory requirements. The minimum retention time will 
meet the strictest standard applicable to a particular site, as dictated by ICH GCP, any 
institutional requirements, applicable laws or regulations, or GSK standards/procedures, 
otherwise, the minimum retention period will default to 25 years after completion of the 
study report.
The investigator/institution must notify GSK of any changes in the archival 
arrangements, including, but not limited to archival at an off-site facility, transfer of 
ownership of the records in the event the investigator leaves the site. 
12.4.
Quality assurance
To ensure compliance with GCP and all applicable regulatory requirements, GSK may 
conduct a quality assurance audit. Regulatory agencies may also conduct a regulatory 
inspection of this study. Such audits/inspections can occur at any time during or after 
completion of the study. If an audit or inspection occurs, the investigator and institution 
agree to allow the auditor/inspector direct access to all relevant documents and to allocate 
his/her time and the time of his/her staff to the auditor/inspector to discuss findings and 
any relevant issues.
12.5.
Posting of information on publicly available clinical trial 
registers and publication policy
GSK assures that the key design elements of this protocol will be posted on the GSK 
website and in publicly accessible database(s) such as clinicaltrials.gov, in compliance 
with the current regulations.
GSK also assures that results of this study will be posted on the GSK website and in 
publicly accessible regulatory registry(ies) within the required time-frame, in compliance 
with the current regulations. The minimal requirement is to have primary endpoint 
summary results disclosed at latest 12 months post PCD and to have secondary endpoint 
 
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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 pediatric population conducted in at least one EU member state will be posted on 
publicly available EMA registers within 6 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 6 months 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. For this multi-country study, summaries of the 
results will be posted on publicly available EMA registers within 6 months of EoS (as 
defined in the protocol) in all countries, in order to have sufficient power to answer study 
objectives.
GSK also aims to publish the results of these studies in searchable, peer reviewed 
scientific literature and follows the guidance from the International Committee of 
Medical Journal Editors.
12.6.
Provision of study results to investigators
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the study report. The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually-
agreeable location.
GSK Biologicals will also provide the investigator with the full summary of the study 
results. The investigator is encouraged to share the summary results with the study 
subjects, as appropriate.
12.7.
Data Sharing
Under the framework of the SHARE initiative, results of GSK studies may be combined 
with non- GSK studies, to investigate further about the study product(s) and other 
product(s), and /or the disease/condition under investigation and related diseases and 
conditions.
13.
COUNTRY SPECIFIC REQUIREMENTS 
13.1.
Requirements for Belgium 
Belgium will not use placebo, and will only use Bexsero.
 
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14.
REFERENCES
American Academy of Pediatrics Subcommittee on Diagnosis and Management of 
Bronchiolitis. Diagnosis and management of bronchiolitis. Pediatrics. 2006; 118: 1774-
93.
Anderson R, Huang Y, Langley JM. Prospects for defined epitope vaccines for 
respiratory syncytial virus. Future Microbiol. 2010; 5(4): 585-602.
Antonis AFG, Schrijver RS, Daus F, et al. Vaccine-Induced Immunopathology during 
Bovine Respiratory Syncytial Virus Infection: Exploring the Parameters of Pathogenesis. 
J Virol. 2003; 77(22): 12067–73.
Barbas CF, Crowe JE, Cababa D, et al. Human monoclonal Fab fragments derived from a 
combinatorial library bind to respiratory syncytial virus F glycoprotein and neutralize 
infectivity. Proc Natl Acad Sci USA. 1992; 89(21): 10164-8.
Barnes E, Folgori A, Capone S, et al. Novel adenovirus-based vaccines induce broad and 
sustained T cell responses to HCV in man. Sci Transl Med. 2012; 4(115): 115ra1.
Bates JT, Keefer CJ, Slaughter JC, et al. Escape from neutralization by the respiratory 
syncytial virus-specific neutralizing monoclonal antibody palivizumab is driven by 
changes in on-rate of binding to the fusion protein. Virology. 2014; 454-455: 139-44.
Borchers AT, Chang C, Gershwin ME, et al. Respiratory syncytial virus – a 
comprehensive review. Clin Rev Allergy Immunol. 2013; 45(3): 331-79.
Boukhvalova MS, Prince GA, Soroush L et al. The TLR4 agonist, monophosphoryl lipid 
A, attenuates the cytokine storm associated with respiratory syncytial virus vaccine-
enhanced disease. Vaccine. 2006; 24: 5027-35.
Boyce TG, Mellen BG, Mitchel EF Jr et al. Rates of hospitalization for respiratory 
syncytial virus infection among children in medicaid. J. Pediatr. 2000; 137: 865-70.
Capone S, D'Alise AM, Ammendola V, et al. Development of chimpanzee adenoviruses 
as vaccine vectors: challenges and successes emerging from clinical trials. Expert Rev 
Vaccines. 2013; 12(4), 379–93.
Cardenas S, Auais A, Piedimonte G. Palivizumab in the prophylaxis of respiratory 
syncytial virus infection. Expert Rev Anti Infect Ther. 2005; 3(5): 719-26.
Castilow, EM, Varga SM. Overcoming T cell-mediated immunopathology to achieve 
safe RSV vaccination. Future Virol. 2008; 3(5): 445-54.
Chin J, Magoffin RL, Shearer LA et al. Field evaluation of a respiratory syncytial virus 
vaccine and a trivalent parainfluenza virus vaccine in a pediatric population. Am J 
Epidemiol. 1969; 89: 449-63.
 
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Cohen C, Walaza S, Moyes J, et al. Epidemiology of Viral-Associated Acute Lower 
Respiratory Tract Infection among Children <5 Years of Age in a High HIV Prevalence 
Setting, South Africa, 2009-2012. Pediatr Infect Dis J. 2015; 34(1): 66–72.
Colloca S, Barnes E, Folgori A, et al. Vaccine vectors derived from a large collection of 
simian adenoviruses induce potent cellular immunity across multiple species. Sci Transl 
Med. 2012; 4(115): p. 115ra2.
Connors M, Kulkarni AB, Firestone CY et al. Pulmonary histopathology induced by 
respiratory syncytial virus (RSV) challenge of formalin-inactivated RSV-immunized 
BALB/c mice is abrogated by depletion of CD4+ T cells. J Virol. 1992; 66: 7444-51.
Connors M, Giese NA, Kulkarni AB et al. Enhanced pulmonary histopathology induced 
by respiratory syncytial virus (RSV) challenge of formalin-inactivated RSV-immunized 
BALB/c mice is abrogated by depletion of interleukin-4 (IL-4) and IL-10. J Virol. 1994; 
68: 5321-5.
Delgado MF, Coviello S, Monsalvo AC et al. Lack of antibody affinity maturation due to 
poor Toll-like receptor stimulation leads to enhanced respiratory syncytial virus disease. 
Nat. Med. 2009; 15: 34-41.
Deshpande SA and Northern V. The clinical and health economic burden of respiratory 
syncytial virus disease among children under 2 years of age in a defined geographical 
area. Arch Dis Child. 2003; 88: 1065-9.
Division of AIDS table for grading severity of adult and pediatric adverse events (2003): 
http://www.icssc.org/Documents/Resources/AEManual2003AppendicesFebruary_06_20
03%20final.pdf (last access: 12-APR-2016).
Division of AIDS table for grading severity of adult and pediatric adverse events (2004): 
http://www.niaid.nih.gov/labsandresources/resources/daidsclinrsrch/documents/daidsaegr
adingtable.pdf (last access: 12-APR-2016).
Division of AIDS table for grading severity of adult and pediatric adverse events (2007): 
https://www.niaid.nih.gov/LabsAndResources/resources/DMIDClinRsrch/Documents/dm
idadulttox.pdf (last access: 12-APR-2016).
Dunn SR, Ryder AB, Tollefson et al. Seroepidemiologies of human metapneumovirus 
and respiratory syncytial virus in young children, determined with a new recombinant 
fusion protein enzyme-linked immunosorbent assay. Clin Vaccine Immunol. 2013; (10): 
1654-6. 
Fisher RG, Gruber WC, Edwards KM, et al. Twenty years of outpatient respiratory 
syncytial virus infection: a framework for vaccine efficacy trials. Pediatrics. 1997; 99(2): 
E7.
Fulginiti VA, Eller JJ, Sieber OF et al. A field trial of two inactivated respiratory virus 
vaccines ; an aqueous trivalent parainfluenza virus vaccine and an Alum-precipitated 
respiratory syncytial virus vaccine. Am J Epidemiol. 1969; 89: 435-48.
 
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García CG, Bhore R, Soriano-Fallas A, et al. Risk factors in children hospitalized with 
RSV bronchiolitis versus non-RSV bronchiolitis. Pediatrics. 2010; 126: e1453-60.
Graham BS. Biological challenges and technological opportunities for respiratory 
syncytial virus vaccine development. Immunol Rev. 2011; 239:149-66.
Hall CB, Weinberg GA, Iwane MK, et al. The burden of respiratory syncytial virus 
infection in young children. N Engl J Med. 2009; 360: 588-98.
HCV001 Clinical Study Report. Okairos. A phase I study to assess the safety and 
immunogenicity of new Hepatitis C virus vaccine candidates AdCh3NSmut and 
Ad6NSmut. June 2011.
Hertz MI, Englund JA, Snover D, et al. Respiratory syncytial virus-induced acute lung 
injury in adult patients with bone marrow transplants: a clinical approach and review of 
the literature. Medicine (Baltimore). 1989; 68(5): 269-81.
Holman RC, Curns AT, Cheek JE, et al. Respiratory syncytial virus hospitalizations 
among American Indian and Alaska Native infants and the general United States infant 
population. Pediatrics. 2004; 114: e437-44.
Iwane MK, Edwards KM, Szilagyi PG, et al. Population-based surveillance for 
hospitalizations associated with respiratory syncytial virus, influenza virus, and 
parainfluenza viruses among young children. Pediatrics. 2004; 113: 1758-64.
Kapikian AZ, Mitchell RH, Chanock RM et al. An epidemiologic study of altered clinical 
reactivity to respiratory syncytial (RS) virus infection in children previously vaccinated 
with an inactivated RS virus vaccine. Am J Epidemiol. 1969; 89: 405-21.
Kim HW, Canchola JG, Brandt CD, et al. Respiratory syncytial virus disease in infants 
despite prior administration of antigenic inactivated vaccine. Am J Epidemiol. 1969;
89(4): 422-34.
Krilov LR. Respiratory syncytial virus disease: update on treatment and prevention. 
Expert Rev. Anti. Infect. Ther. 2011; 9(1): 27–32.
Kutsaya A, Teros-Jaakkola T, Kakkola L, et al. Prospective clinical and serological 
follow-up in early childhood reveals a high rate of subclinical RSV infection and a 
relatively high reinfection rate within the first 3 years of life. Epidemiol Infect. 2016; 
144(8): 1622-33. 
Liniger M, Zuniga A, Naim HY. Use of viral vectors for the development of vaccines. 
Expert Review of Vaccines. 2007; 6(2): 255-66.
Madhi SA, Kuwanda L, Cutland C, et al. Five-year cohort study of hospitalization for 
respiratory syncytial virus associated lower respiratory tract infection in African children. 
J Clin Virol. 2006; 36: 215-21.
 
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Magro M, Mas V, Chappell K, et al. Neutralizing antibodies against the preactive form of 
respiratory syncytial virus fusion protein offer unique possibilities for clinical 
intervention. Proc Natl Acad Sci U S A. 2012; 109: 3089-94.
Modjarrad K, Giersing B, Kaslow DC, Smith PG, Moorthy VS, the WHO RSV Vaccine 
Consultation Expert Group. WHO consultation on Respiratory Syncytial Virus Vaccine 
Development Report from a World Health Organization Meeting held on 23-24 March 
2015. Vaccine. 2016;34(2):190-7.
Moghaddam A, Olszewska W, Wang B et al. A potential molecular mechanism for 
hypersensitivity caused by formalin-inactivated vaccines. Nat Med 2006; 12: 905-7.
Murphy BR, Prince GA, Walsh EE et al. Dissociation between serum neutralizing and 
glycoprotein antibody responses of infants and children who received inactivated 
respiratory syncytial virus vaccine. J Clin Microbiol.1986; 24: 197-202.
Murphy BR and Walsh BE. Formalin-inactivated respiratory syncytial virus vaccine 
induces antibodies to the fusion glycoprotein that are deficient in fusion-inhibiting 
activity. J Clin Microbiol.1988; 26: 1595-7.
Murray J, Saxena S, Sharland M. Preventing severe respiratory syncytial virus disease: 
passive, active immunisation and new antivirals. Arch Dis Child. 2014; 99(5): 469-73.
Openshaw PJ. Potential therapeutic implications of new insights into respiratory syncytial 
virus disease. Respir Res. 2002; 3 Suppl 1:S15-20.
Paramore LC, Ciuryla V, Ciesla G et al. Economic impact of respiratory syncytial virus-
related illness in the US: an analysis of national databases. Pharmacoeconomics. 2004; 
22: 275-84.
Phipps S, Lam CE, Mahalingam S et al. Eosinophils contribute to innate antiviral 
immunity and promote clearance of respiratory syncytial virus. Blood. 2007; 110: 1578-
86.
Piedra PA, Jewell AM, Cron SG, et al. Correlates of immunity to respiratory syncytial 
virus (RSV) associated-hospitalization: establishment of minimum protective threshold 
levels of serum neutralizing antibodies. Vaccine. 2003; 21(24): 3479-82.
Polack FP, Teng MN, Collins PL, et al. A role for immune complexes in enhanced 
respiratory syncytial virus disease. J Exp Med. 2002; 196: 859-865.
Polack FP. Atypical measles and enhanced respiratory syncytial virus disease (ERD) 
made simple. Pediatr Res. 2007; 62(1): 111-5.
Prince GA, Curtis SJ, Yim KC et al. Vaccine-enhanced respiratory syncytial virus disease 
in cotton rats following immunization with Lot 100 or a newly prepared reference 
vaccine. J. Gen. Virol. 2001; 82: 2881-8.
 
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Rietveld E, De Jonge HC, Polder JJ, et al. Anticipated costs of hospitalization for 
respiratory syncytial virus infection in young children at risk. Pediatr Infect Dis J. 2004; 
23: 523-9.
Roy S, Medina-Jaszek A, Wilson MJ, et al. Creation of a panel of vectors based on ape 
adenovirus isolates. J Gene Med. 2011; (1): 17-25.
RSV001 Interim Study Report. Okairos. A phase I study to assess safety and 
immunogenicity of a new Respiratory Syncytial Virus (RSV) vaccine based on the RSV 
viral proteins F, N and M2-1 encoded by simian Adenovirus (PanAd3-RSV) and 
Modified Vaccinia virus Ankara (MVA-RSV). Version 1.0, dated 21 Feb 2014.
Simoes EAF. Respiratory syncytial virus infection. Lancet. 1999; 354: 847–52.
Stevens WW, Sun J, Castillo JP, et al. Pulmonary eosinophilia is attenuated by early 
responding CD8(+) memory T cells in a murine model of RSV vaccine-enhanced disease. 
Viral Immunol. 2009; 22(4): 243-51.
Townsend AR, Skehel JJ. The influenza A virus nucleoprotein gene controls the 
induction of both subtype specific and cross-reactive cytotoxic T cells. J Exp Med. 1984; 
160(2): 552-63. 
United Nations (1986). How to Weigh and Measure Children: Assessing the Nutritional 
Status of Young Children. 
http://unstats.un.org/unsd/publication/unint/dp_un_int_81_041_6E.pdf (Accessed: 12-
APR-2016).
US Food and Drug Administration. Pediatric Exclusivity Study Age Group 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirement
s/ElectronicSubmissions/DataStandardsManualmonographs/ucm071754.htm (last access: 
12-APR-2016).
Vicente D, Montes M, Cilla G, et al. Hospitalization for respiratory syncytial virus in the 
pediatric population in Spain. Epidemiol Infect. 2003; 131: 867-72.
Waris ME, Tsou C, Erdman DD et al. Respiratory syncytial virus infection in BALB/c 
mice previously immunized with formalin-inactivated virus induces enhanced pulmonary 
inflammaroty response with a predominant Th2-like pattern. J. Virol. 1996; 70: 2852-60.
Welliver TP, Garofalo RP, Hosakote Y, et al. Severe human lower respiratory tract 
illness caused by respiratory syncytial virus and influenza virus is characterized by the 
absence of pulmonary cytotoxic lymphocyte responses. J Infect Dis. 2007; 195(8): 1126-
36.
 
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APPENDIX A
LABORATORY ASSAYS
Assay descriptions could be subjects to change, due to assay re-development and/or 
qualification.
RSV A Neutralization assay
The serum neutralization assay is a functional assay that measures the ability of serum 
antibodies to neutralize RSV entry and replication in a host cell line.
Virus neutralization is performed by incubating a fixed amount of RSV-A strain (Long,
ATCC No. VR-26) 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 three 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].
ELISA

Anti-RSV protein F ELISA
The anti-F protein IgG ELISA is an indirect ELISA allowing the detection and the 
quantitation of specific IgG antibodies directed against the RSV F protein in human 
serum samples. PreF 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 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-preF IgG antibodies present in the serum sample. The optical 
density of each sample dilution is then interpolated on the reference standard. The 
corresponding antibody concentration, corrected for the dilution factor, is 
expressed in arbitrary ELISA Laboratory Units per milliliter (ELU/mL). 
 
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
Palivizumab competitive assay
Palivizumab monoclonal antibody (Synagis) is used as a passive treatment that 
protects against RSV infection by binding to the antigenic site II epitope of the RSV 
F antigen. 
First, F protein antigens purified from CHO expression system are coated onto 96-
well microplates. Then, after a washing and a blocking step, serial two-fold dilutions 
of test sera, positive control serum, and palivizumab antibody reference standard are 
added in sequence with competitor antibodies (horseradish peroxidase-conjugated 
palivizumab) and incubated to allow specific binding of antibodies directed against 
the F protein antigens. If palivizumab-like antibodies are present in serum samples, 
they will compete with the horseradish peroxidase-conjugated palivizumab 
antibodies for binding to the F protein coated antigen. After a washing step, the 
horseradish peroxidase substrate solution (TMB/H2O2) is added and a colored 
product develops in a manner that is inversely proportional to the amount of 
palivizumab-like antibodies contained in the test serum. The color is quantified by 
reading the optical densities at 450-620 nm using a spectrophotometer. Antibody 
concentrations of individual serum and control samples are determined after 
interpolation from the ELISA standard curve using a four-parameter equation and are 
expressed as palivizumab-equivalent antibodies in microgram per millilitre (µg/mL).
Reverse Transcription Polymerase Chain Reaction (RT-PCR)

Quantitative RT-PCR able to discriminate RSV-A and RSV-B subtypes:
Briefly, RSV A and RSV B RNAs extracted from the nasal 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 RT-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 nasal swabs from individuals suspected of 
respiratory tract infections. The following virus types and subtypes can be identified 
in the assay:

Influenza A virus (Flu A)

Influenza B virus (Flu 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 respiratory syncytial virus A (RSV A)

Human respiratory syncytial virus B (RSV B)
 
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
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 26
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 27
Outsourced laboratories
Laboratory
Address
NÉOMED-LABS Inc.
525, Cartier Ouest Laval,
Quebec
Canada H7V 3S8
 
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APPENDIX C TOXICITY GRADING FOR HEMATOLOGY AND 
BIOCHEMISTRY PARAMETERS
Table 28
Toxicity grading scales for hematology and biochemistry 
parameters applicable for this study
Component
Grade 1
Grade 2
Grade 3
Grade 4
Hemoglobin (g/dL)
9.0 to < 10.5
8.0 to < 9.0
7.0 to < 8.0
< 7.0
Leukocytes (cell/mm3)
2500 to < 3500
1500 to < 2500
1000 to < 1500
< 1000
Absolute neutrophil count 
(cell/mm³)
1000 to < 1300
750 to < 1000
500 to < 750
< 500
Absolute lymphocyte count 
(cell/mm³)
600 to < 650
500 to < 600
350 to < 500
< 350
Platelets (cell//mm3)
75000 to < 150000
50000 to < 75000
25000 to < 50000
< 25000
Alanine Aminotransferase
(increase by factor)
1.1 to < 2.0 xULN
2.0 to < 3.0 xULN
3.00 to ≤ 8.0 xULN
> 8.0 xULN
Aspartate Aminotransferase
(increase by factor)
1.1 to < 2.0 xULN
2.0 to < 3.0 xULN
3.00 to ≤ 8.0 xULN
> 8.0 xULN
Creatinine (mg/dL)
0.6 to < 0.9
0.9 to < 1.2
1.2 to ≤ 1.5
> 1.5
Grading scale adapted from Division of AIDS (2003), Division of AIDS (2004) and Division of AIDS (2007).
ULN: upper limit of normal.
 
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APPENDIX D
THE SYMPTOMS AND GRADING FOR 
ASSESSMENT VISITS AND WORSENING VISITS
HISTORY FROM PARENT OR CARER - PART 1
Symptoms of RTI
Cough
Yes/No (if Yes: start date and end date)
Runny nose
Yes/No (if Yes: start date and end date)
Blocked nose
Yes/No (if Yes: start date and end date)
Wheezing
Yes/No (if Yes: start date and end date)
Difficulty in breathing
Yes/No (if Yes: start date and end date)
Parental/Carer concern
Parental concern
Yes/No 
MEDICAL OBSERVATION - PART 2a*
Temperature
Record temperature and route of measurement
Heart rate
Beats per minute when child is settled
Respiratory rate
Breaths per minute counted over one minute
Lower chest wall indrawing (subcostal recession)
Yes/No
SpO2
% measured in room air when quiet and not feeding (NB 
altitude is collected for each participating site)
Nasal swab taken for testing at central laboratory
Yes/No
Specimen taken for RSV and RVP testing at local 
laboratory
Yes/No (If Yes specify type of specimen test and result: 
positive/negative)
Has a blood sample been taken for assessment of 
mechanism of illness?
Yes/No/ Not available
MEDICAL OBSERVATION - PART 2b*
Must be completed in full if:

The parent or carer reports wheezing or difficulty in breathing

The respiratory rate is > 40/minute for subject 12-30 months of age

Lower chest wall indrawing is observed

SpO2 measured in room air by pulse oximetry is < 95%
N.B. May be completed in part or in full for any child attending an assessment visit
Signs of 
increased 
respiratory 
effort
Audible wheeze
Yes/No/Not available
Grunting
Yes/No/Not available
Nasal flaring
Yes/No/Not available
Intercostal recession
Yes/No/Not available
Signs 
associated with 
severity
Apnea outside medical facility Has an episode of apnea > 20 seconds occurred outside a 
medical facility? Yes/No/Not available (if Yes provide all 
details [free text field])
Apnea under medical 
observation
Has an episode of apnea > 20 seconds occurred during 
medical observation? Yes/No/Not available (if Yes provide all 
details [free text field])
Peripheral cyanosis
Yes/No/Not available
Central cyanosis 
Yes/No/Not available
Irritability/agitation
0 = content, happy, interactive
1 = mildly irritable when touched, occasional crying, can be 
comforted, is interactive
2 = moderately irritable, intermittently crying, resists 
comforting, less interactive
3 = extremely irritable, cannot be comforted, crying 
throughout examination or not interactive
Not available
Lethargy/excessive 
sleepiness
0 = interactive
1 = mildly lethargic/sleepy is normally interactive when 
roused
2 = moderately lethargic/ sleepy, less interactive than normal 
when roused
3 = extremely lethargic/sleepy, is not interactive when roused
Not available
 
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Conscious level
A = The child is awake, alert, and interactive with parents and 
care providers
V =The child responds only if the care provider or parents 
call the child’s name or speak loudly
P =The child responds only to painful stimuli, such as 
pinching the nail bed of a toe or finger.
U = The child is unresponsive to all stimuli
Not available
Assessment of feeding ability 0 = Normal feeding
1 = Reduced ability to feed
2 = Unable to feed
Not available
Skin turgor
Yes → > 2 seconds
No → 2 seconds
Not available
Findings on 
auscultation
Wheeze on auscultation with 
stethoscope
Yes/No/Not available
Crackles
Yes/No/Not available
Investigations
Chest X-ray if available**
Collected? Yes/No/Not available (If Yes: specify date and 
specify the presence or absence of the following features: 
hyperexpansion, peribronchial thickening, interstitial 
infiltrates, segmental or lobar consolidation, pleural effusion, 
atelectasis, other:  please specify)
Blood culture if available**
Collected? Yes/No (If Yes, specify date and  coded results as 
1. Pneumococcus, 2. Haemophilus influenza 3. 
Meningococcus, 4. Salmonella, 5. Other pathogenic 
organism, 6. Contaminant, 7. No isolate, 8. No result [missing 
confirmed] and note if 1 to 6: was the period of incubation to 
positivity detection > 48 hours? Yes/No, if 1, 2, 3 or 4 specify 
serotype/group, if 5 or 6 specify organism and if 8 comment)
Complete blood count If 
available**
Collected? Yes/No/Not available (if Yes specify date of 
collection or tick box if date is same as visit date and specify 
laboratory name, record results for hematology blood count: 
hemoglobin, platelets, total white cell count, neutrophil 
count, lymphocyte count)
Inpatient care
Hospitalization indicated? 
Hospitalization?
Yes/No (if Yes, specify start date of hospitalization and total 
number of calendar days on which the child was hospitalized 
for at least one hour)
If yes: Requirement for 
monitoring/nursing 
observation
Yes/No (if Yes total number of calendar days on which the 
requirement for monitoring/nursing observation was done for 
at least one hour)
If yes: Requirement for 
nasogastric or intravenous 
fluids
Yes/No (if Yes specify start date of fluids and specify total 
number of calendar days on which nasogastric or 
intravenous fluids were given for at least one hour)
If yes: Requirement for 
supplemental oxygen
Yes/No (if Yes specify start date of oxygen and specify total 
number of calendar days on which oxygen was administered 
for at least one hour)
If yes: Requirement for 
respiratory support excluding 
mechanical ventilation (e.g. 
high flow, continuous 
positive airway pressure 
[CPAP])
Yes/No (if Yes specify start date of respiratory support and 
specify total number of calendar days on which respiratory 
support [excluding mechanical support] was given for at 
least one hour)
If yes: Requirement of 
mechanical ventilation 
Yes/No (if Yes specify start date of mechanical ventilation 
and specify total number of calendar days on which 
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If yes: Requirement for 
pediatric intensive care unit 
management
Yes/No (if Yes specify start date of pediatric care and specify 
total number of calendar days on which the child was cared 
for on pediatric intensive care unit for at least one hour)
Was the primary reason for 
hospitalization social in 
nature?
Yes/No
In the opinion of the principal 
investigator and the RSV 
local result, was RSV-LRTI 
the principal reason for 
admission to hospital?
Yes/No (If No, comment)
WORSENING INFORMATION OF RTI EPISODE (Worsening episode) - PART 3*
If in the investigator’s judgment a deterioration in the clinical status has occurred during the same RTI 
episode, then the most extreme value of all deteriorated clinical symptoms and signs (as listed in Part 2a and 
2b) must be captured 
N.B. May be completed in part or in full for any child experiencing a deterioration during the course of a 
disease episode
Maximum temperature***
Record temperature and route of measurement
Maximum respiratory rate***
Breaths per minute counted over one minute
Lower chest wall indrawing  (subcostal recession)***
Yes/No/Not available
Minimum SpO2 recorded***
%  measured in room air (NB altitude is collected 
for each participating site)
Nasal swab taken for testing at central laboratory
Yes/No
Specimen taken for RSV and RVP testing at local 
laboratory 
(optional sample if the previous swab from the 
same RTI episode was RSV-positive)
Yes/No (If Yes specify type of specimen test and result: 
positive/negative)
Not available
Signs of increased 
respiratory effort 
Audible wheeze***
Yes/No/Not available
Grunting***
Yes/No/Not available
Nasal flaring***
Yes/No/Not available
Intercostal recession***
Yes/No/Not available
Signs associated with 
severity observed 
Apnea outside medical 
facility observed during 
disease episode*** 
Has an episode of apnea > 20 seconds occurred outside a 
medical facility? Yes/No/Not available (if Yes provide all 
details [free text field])
Apnea under medical 
observation*** 
Has an episode of apnea > 20 seconds occurred during 
medical observation? Yes/No/Not available (if Yes provide 
all details [free text field])
Peripheral cyanosis***
Yes/No/Not available
Central cyanosis*** 
Yes/No/Not available
Irritability/agitation (record 
highest score)***
0 = content, happy, interactive
1 = mildly irritable when touched, occasional crying, can 
be comforted, is interactive
2 = moderately irritable, intermittently crying, resists 
comforting, less interactive
3 = extremely irritable, cannot be comforted, crying 
throughout examination or not interactive
Not available
Lethargy/excessive 
sleepiness (record highest 
score)***
0 = interactive
1 = mildly lethargic/sleepy is normally interactive when 
roused
2 = moderately lethargic/ sleepy, less interactive than 
normal when roused
3 = extremely lethargic/sleepy, is not interactive when 
roused
Not available
 
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Conscious level (record 
lowest level of 
consciousness)***
A = The child is awake, alert, and interactive with parents 
and care providers
V =The child responds only if the care provider or parents 
call the child’s name or speak loudly
P =The child responds only to painful stimuli, such as 
pinching the nail bed of a toe or finger.
U = The child is unresponsive to all stimuli
Not available
Assessment of feeding 
ability (record highest 
score)***
0 = Normal feeding
1 = Reduced ability to feed
2 = Unable to feed
Not available
Skin turgor*** 
Yes → > 2 seconds
No → 2 seconds
Not available
Findings on 
auscultation 
Wheeze on auscultation*** Yes/No/Not available
Crackles***
Yes/No/Not available
* Observation done by qualified medical/nursing personnel
** Test not required per protocol but if taken as part of clinical management result should be recorded
*** Record if a deterioration in this parameter has occurred relative to that documented at the assessment 
visit during the course of this disease episode
 
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APPENDIX E
AMENDMENTS AND ADMINISTRATIVE 
CHANGES TO THE PROTOCOL
GlaxoSmithKline Biologicals SA
Vaccines R &D
Protocol Amendment 1
eTrack study number 
and Abbreviated Title
204894 (RSV PED-011)
IND number
16999
EudraCT number
2018-000431-27
Amendment number:
Amendment 1
Amendment date:
16 July 2018
Co-ordinating author:

(Scientific Writer)
Rationale/background for changes:

In response to feedback from regulatory authorities, this study will evaluate two 
regimens of the ChAd155-RSV vaccine: either one dose or two doses will be 
given and the study sample size has been adjusted accordingly. The one dose 
regimen will administer a single vaccination with a lower dose of 1.5x1010 viral 
particles (vp) while the two dose regimen will administer 5x1010 vp for both 
vaccinations with a one month interval between doses. Unless the higher 5x1010 vp 
dose is not well-tolerated in subjects 12-23 months of age in the ongoing study 
204838 (RSV PED-002),we intend to study this high dose as a 1 or 2 dose regimen 
going forward.

The meningococcal vaccine NeisVac-C was removed and the pneumococcal 
polysaccharide conjugate vaccine Synflorix was added as one of the potential 
active comparator vaccines to be considered in countries where it is currently 
licensed.

A placebo group was added to accommodate this request from countries that were 
not able to identify a suitable active comparator.

A cross-reference to the Informed Consent Form (ICF) was added for the local 
choice of comparator/placebo (Sections 1.2.6 and 3).

Serological testing of baseline samples to determine exposure status will be 
performed in-stream to ensure at least 50% of subjects with a negative RSV 
exposure status at screening based on in-stream baseline serological testing. The 
sample size will be adjusted as needed through additional recruitment. The 
discussion on sample size determination has been simplified and assumptions have 
been further justified (Section 11.4).
 
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
The primary analysis for incidence of LRTI will be conducted in infants with a 
negative RSV exposure status at screening based on in-stream baseline serological 
testing.

Immunogenicity analyses can be adjusted to exclude those infants with an 
infection prior to sampling.

The wording for the timing of the second dose administration has been adapted for 
clarity.

A statement has been added that the final confirmation of RSV presence during 
RTI assessment will be determined by the definitive results from the central 
testing laboratory.

Clarification was provided that the Respiratory Viral Panel (RVP) testing will 
qualitatively assess potential co-infections from all RSV-A/B positive and 
confirmed LRTI cases (Section 6.7.3).

The symptoms and grading for assessment visits and worsening visits have been 
added (APPENDIX D).

In addition, some typographical errors have been corrected throughout the 
protocol.
Amended text has been included in bold italics and deleted text in strikethrough in 
the following sections:
On the protocol cover page the other study comparator vaccines were amended.
Other study vaccines

GSK’s pneumococcal polysaccharide conjugate 
vaccine (Synflorix)

GSK’s meningococcal group A, C, W-135 and Y 
conjugate vaccine licensed to Pfizer
(NimenrixMenveo)

Pfizer’s meningococcal group C polysaccharide 
conjugate vaccine (NeisVac-C)

SalinePlacebo (Formulation buffer S9b)
The detailed title was amended.
Detailed title
A Phase 1/2, randomized, observer-blind, controlled, 
multi-center study to evaluate safety, reactogenicity 
and immunogenicity of GSK Biologicals’ respiratory 
syncytial virus (RSV) investigational vaccine based on 
the RSV viral proteins F, N and M2-1 encoded by 
chimpanzee-derived adenovector (ChAd155-RSV) 
(GSK3389245A), when administered intramuscularly 
as a single dose or as two doses according to a 0, 1-
month schedule, to infants aged 6 and 7 months.
 
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On the protocol cover page and on the Sponsor Signatory Approval page the 
Contributing authors have been added.
Contributing authors

 (Clinical Research and 
Development Lead)

 (Project Statistician)

 (Study Delivery Lead)

 (Study Delivery Lead)

 (Study Delivery Lead)

 (Study Delivery Lead)

 (Clinical Read-out Team 
Leader)

 (Clinical and Epidemiology 
Research and Development Project Lead)

 (Clinical and 
Epidemiology Research and Development 
Project Lead)
On the Signatory Approval page the EudraCT number was added and the Sponsor 
signatory has been replaced.
EudraCT number
2018-000431-27
Sponsor signatory
, DirectorAntonio Gonzalez Lopez 
(Clinical and Epidemiology Research & 
Development Project Lead)
In the Synopsis, the following changes have been made:
Rationale for the 
study and study 
design

Rationale for the study
GSK Biologicals is developing the pediatric candidate RSV 
vaccine (ChAd155-RSV vaccine) to protect infants from RSV 
diseases.
The purpose of this study is to provide critical information on 
the safety, reactogenicity and immunogenicity profile of the 
ChAd155-RSV vaccine in infants likely to be unexposed to 
RSV before moving to a dose selection and a proof-of-
concept trial in infants. This An important aspect of this 
phase I/II study will be to compare a single lower dose of 
1.5x1010 viral particles (vp) and two higher doses of 5x1010
vp according to a 0, 1 month schedule administered to 
infants aged 6 and 7 months likely to be unexposed to RSV, 
which is powered to statistically exclude a level of risk of 
 
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PPD
PPD
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‘vaccine-induced enhanced RSV disease’ after vaccination of 
infants aged 6 and 7 months, likely to be unexposed to RSV,
associated with the ChAd155-historic FI-RSV vaccine trials.
(Amended 16 July 2018)

Rationale for the study design
Study population: The immunogenicity, safety and 
reactogenicity of the pediatric candidate RSV vaccine 
(ChAd155-RSV vaccine) has been evaluated in healthy adults 
aged 18 to 45 years (study 201974 [RSV PED-001; 
NCT02491463]). A clinical study is currently being 
conducted in RSV-seropositive infants aged 12 to 23 months 
(study 204838 [RSV PED-002]). The safety profile of the 
ChAd155-RSV vaccine in adults (study 201974 [RSV PED-
001; NCT02491463]) has been evaluated and determined to 
be satisfactory by an Independent Data Monitoring 
Committee (IDMC). At the condition ofShould there be a
satisfactory safety profile of the ChAd155-RSV vaccine in 
RSV-seropositive infants, as evaluated by an IDMC on Day 
60 data (i.e., Day 30 days post-dDose 2 of the highest dose 
level) of the study RSV PED-002, the present study will be 
performed. This study will be conducted onin infants aged 6 
and 7 months, (having a low chance of natural exposure to 
RSV before inclusion in the study,). The primary analysis for 
incidence of LRTI will be conducted in infants with a 
negative RSV exposure status (at screening based on in-
stream baseline serological testing). This study will support 
the decision to allow age de-escalatione to the targeted 
population (infants as from 6 weeks of age).) in the 
subsequent study.
Control vaccines: Active controls: Active 
controlscomparators are included as a control for the 
reactogenicity, safety and immunogenicity assessments. The 
choice of one of four meningococcalcontrol vaccines, as 
active comparators has been driven by the fact that, in most 
countries at least one of these vaccines meet the criteria of 
being of medical benefit, and where possible licensed for 
infants and used with a similar dose and schedule as the 
investigational RSV vaccine, while not being part of a 
national immunization program. The choice of which active 
control meningococcal comparator vaccine willto be used will
be done at the country level and will be used according to its 
approved label.
To provide benefit to all trial participants and to maintain the 
study blind until the end of follow up, the ChAd155-RSV 
 
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vaccine recipients will also receive immunization with the 
selected meningococcal vaccine.
A placebo group was added to accommodate a request from 
countries that were not able to identify a suitable active 
comparator.

Regimen, dose and route of administration: A 
vaccination regimen based on
This study will evaluate two intramuscular (IM) injections (in 
the anterolateral thigh) of 5 x 1010 viral particles (vp)regimens 
of the ChAd155-RSV vaccine ; either one lower dose of 
1.5x1010 vp or two doses of 5x1010 vp will be administered
according to a 0, 1-month . For the two dose schedule
(4-week, an interval of approximately one month between 
vaccinations) will be dosing will be used. A single dose arm 
was added in this 6-7 month-old study population before 
going to target population in subsequent studies.
The dose levels to be evaluated in this study. This dose level 
is the same as the highest dose have previously been
administered to RSV-seropositive infants aged 12 to 23 
months (study RSV PED-002 [204838]) and will have been 
shown to have a satisfactory safety profile and reviewed by 
the IDMC. This doseThese doses might be modified 
following review by the IDMC of the safety data from study 
RSV PED-002 (204838). However if no significant safety 
concerns are identified with the highest ChAd155-RSV 
vaccine dose of 5x1010 vp administered in the RSV PED-002 
study, itthat dose will be the highest does level evaluated in 
this study.
The 4-week interval regimen has been tested in preclinical 
models and results from a In the bovine RSV challenge model 
in which seronegative, colostrum-restricted newborn calves
were vaccinated with , both a single and two dosesdose 
regimen of 5x1010 vp ChAd155-RSV, have been evaluated. 
The two dose regimen was given at an interval of four weeks 
apart. Both regimens showed that dose regimen was 
immunogenic and protected calves from a similar level of 
protection against challenge with bovine RSV disease and 
infection and, but the two dose regimen showed higher 
immunogenicity. Neither regimen was not associated towith
pulmonary pathology.
A Phase I clinical trial evaluated a simian adenoviral vector-
based RSV vaccine with the same insert as ChAd155-RSV 
candidate vaccine (PanAd3-RSV) [RSV001 Interim Study 
 
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Report, 2014]. Data from this trial, with 42 subjects, showed 
that a vaccination regimen based on two IM injections, 
separated by four weeks, was safe and immunogenic.
In this study, infants aged 6 and 7 months will be 
administered with Dose 1the first dose of the ChAd155-RSV 
vaccine before the RSV season to increase the probability of 
enrolling infants unexposed to RSV, and then followed up 
through the RSV season. The second dose will be given one 
month after the first dose.
Objectives
Primary

To evaluate the safety and reactogenicity of the RSV 
investigational vaccine (5x1010 vp) when administered 
IM as one (1.5x1010 vp) dose or as two IM(5x1010 vp) 
doses according to a 0, 1-month schedule, up to 3060 
days after Dose 21 (i.e., Day 61) in infants aged 6 and 7 
months.
Secondary

To evaluate the occurrence of RSV respiratory tract 
infections of any severity from Visit 1 (Day 1, after Dose 
1) up to the end of the first RSV transmission season, in 
infants aged 6 and 7 months.

To evaluate the safety of two IM doses of the RSV 
investigational vaccine (5x1010 vp) when administered
IM as one (1.5x1010 vp) dose or as two (5x1010 vp) doses 
according to a 0, 1-month schedule, from study start 
(Day 1) up to the end of the second RSV transmission 
season, in infants aged 6 and 7 months.

To evaluate the occurrence of very severe RSV LRTI 
from Visit 1 (Day 1, after Dose 1) up to the end of the 
first RSV transmission season in RSV infected infants 
aged 6 and 7 months with a negative RSV exposure 
status (at screening based on in-stream baseline 
serological testing).

To evaluate the humoral immunogenicity induced by two 
IM doses of the RSV investigational vaccine (5x1010 vp) 
when administered IM as one (1.5x1010 vp) dose or as 
two (5x1010 vp) doses according to a 0, 1-month schedule, 
from study start (Day 1) up to the end of the first RSV 
transmission season, in infants aged 6 and 7 months.
 
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Tertiary

If deemed necessary, to further characterize the immune 
response of the RSV investigational vaccine when one 
(1.5x1010 vp) dose or two IM(5x1010 vp) doses are
administered IM according to a 0, 1-month schedule into
infants aged 6 and 7 months.
Study design

Experimental design: Phase I/II, observer-blind, 
randomized, controlled, multi-centric study with twothree
parallel groups.

Epoch 004: follow-up starting after Visit 7 (end of 
the secondfirst RSV transmission season)* and 
ending at Visit 8 (end of the second RSV 
transmission season).

End of Study (EoS): Last testing results released of 
samples collected at Visit 8 (end of the second RSV 
transmission season) related to primary and secondary 
endpoints.*
* Up to Visit 8 (end of the second RSV season), there 
will be monthly nasal swab to detect asymptomatic RSV 
infections during the RSV season andor if following 
active or a passive surveillance contacts, a subject 
presents symptoms of respiratory tract infection (RTI), a 
nasal swab will be collected.
 
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Synopsis Table 1
Study groups and epochs foreseen in the study
Old Synopsis Table 1
Study groups
Number of 
subjects*
Age (Min/Max)
Epochs
Epoch 001
Epoch 002
Epoch 003
Epoch 004
RSV + Bexsero
15 **
6  – 7 months
x
x
x
x
RSV + Nimenrix
15 **
6 – 7 months
x
x
x
x
RSV + Menveo
15 **
6 – 7 months
x
x
x
x
RSV + NeisVac-C
5 **
6 – 7 months
x
x
x
x
Bexsero
15 **
6 – 7 months
x
x
x
x
Nimenrix
15 **
6 – 7 months
x
x
x
x
Menveo
15 **
6 – 7 months
x
x
x
x
NeisVac-C
5 **
6 – 7 months
x
x
x
x
New Synopsis Table 1
Study groups
Numbers of 
subjects*
Age (Min/Max)
Epochs
Epoch 001
Epoch 002
Epoch 003
Epoch 004
1D RSV + Bexsero
50**
6 – 7 months
N/A
x
x
x
1D RSV + Nimenrix
6 – 7 months
N/A
x
x
x
1D RSV + Synflorix
6 – 7 months
N/A
x
x
x
1D RSV + Menveo
6 – 7 months
N/A
x
x
x
1D RSV + Placebo
6 – 7 months
N/A
x
x
x
2D RSV + Bexsero
50**
6 – 7 months
N/A
x
x
x
2D RSV + Nimenrix
6 – 7 months
N/A
x
x
x
2D RSV + Synflorix
6 – 7 months
N/A
x
x 
x
2D RSV + Menveo
6 – 7 months
N/A
x
x
x
2D RSV + Placebo
6– 7 months
N/A
x
x
x
Bexsero
50**
6 – 7 months
N/A
x
x
x
Nimenrix
6 – 7 months
N/A
x
x
x
Synflorix 
6 – 7 months
N/A
x
x
x
Menveo
6 – 7 months
N/A
x
x
x
Placebo
6 – 7 months
N/A
x
x
X
1D: 1 Dose (1.5x1010 vp/dose); RSV: ChAd155-RSV vaccine; 2D: 2 Dose (5x1010 vp)./dose); N/A: Not Applicable.
* Note that across allfor both 1D and 2D RSV vaccine + active comparator/placebo groups the total number of 
subjects is 50100 and that for eachboth RSV vaccine + active comparator/placebo groups there will be a 1:1:1
ratio maintained with the samecorresponding active comparator/placebo group.
** Note that these numbers of subjects anticipated to receive the control vaccines within participating countries 
are approximation ofnot yet known, but the distribution and supplies will be prepared to allow flexible enrolment 
across countries (for any comparator the range of subjects is 0 – 50 may be enrolled) but the overall total of 1500
subjects will be respected.
 
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Synopsis Table 2
Study groups and treatment foreseen in the study
Old Synopsis Table 2
Treatment 
name
Vaccine/ 
Product name
Study Groups
RSV + 
Bexsero
RSV + 
Nimenrix
RSV + 
Menveo
RSV + 
NeisVac-C Bexsero Nimenrix Menveo
NeisVac-C
RSV ChAd ChAd155-RSV
x
x
x
x
Saline
FB
x
x
x
x
Bexsero
Bexsero
x
x
Nimenrix
Nimenrix
x
x
Menveo 
x
x
NeisVac-C
Neiss Vac-C
x
x
New Synopsis Table 2
Treatment name
1D RSV ChAd 
2D RSV ChAd
Bexsero Nimenrix Synflorix
Menveo 
FB
Vaccine/ 
Product name
1D ChAd155-RSV 
1.5X1010 vp/dose
2D ChAd155-RSV
5X1010 vp/dose
Bexsero
Nimenrix
Synflorix
Menveo
FB
Study Groups
1D RSV + Bexsero
x
x
x
1D RSV + Nimenrix
x
x
x
1D RSV + Synflorix
x
x
x
1D RSV + Menveo
x
x
x
1D RSV + Placebo
x
x
2D RSV + Bexsero
x
x
2D RSV + Nimenrix
x
x
2D RSV + Synflorix
x
x
2D RSV + Menveo
x
x
2D RSV + Placebo
x
Bexsero
x
x
Nimenrix
x
x
Synflorix
x
x
Menveo
x
x
Placebo
x
ChAd155-RSV: Chimpanzee Adenovirus Type 155 RSV vaccine (5x1010 vp); FB: Formulation buffer S9b; RSV ChAd: 
Treatment with ChAd155-RSV vaccine; 1D: 1 Dose (1.5x1010 vp/dose); 2D: 2 Dose (5x1010 vp)./dose).

Control: meningococcal vaccine Controls: active 
controlscomparator vaccines (Bexsero, or Nimenrix, 
or Synflorix, or Menveo, or NeisVac-C) and saline
(Placebo (Formulation buffer S9b).*[FB])* 
* The choice of active control comparator vaccine or 
Placebo is done at the country level.

Vaccination schedules:

RSV investigational vaccine:
o
In the 1 Dose (1D) groups, a single lower dose of 
1.5x1010 vp will be administered IM at Day 1 
 
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(Visit 1). Formulation buffer will be 
administered in the 1D groups at Day 31 
(Visit 3). In the 2 Dose (2D) groups, two IM 
vaccine doses of 5x1010 vp will be administered 
IM according to a 0, 1-month schedule, (i.e., at 
Day 1 [Visit 1] and Day 31) ( [Visit 3]) (see
Synopsis Table 3). Dose 1 will be administered 
before the first RSV season. and the second dose 
will be given one month after the first dose (RSV 
seasons will be determined for each country based 
on local epidemiological data and documented in 
the Study Procedures Manual (SPM).[SPM]. The 
RSV season is defined as the period of the year 
when 70% of the RSV cases have occurred in 
previous years. For the calculation, where 
available, data from up to the ten previous years 
should be applied. If the data permit calculation of 
the actual date of the beginning of the season, 
rather than approximation to the nearest month, 
this is desirable.).

Comparator or Placebo:
o
In countries where Bexsero or NimenrixFor 
Bexsero, Nimenrix, and NeisVac-C is used as a 
control, two primary doses will be administered 
IM with at least a 2 month interval with abetween 
these primary doses. A booster dose will be
administered IM in the second year of life (at 
Day 365 (Visit 7), with an interval of at least 2 
months between the primary series and booster 
dose. The first Bexsero or Nimenrix dose will be 
administered at Day 1 (Visit 1) (in the groups 
receiving only Bexsero or Nimenrix, 
respectively). In the groups receiving only 
Bexsero or Nimenrix, the second dose will be at 
Day 61 (Visit 5). The first Bexsero or Nimenrix
dose to be administered to the 1D and 2D RSV 
groups will be at Day 61 (Visit 5), following the 1 
or 2 RSV vaccine doses, respectively. The second 
dose of Bexsero or Nimenrix in the 1D and 2D 
groups will be at Day 121 (Visit 6). Formulation 
buffer will be administered, when neither RSV 
vaccine nor comparator is scheduled, at the 5 
vaccination visits (see Synopsis Table 4). 3).
o
In countries where Synflorix is used as a control,
two doses will be administered IM with at least a 
1 month interval between these primary doses. A 
 
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booster dose will be administered IM in the 
second year of life at Day 365 (Visit 7). The first 
Synflorix dose will be administered at Day 31 
(Visit 3) (in the group receiving only Synflorix). 
In the group receiving only Synflorix, the second 
dose will be at Day 61 (Visit 5). The first 
Synflorix dose to be administered to the 1D and 
2D RSV groups will be at Day 61 (Visit 5), 
following the 1 or 2 RSV vaccine doses, 
respectively. The second dose of Synflorix in the 
1D and 2D groups will be at Day 121 (Visit 6). 
Formulation buffer will be administered, when 
neither RSV vaccine nor comparator is 
scheduled, at the 5 vaccination visits (see
Synopsis Table 3).
o
In countries where Menveo is used as a control, 
two doses will be administered IM at least 3 
months apart with the second dose in the second 
year of life. at Day 365 (Visit 7). The first Menveo
dose will be administered as a comparator at 
Day 31 (Visit 3 (opposing the second RSV 
vaccine dose) from 7 months of age.) (in the 
group receiving only Menveo). The first Menveo
dose to be administered to the 1D and 2D RSV 
groups will be at Day 61 (Visit 5,), following the 
1 or 2 RSV vaccine administrations.doses, 
respectively. Since the second Menveo dose has to 
be administered in the second year of life, at 
Day 365 (Visit 7), no administration will be 
performed at Day 121 and therefore in those 
countries the second Menveo dose(Visit 6). 
Formulation buffer will be at Visit 7, at the end 
of the first RSV season (refer to administered, 
when neither RSV vaccine nor comparator is 
scheduled, at the 4 vaccination visits (see
Synopsis Table 3).
o
In countries where Placebo is used as a control, 
one dose will be administered IM at Day 31 
(Visit 3) in the 1D RSV + Placebo group and two 
IM doses will be administered IM according to a 
0, 1-month schedule at Day 1 (Visit 1) and 
Day 31 (Visit 3) in the Placebo group (see 
Synopsis Table 3).
 
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Synopsis Table 3
Vaccines administered and vaccination schedules
Old Synopsis Table 3
Groups
Age* (Months) / (Visit, Day)
6-7 / (V1, D1)
7-8 / (V3, D31) 8-9 / (V5, D61)
10-11 / (V6, D121)**
14-18 / (V7)
RSV + Bexsero
RSV ChAd
RSV ChAd
Bexsero
Bexsero
Bexsero
Bexsero
Bexsero
Saline
Bexsero
Saline
Bexsero
RSV + Nimenrix
RSV ChAd
RSV ChAd
Nimenrix
Nimenrix
Nimenrix
Nimenrix
Nimenrix
Saline
Nimenrix
Saline
Nimenrix
RSV + Menveo
RSV ChAd
RSV ChAd
Menveo
Menveo
Menveo
Saline
Menveo
Saline
Menveo
RSV + NeisVac-C
RSV ChAd
RSV ChAd
NeisVac-C
NeisVac-C
NeisVac-C
NeisVac-C
NeisVac-C
Saline
NeisVac-C
Saline
NeisVac-C
New Synopsis Table 3
Groups
Age* (Months) / (Visit, Day)
6-7 / (V1, D1)
7-8 / (V3, D31) 8-9 / (V5, D61)
10-11 / (V6, D121)**
14-18 / (V7, D365)
1D RSV + Bexsero
1D RSV ChAd FB
Bexsero
Bexsero
Bexsero
2D RSV + Bexsero
2D RSV ChAd 2D RSV ChAd Bexsero
Bexsero
Bexsero
Bexsero
Bexsero
FB
Bexsero
FB
Bexsero
1D RSV + Nimenrix
1D RSV ChAd FB
Nimenrix
Nimenrix
Nimenrix
2D RSV + Nimenrix
2D RSV ChAd 2D RSV ChAd Nimenrix
Nimenrix
Nimenrix
Nimenrix
Nimenrix
FB
Nimenrix
FB
Nimenrix
1D RSV + Synflorix
1D RSV ChAd FB
Synflorix
Synflorix
Synflorix
2D RSV + Synflorix
2D RSV ChAd 2D RSV ChAd Synflorix
Synflorix
Synflorix
Synflorix
FB
Synflorix
Synflorix
FB
Synflorix
1D RSV + Menveo
1D RSV ChAd FB
Menveo
Menveo
2D RSV + Menveo
2D RSV ChAd 2D RSV ChAd Menveo
Menveo
Menveo
FB
Menveo
FB
Menveo
1D RSV + Placebo
1D RSV ChAd FB
2D RSV + Placebo
2D RSV ChAd 2D RSV ChAd
Placebo
FB
FB
V: Visit; D: Day; 1D: 1 Dose (1.5x1010 vp/dose); 2D: 2 Dose (5x1010 vp/dose); RSV ChAd: Treatment with ChAd155-
RSV vaccine (5x1010 vp); V: Visit.; FB: Formulation buffer S9b.
* Assumes enrolled at 6 and 7 months of age for the vaccine Dose 1 to be administered before the first RSV season 
(RSV seasons will be determined for each country based on local epidemiological data).
** In countries where Menveo or Placebo is used as a comparator, no administration will be performed at Day 121 and 
therefore in those countries there will be no Visit 6 and it will be administered at the end of the first RSV season at 
Visit 7.

Treatment allocation: infants will be randomized using a 
centralized randomization system on internet (SBIR) before 
first vaccination and after assessment of eligibility (i.e., 
after screening conclusion). The randomization algorithm 
will use a minimization procedure accounting for country.
as a minimization factor and the grouping 
comparator/placebo as a stratification factor.
 
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
Nasal swab: there will be monthly nasal swab to detect 
asymptomatic RSV infections during the RSV season 
and if following active or a passive surveillance 
contacts, a subject presents symptoms of respiratory 
tract infection (RTI), a nasal swab will be collected (as 
well as a sample for local testing i.e., the type of 
sample to be determined locally [e.g., swab, etc.]).

Study visits: Other than the screening visit and assessment 
visits for active/passive surveillance, there will be 8 study 
visits except in countries where Menveo or Placebo is used 
as a control where there will be 7 study visits.

In countries where Menveo is used as a comparator, no 
administration will be performed at Day 121 and 
therefore in those countries there will be no Visit 6 and 
itMenveo will be administered at the end of the first 
RSV season at Visit 7.

In countries where Placebo is used as a control, no 
vaccine administration will be performed after Visit 3 
and therefore in those countries there will be no Visit 
6. There will be a Visit 5 and Visit 7 for countries 
using Placebo and all other study procedures will 
occur at these visits except vaccination.

Visit 2 (Day 8), Visit 4 (Day 38), and Visit 8 (Day 730) 
(no blood sampling for immune response and no 
vaccine administration) may take place in the 
subject’s home or at the investigators clinical facility 
as appropriate to the circumstances in the judgment 
of the investigator.

Surveillance for spontaneous or excessive bleeding.
Subjects’ parent(s)/LAR(s) will be instructed to contact the 
investigator/study staff if their child presents symptoms of 
spontaneous bleeding or easy bruising or if their child 
develops a rash, within 30 days after either vaccination, in 
order to detect any thrombocytopenic petechiae or purpura. 
The investigator will, based on his/her medical judgment, 
measure the total blood count and appropriately 
investigate infants with clinical suspicion of low platelets.
Case definition
During the analysis of the study, all cases identified during the 
surveillance of RSV-RTI will be definitively classified as either 
RTI, LRTI, severe LRTI or very severe LRTI according to the 
standardized case definitions (see Synopsis Table 75) based on 
the available World Health Organization (WHO) case 
definitions.
 
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Synopsis Table 5
Case definitions for data analysis
Case
At sea level up to 2500 meters elevation
Above 2500 meters elevation
RSV-RTI
Runny nose OR blocked nose OR cough
AND 
Confirmed RSV infection 4
Same
RSV-LRTI
History of cough OR difficulty breathing 1
AND
SpO2 < 95% 2, OR RR increase 3
AND
Confirmed RSV infection 4
Same but with SpO2 <92%
RSV severe RSV-LRTI
Meeting the case definition of RSV-LRTI 
AND
SpO2 < 93% 2, OR lower chest wall in-
drawing
Same but with SpO2 <90%
RSV very severe RSV-
LRTI
Meeting the case definition of RSV-LRTI 
AND 
SpO2 < 90% 2, OR inability to feed, OR 
failure to respond / unconscious
Same but with SpO2 <88%
RSV hospitalization
Confirmed RSV infection 5
AND
Hospitalized for acute medical condition 6
Same
All-cause LRTI
History of cough OR difficulty breathing 1
AND 
SpO2 < 95% 2, OR RR increase 3
Same but with SpO2 <92%
Definitions based on [Modjarrad, 2016]
LRTI = lower respiratory tract infections; RR = respiratory rate; RTI = respiratory tract infections; SpO2 = Blood oxygen 
saturation by pulse oximetry.
1 Based on history reported by parents/LARs and includes difficulty breathing (e.g., showing signs of wheezing or 
stridor, tachypnoea, flaring [of nostrils], chest in-drawing, apnoea) associated with nasal obstruction.
Number of subjects
The target will be to enroll approximately 1500 infants likely to 
be unexposed to RSV to ensure thatwith about 50 infants 
receivefor each of three randomization groups. If necessary, 
the sample size will be increased through additional 
recruitment in order to achieve at least one dose of5 RSV 
investigational infected infants, with a negative RSV exposure 
status (at screening based on in-stream baseline serological 
testing), in each RSV vaccine group. Dose 1 of the ChAd155-
RSV vaccine should be administered before the first RSV 
season and second dose will be given one month after the first 
dose (RSV seasons will be determined for each country based 
on local epidemiological data and documented in the SPM. 
The RSV season is defined as the period of the year when 70% 
of the RSV cases have occurred in previous years. For the 
calculation, where available, data from up to the ten previous 
years should be applied. If the data permit calculation of the 
actual date of the beginning of the season, rather than 
approximation to the nearest month, this is desirable).
 
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Endpoints
Secondary

Occurrence of RSV-RTI, RSV-LRTI, severe RSV-LRTI 
and very severe RSV-LRTI (according to standardized 
case definitions) as from first vaccination (Day 1) up to 
the end of the second RSV transmission season.

Occurrence of very severe RSV-LRTI (according to 
standardized case definitions) among RSV infected 
infants with a negative RSV exposure status (at screening 
based on in-stream baseline serological testing) from first 
vaccination (Day 1) up to the end of the first RSV 
transmission season.

Humoral response to the investigational RSV vaccine, pre-
vaccination (Screening), post-Dose 1 (Day 31) and post-
Dose 2 (Day 61):

Palivizumab-competing antibody concentrations.
Tertiary

Humoral response to the investigational RSV vaccine, 
pre-vaccination (Screening), post-Dose 1 (Day 31) and 
post-Dose 2 (Day 61).

Palivizumab-competing antibody concentrations.
The LIST OF ABBREVIATIONS has been amended as follows:
ES:
Exposed Set
FB:
Formulation buffer (S9b)
HRP:
Horse-Radish Peroxidase
PPS:
Per-Protocol Set
SAP:
Statistical Analysis Plan
TLR:
Toll-like receptor
TCV:
Total Vaccinated Cohort
UK:
United Kingdom
 
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The following terms have been amended or added to the GLOSSARY OF TERMS
End of Study
(Synonym of End of 
Trial)
Synonymous with 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, study completion 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. Study completion 
must be achieved no later than 8 months after LSLV.
Exposed Set
All subjects who received at least 1 dose of the study 
treatment. The allocation in a group is done in function 
of the administered treatment.
Per Protocol Set 
All subjects who received at least 1 dose of the study 
treatment to which they are randomised and have post-
vaccination data (Full Analysis Set) minus subjects with 
protocol deviations that lead to exclusion.
The TRADEMARKS have been amended as follows:
Trademarks of the GSK group of 
companies
Generic description
Synflorix
Pneumococcal polysaccharide conjugate 
vaccine (adsorbed)
Trademarks not owned by the GSK group 
of companies
Generic description
NeisVac-C (Pfizer)
Meningococcal group C polysaccharide 
conjugate vaccine (tetanus toxoid protein 
conjugate)
TrueBlue (SeraCare)
Peroxidase substrate
In Section 1.1.3.2. Serum immune responses to the FI-RSV vaccine and to 
subsequent RSV infection, the following changes have been made:
When the sera of these infants and children were later compared with those of infants and 
children with natural RSV infection, it could be observed that FI-RSV vaccination 
induced high total IgG antibody titrestiters, but a relatively low level of neutralising 
antibody titrestiters [Murphy, 1986].
 
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In Section 1.1.3.4. Animal models for “FI-RSV enhanced RSV disease”, the 
following changes was made:
In general, animal models suggest that the immunopathology seen with the FI-RSV 
vaccine was a result of a poor functional antibody response [Graham, 2011; Openshaw, 
2002] An unbalanced cellular immune response skewed towards Th2 (disturbed Th1/Th2 
balance) could also be observed in mouse models [Connors, 1992; Connors, 1994; Waris, 
1996], but is not consistently supported by data from other model animals [Antonis, 
2003; Castilow, 2008; Phipps, 2007].
The Section 1.1.6. Pre-clinical experience. the following statement was added:
Please refer to the current IB for information regarding the pre-clinical studies of GSK 
Biologicals’ investigational ChAd155-RSV vaccine.
The Section 1.1.7. Clinical experience, the following statement was amended:
Please refer to the current IB for information regarding the pre-clinical and clinical
studies of GlaxoSmithKline (GSK) Biologicals’ investigational ChAd155-RSV vaccine.
The Section 1.2.1. Rationale for the study, the following changes were made:
The purpose of this study is to provide critical information on the safety, reactogenicity 
and immunogenicity profile of the ChAd155-RSV vaccine in infants likely to be 
unexposed to RSV before moving to a dose-selection and a proof-of-concept trial in 
infants. This An important aspect of this phase I/II study will be to compare a single 
lower dose of 1.5x1010 viral particles (vp) and two higher doses of 5x1010 vp according 
to a 0, 1 month schedule administered to infants aged 6 and 7 months likely to be 
unexposed to RSV, which is powered to statistically exclude a level of risk of ‘vaccine-
induced enhanced RSV disease’ after vaccination of infants aged 6 and 7 months, likely 
to be unexposed to RSV, associated with the ChAd155-historic FI-RSV vaccine trials in 
young infants [Kim, 1969].
The Section 1.2.2.1. Study population, the following changes were made:
The immunogenicity, safety and reactogenicity of the pediatric candidate RSV vaccine 
(ChAd155-RSV vaccine) has been evaluated in healthy adults aged 18 to 45 years (study 
201974 [RSV PED-001; NCT02491463]). A clinical study is currently being conducted 
in RSV-seropositive infants aged 12 to 23 months (study 204838 [RSV PED-002]). The 
safety profile of the ChAd155-RSV vaccine in adults (study 201974 [RSV PED-001; 
NCT02491463]) has been evaluated satisfactory by an Independent Data Monitoring 
Committee (IDMC). At the condition ofShould there be a satisfactory safety profile of 
the ChAd155-RSV vaccine in RSV-seropositive infants, as evaluated by an IDMC on 
Day 60 data (i.e., Day 30 days post-Dose 2 of the highest dose level) of the study RSV 
PED-002, the present study will be performed. This study will be conducted on infants 
aged 6 and 7 months (having a low chance of natural exposure to RSV before inclusion in
the study),). The primary analysis for incidence of LRTI will be conducted in infants 
with a negative RSV exposure status (at screening based on in-stream serological 
testing). This study will support the decision to allow age de-escalatione to the targeted 
population (infants as from 6 weeks of age).
 
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The Section 1.2.2.2. Choice of study population, the following change was made:
Infants of this age are more likely to be unexposed to RSV compared to older infants. 
Most of the infants (50% to 70%) are estimated to be RSV-exposed at one year of age.
[Dunn, 2013].
The Section 1.2.2.3. In-stream serological testing of baseline samples to determine 
exposure status, was added:
Subjects will not be screened for serostatus as criterion for enrolment in the study, due 
to the potential presence and detection of residual maternal antibodies (Refer to 
Section 6.7.3 for more details on the determination of a negative RSV exposure status). 
The assumption is that the majority of infants are previously unexposed (see Section 
1.2.2.2). Serological testing of baseline samples to determine exposure status will be 
performed in-stream to ensure at least 50% of infants with a negative RSV exposure 
status (at screening based on in-stream baseline serological testing) and the sample 
size will be adjusted as needed through additional recruitment (Section 11.4).
The Section 1.2.3. Rationale for regimen, dose and route of administration, was 
amended as follows:
A vaccination regimen based on This study will evaluate two IM injections (in the 
anterolateral thigh) of 5 x 1010 viral particles (vp)regimens of the ChAd155-RSV
vaccine; either one dose of 1.5x1010 vp or two doses of 5x1010 vp will be administered
according to a 0, 1-month . For the two dose schedule (4-weekan interval of 
approximately one month between vaccinations)dosing will be evaluatedused. A single 
dose arm was added in this study. This dose level is the same as the highest dose6-7 
month-old study population before going to target population in subsequent studies.
The dose levels to be evaluated in this study have previously been administered to RSV-
seropositive infants aged 12 to 23 months (study RSV PED-002 [204838]) and will have 
been shown to have a satisfactory safety profile and reviewed by the IDMC. This 
doseThese doses might be modified following review by the IDMC of the safety data 
from study RSV PED-002 (204838). However, if no significant safety concerns are 
identified with the highest ChAd155-RSV vaccine dose of 5x1010 vp administered in the 
RSV PED-002 study, itthat dose will be the highest does level evaluated in this study.
The 4-week interval regimen has been tested in preclinical models and results from aIn 
the bovine RSV challenge model in which seronegative, colostrum-restricted newborn 
calves were vaccinated with, both a single and two dosesdose regimen of 5x1010 vp 
ChAd155-RSV have been evaluated. The two dose regimen was given at an interval of 
four weeks apart. Both regimens showed that dose regimen was immunogenic and 
protected calves from a similar level of protection against challenge with bovine RSV
disease and infection and, but the two dose regimen showed higher immunogenicity. 
Neither regimen was not associated towith pulmonary pathology. Low or potentially 
suboptimal dosing could be associated with lack of efficacy but is not likely to be
associated with ERD; this is supported by animal data evaluating protection against a 
delayed challenge after a period of waning immunity. Non-clinical calf data showed 
that a challenge 4 months after the second dose or a challenge after a single dose did 
 
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not induce any sign of ERD and demonstrated similar efficacy against LRTI. Despite 
waning immunity after 4 months, animals were fully protected upon challenge.
Using a different adenovector, PanAd3, the 5 x 1010 vp dose regimen was shown to be 
safe in toxicology studies in mice. Preclinical data in different species (mice, cotton rats, 
non-human primates, and seronegative newborn calves) have shown that this regimen 
induces both anti-RSV F neutralizing antibodies and systemic T-cell responses [Taylor, 
2015; Pierantoni, 2015].
A Phase I clinical trial evaluated a simian adenoviral vector-based RSV vaccine with the 
same insert as ChAd155-RSV candidate vaccine (PanAd3-RSV) [, 2014]. Data from this 
trial, with 42 subjects, showed that a vaccination regimen based on two IM injections, 
separated by four weeks, was safe and immunogenic.
Similarly, the selected one dose level of 1.5x1010 vp is the same as the mid-dose 
administered to RSV-seropositive infants in the RSV PED-002 study that will have 
been shown to have a satisfactory safety profile and reviewed by the IDMC. The 
rationale for using the mid-dose level is to collect safety and immunogenicity data on a 
lower dose and on the one-dose regimen in 6-7 months RSV-naïve infants before 
progressing to the target population i.e. infants as of 6 weeks of age.
If tolerated, both candidate regimens would be evaluated in the target population to 
determine immune response and evaluate efficacy.)
In this study, infants aged 6 to 7 months will be administered with Dose 1the first dose of 
the ChAd155-RSV vaccine before the RSV season to increase the probability of enrolling 
infants unexposed to RSV, and then followed up through the RSV season. The second 
dose will be given one month after the first dose.
In the Section 1.2.4.1.Rationale for RSV disease surveillance the following paragraph 
was deleted:
Subjects will not be screened for serostatus as criterion for enrolment in the study, due to 
the potential presence and detection of residual maternal antibodies. The assumption is 
that the majority of infants are previously unexposed (see Section ). Infants will be 
administered with Dose 1 of the ChAd155-RSV vaccine before the RSV season and then 
followed up through the RSV season.
The Section 1.2.5. Rationale for study blinding, was amended as follows:
Given the different appearance and storage conditions of the investigational RSV vaccine 
and the active control comparator vaccines / saline solutionPlacebo, double blinding is 
not possible and the study will be conducted in an observer-blind manner.
*Refer to the SPM for RSV seasons per site country.
 
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In the Section 1.2.6. Rationale for the use of active controls, the following changes
have been made:
Active comparatorsThe comparator / Placebo groups are included as a control for the 
reactogenicity, safety and immunogenicity assessments. The choice of control between 
an active comparator or Placebo will be done at country level. Refer to the Informed 
Consent Form (ICF) for the local choice of comparator/Placebo.
Active comparators are included as a control for the reactogenicity, safety and 
immunogenicity assessments. The choice of one of four meningococcalcontrol vaccines, 
as active comparators has been driven by the fact that, in most countries at least one of 
these vaccines meet the criteria of being of medical benefit, and where possible licensed 
for infants and used with a similar dose and schedule as the investigational RSV vaccine, 
while not being part of a national immunization program. The choice of which active 
control meningococcal comparator vaccine will be used will be done at the country level 
and will be used according to its approved label.
Since the immunization schedule for the meningococcalactive comparator vaccines for 
infants between 6 and 18 months of age is slightly different, infants in the active control 
group will be administered salineFB at the time of administration of the first dose of the 
investigational RSV vaccine (for either Menveo or Synflorix) or the second dose of the 
investigational RSV vaccine (for either Bexsero or Nimenrix or NeisVac-C). To 
accommodate the various vaccination schedules of the meningococcalactive comparator
vaccines across countries, salineFB may also be offered once during the two to three 
additional vaccinations given to complete the comparator vaccine schedule in the study 
(refer to see Figure 1 and Table 2).
The Section 1.2.7. Rationale for ChAd155 RSV vaccine recipients receiving 
meningococcal active comparator vaccine, was amended as follows:
To provide benefit to all trial participants and to maintain the study blind until the end of 
follow up, the ChAd155-RSV vaccine recipients will also receive immunization with the 
selected meningococcalactive comparator vaccine.
The Section 1.3. Benefit : Risk Assessment, was amended as follows:
HalfApproximately two thirds of the infants (50100) in this study will be exposed to the 
ChAd155-RSV vaccine, whereas all infants will receive either an active control 
comparator vaccine (Bexsero, or Nimenrix, or Synflorix, or Menveo,), or NeisVac-
C)*Placebo (see Figure 1 and Table 2).
* The choice of active control comparator vaccine or Placebo is done at the country 
level.
Please refer to the current IB for the summary of potential risks and benefits of 
ChAd155-RSV vaccine.
 
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Please refer to the local Prescribing Information for information regarding the summary 
of potential risks and benefits of Bexsero, Nimenrix, Synflorix and Menveo and NeisVac-
C.
In Section 1.3.1. Risk Assessment, was amended as follows:
Syncope (fainting) can occur following or even before any vaccination as a psychogenic 
response to the needle injection. Therefore, it is important that procedures are in place to 
avoid injury from fainting.
A broad safety hematology and biochemistry evaluation was performed at each study 
visit in adults during study RSV PED-001 (201974). In this study, no significant safety 
concerns were identified up to 30 days post Dose 2 in healthy adults aged 18 to 45 years
(refer to Section 1.1.7 and to the current IB). Hematology and biochemistry parameters 
are also being intensively evaluated in RSV-seropositive infants aged 12 to 23 months 
during study RSV PED-002 (204838).
No significant safety concerns were identified up to 30 days post Dose 2 in study RSV 
PED-001 with the ChAd155-RSV vaccine in healthy adults aged 18 to 45 years (refer to 
Section  and to the current IB).
Risks linked to the active control comparator meningococcal vaccines
Refer to the local Prescribing Information for potential risks and contraindications related 
to Bexsero, Nimenrix, Synflorix or Menveo or NeisVac-C vaccines.
The Section 1.3.2. Benefit Assessment, was amended as follows
The choice of meningococcalactive comparator vaccine (Bexsero, Nimenrix, Synflorix, 
or Menveo or NeisVac-C) for each participating country ensures that the vaccine may be 
given according to the local label and provides medical benefit in the country. AllWithin 
a given participating country, all infants in both groups of this study will receive the full 
locally recommended vaccination course of meningococcalactive comparator vaccine 
where possible and may be immunized against either invasive meningococcal disease 
caused by Neisseria meningitidis. (with the meningococcal vaccines Bexsero, Nimenrix
or Menveo); or against invasive pneumococcal disease and acute otitis media caused by 
Streptococcus pneumoniae (with the pneumococcal vaccine Synflorix).
The Section 1.3.3. Overall Benefit:Risk Conclusion, was amended as follows
The four meningococcal comparatorcontrol vaccines administered to all participants in 
this study as active controlscomparators, are licensed for infants in the particular country 
where possible, and therefore have demonstrated medical benefit in the prevention of 
invasive meningococcal disease caused by Neisseria meningitidis. (for the 
meningococcal vaccines Bexsero, Nimenrix, Menveo); or against invasive 
pneumococcal disease and acute otitis media caused by Streptococcus pneumoniae (for
the pneumococcal vaccine Synflorix).
 
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The Section 2.1. Primary objectives was amended as follows:

To evaluate the safety and reactogenicity of the RSV investigational vaccine (5x1010
vp) when administered IM as one (1.5x1010 vp) dose or as two IM(5x1010 vp) doses 
according to a 0, 1-month schedule, up to 30 60 days after Dose 21 (i.e., Day 61) in 
infants aged 6 and 7 months.
The Section 2.2. Secondary objectives was amended as follows:

To evaluate the occurrence of RSV respiratory tract infections of any severity from 
Visit 1 (Day 1, after Dose 1) up to the end of the first RSV transmission season, in 
infants aged 6 and 7 months.

To evaluate the safety of two IM doses of the RSV investigational vaccine (5x1010
vp) when administered IM as one (1.5x1010 vp) dose or as two (5x1010 vp) doses 
according to a 0, 1-month schedule, from study start (Day 1) up to the end of the 
second RSV transmission season in infants aged 6 and 7 months.

To evaluate the occurrence of very severe RSV-LRTI from Visit 1 (Day 1, after 
Dose 1) up to the end of the first RSV transmission season in RSV infected infants 
aged 6 and 7 months with a negative RSV exposure status (at screening based on 
in-stream baseline serological testing).

To evaluate the humoral immunogenicity induced by two IM doses of the RSV 
investigational vaccine (5x1010 vp) when administered IM as one (1.5x1010 vp) dose 
or as two (5x1010 vp) doses according to a 0, 1-month schedule, from study start 
(Day 1) up to the end of the first RSV transmission season, in infants aged 6 and 7 
months.
The Section 2.3. Tertiary objectives was amended as follows:

If deemed necessary, to further characterize the immune response of the RSV 
investigational vaccine when one (1.5x1010 vp) dose or two IM(5x1010 vp) doses are
administered IM according to a 0, 1-month schedule into infants aged 6 and 7 
months.
 
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The Section 3. STUDY DESIGN OVERVIEW was amended as follows:
Old Study Design Figure 1
End of RSV 
season 2
IDMC review b
SE to D8
= Blood sample for safety
BSS
BSS
Surveillance period for RSV RTI a
BSH
BSH
BSH
= Blood sample for humoral immunogenicity
BSH
Nasal swab, as applicable c
BSH
Vaccination phase
FU phase
Screening
Epoch 002
Epoch 003
Epoch 004
Epoch 001
D121
V6 ‡
D61
V5
End of RSV 
season 1
V7
V8 †
D1
D8
D31
D38
V1*
V2 †
V3
V4 †
Visit
Day
SCREENING
D-30 to D-1
IDMC/iSRC review b
SE to D8
RSV+Bexsero (N=15**)
RSV
Dose 1
Dose 2
Bexsero (N=15**)
Bexsero
Bexsero
Bexsero
Bexsero
Saline
Bexsero
Bexsero
Saline
RSV+Nimenrix (N=15**)
RSV
RSV
Nimenrix (N=15**)
Nimenrix
Nimenrix
Nimenrix
Nimenrix
Saline
Nimenrix
Nimenrix
Saline
RSV+Menveo
(N=15**)
RSV
RSV
Menveo
(N=15**)
Menveo
Menveo
Saline
Menveo
Saline
Menveo
RSV+NeisVac-C (N=5**)
RSV
RSV
NeisVac-C (N=5**)
NeisVac-C
NeisVac-C
NeisVac-C
NeisVac-C
Saline
NeisVac-C
NeisVac-C
Saline
RSV
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New Study Design Figure 1
End of RSV 
season 2
SE to D8
= Blood sample for safety
BSS
BSS
Surveillance period for RSV RTI a
BSH
BSH
BSH
= Blood sample for humoral immunogenicity
BSH
Nasal swab, as applicable c
BSH
Vaccination phase
FU phase
Screening
Epoch 002
Epoch 003
Epoch 004
Epoch 001
D121
V6 ‡
D61
V5
End of RSV 
season 1
V7
V8 †
D1
D8
D31
D38
V1*
V2 †
V3
V4 †
Visit
Day
SCREENING
D-30 to D-1
IDMC/iSRC review b
SE to D8
2D RSV+Bexsero
2D RSV
Dose 1
Dose 2
Bexsero
Bexsero
Bexsero
Bexsero
Bexsero
FB
Bexsero
Bexsero
FB
2D RSV+Nimenrix
2D RSV
2D RSV
Nimenrix
Nimenrix
Nimenrix
Nimenrix
Nimenrix
FB
Nimenrix
Nimenrix
FB
2D RSV+Menveo
2D RSV
2D RSV
Menveo
Menveo
Menveo
FB
Menveo
FB
Menveo
2D RSV+Synflorix
2D RSV
2D RSV
Synflorix 
Synflorix
Synflorix
Synflorix
FB
Synflorix
Synflorix
Synflorix
FB
2D RSV
1D RSV+Bexsero
1D RSV
Bexsero
Bexsero
Bexsero
FB
1D RSV+Nimenrix
1D RSV
FB
Nimenrix
Nimenrix
Nimenrix
1D RSV+Menveo
1D RSV
FB
Menveo
Menveo
1D RSV+Synflorix
1D RSV
FB
Synflorix
Synflorix
Synflorix
IDMC review b
2D RSV+ Placebo
2D RSV
2D RSV
Placebo   
FB
FB
1D RSV+ Placebo
1D RSV
FB
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D: Day; FU: follow-up; IDMC: Independent Data Monitoring Committee; iSRC: internal Safety Review Committee; RSV: respiratory syncytial virus; RTI: respiratory tract infection; SE: 
solicited events; V: Visit 1D: 1 Dose (1.5x1010 vp/dose); 2D: 2 Dose (5x1010 vp/dose); FB: Formulation buffer S9b.
* Vaccine Dose 1 at Day 1 will be administered before the first RSV season (refer to Section 5.1 for definition of RSV season).
** Total number of infants in administered the ChAd155-RSV vaccine = approximately 50 and in the active control comparator groups = approximately 50.
† Visit 2 (Day 8), Visit 4 (Day 38), and Visit 8 (Day 730) (no blood sampling for immune response and no vaccine administration) may take place in the subject’s home or at the 
investigators clinical facility as appropriate to the circumstances in the judgment of the investigator. For the United Kingdom (UK) only, Visit 5 (Day 61) and Visit 7 (both with 
blood sampling) may also take place in the subject’s home or at the investigators clinical facility as appropriate to the circumstances in the judgment of the 
investigator.)
‡ In countries where Menveo or Placebo is used as a comparator, no administration will be performed at Day 121 and therefore in those countries there will be no Visit 6 and it will be 
administered at the end of the first RSV season at Visit 7 (refer to Table 2 and Table 7).
a Surveillance for RSV-RTI comprises monthly nasal swab collected to detect asymptomatic RSV infections during RSV season and active and passive surveillance contacts for RSV 
symptomatic RTI. Of note the swab may be omitted if a nasal swab has been taken at a symptomatic visit in the same month (see Section 9.2). Data about RSV–RTI incidence 
will be reviewed monthly by an IDMC.
b An iSRC will review all accumulating safety data monthly until the IDMC reviews has reviewed all safety data up to 30 days after administration of Dose 2 (i.e., Day 61). The IDMC will 
review all accumulating safety data monthly throughout the period of vaccination and accumulating SAEs until the end of the second RSV transmission season. Refer to Sections 
9.10.2 and 9.10.3.
c Refer to Section 6.6.12.3.
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Old Vaccines administered and vaccination schedules Table 2
Groups
Age* (Months) / (Visit, Day)
6-7 / (V1, D1)
7-8 / (V3, D31) 8-9 / (V5, D61)
10-11 / (V6, D121)**
14-18 / (V7)
RSV + Bexsero
RSV ChAd
RSV ChAd
Bexsero
Bexsero
Bexsero
Bexsero
Bexsero
Saline
Bexsero
Saline
Bexsero
RSV + Nimenrix
RSV ChAd
RSV ChAd
Nimenrix
Nimenrix
Nimenrix
Nimenrix
Nimenrix
Saline
Nimenrix
Saline
Nimenrix
RSV + Menveo
RSV ChAd
RSV ChAd
Menveo
Menveo
Menveo
Saline
Menveo
Saline
Menveo
RSV + NeisVac-C
RSV ChAd
RSV ChAd
NeisVac-C
NeisVac-C
NeisVac-C
NeisVac-C
NeisVac-C
Saline
NeisVac-C
Saline
NeisVac-C
New Vaccines administered and vaccination schedules Table 2
Groups
Age* (Months) / (Visit, Day)
6-7 / (V1, D1)
7-8 / (V3, D31) 8-9 / (V5, D61)
10-11 / (V6, D121)**
14-18 / (V7, D365)
1D RSV + Bexsero
1D RSV ChAd FB
Bexsero
Bexsero
Bexsero
2D RSV + Bexsero
2D RSV ChAd 2D RSV ChAd Bexsero
Bexsero
Bexsero
Bexsero
Bexsero
FB
Bexsero
FB
Bexsero
1D RSV + Nimenrix
1D RSV ChAd FB
Nimenrix
Nimenrix
Nimenrix
2D RSV + Nimenrix
2D RSV ChAd 2D RSV ChAd Nimenrix
Nimenrix
Nimenrix
Nimenrix
Nimenrix
FB
Nimenrix
FB
Nimenrix
1D RSV + Synflorix
1D RSV ChAd FB
Synflorix
Synflorix
Synflorix
2D RSV + Synflorix
2D RSV ChAd 2D RSV ChAd Synflorix
Synflorix
Synflorix
Synflorix
FB
Synflorix
Synflorix
FB
Synflorix
1D RSV + Menveo
1D RSV ChAd FB
Menveo
Menveo
2D RSV + Menveo
2D RSV ChAd 2D RSV ChAd Menveo
Menveo
Menveo
FB
Menveo
FB
Menveo
1D RSV + Placebo
1D RSV ChAd FB
2D RSV + Placebo
2D RSV ChAd 2D RSV ChAd
Placebo
FB
FB
V: Visit; D: Day; 1D: 1 Dose (1.5x1010 vp/dose); 2D: 2 Dose (5x1010 vp/dose); RSV ChAd: Treatment with ChAd155-
RSV vaccine (5x1010 vp); V: Visit.; FB: Formulation buffer S9b.
* Assumes enrolled at 6 and 7 months of age for the vaccine Dose 1 to be administered before the first RSV season; 
the second dose will be given one month after the first dose. (RSV seasons will be determined for each 
country based on local epidemiological data [The RSV season is defined as the period of the year when 70% of 
the RSV cases have occurred in previous years. For the calculation, where available, data from up to the ten 
previous years should be applied. If the data permit calculation of the actual date of the beginning of the season, 
rather than approximation to the nearest month, this is desirable. Refer to the SPM for RSV seasons per 
site.])country.])
** In countries where Menveo or Placebo is used as a comparator, no administration will be performed at Day 121 and 
therefore in those countries there will be no Visit 6 and it will be administered at the end of the first RSV season at 
Visit 7.
 
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
Experimental design: Phase I/II, N/Aobserver-blind, randomized, controlled, multi-
centric study with twothree parallel groups.

Epoch 004: follow-up starting after Visit 7 (end of the secondfirst RSV 
transmission season)* and ending at Visit 8 (end of the second RSV 
transmission season).
*Any safety, immunogenicity and disease surveillance data collected beyond
Visit 5 (Day 61) will be collected in Epoch 003. Any safety, immunogenicity 
and disease surveillance data collected beyond Visit 7 (end of the first RSV 
transmission season) will be collected in Epoch 004. Refer to the SPM for RSV 
transmission seasons per country.
** Refer to the SPM for RSV transmission seasons per site.

Primary Completion Date (PCD): Visit 5 (Day 61).
Refer to glossary of terms for the definition of PCD.

End of Study (EoS): Last testing results released of samples collected at Visit 8 (end 
of the second RSV transmission season).*) related to primary and secondary 
endpoints.*)
* Up to Visit 8 (end of the second RSV season), there will be monthly nasal swab to 
detect asymptomatic RSV infections during the RSV season andor if following 
active or a passive surveillance contacts, a subject presents symptoms of respiratory 
tract infection (RTI), a nasal swab will be collected.
Refer to the glossary of terms for the definition of EoS.
Old Study groups and epochs foreseen in the study Table 3
Study groups
Number of 
subjects*
Age (Min/Max)
Epochs
Epoch 001
Epoch 002
Epoch 003
Epoch 004
RSV + Bexsero
15 **
6  – 7 months
x
x
x
x
RSV + Nimenrix
15 **
6 – 7 months
x
x
x
x
RSV + Menveo
15 **
6 – 7 months
x
x
x
x
RSV + NeisVac-C
5 **
6 – 7 months
x
x
x
x
Bexsero
15 **
6 – 7 months
x
x
x
x
Nimenrix
15 **
6 – 7 months
x
x
x
x
Menveo
15 **
6 – 7 months
x
x
x
x
NeisVac-C
5 **
6 – 7 months
x
x
x
x
 
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New Study groups and epochs foreseen in the study Table 3
Study groups
Numbers of 
subjects*
Age (Min/Max)
Epochs
Epoch 001
Epoch 002
Epoch 003
Epoch 004
1D RSV + Bexsero
50**
6 – 7 months
N/A
x
x
x
1D RSV + Nimenrix
6 – 7 months
N/A
x
x
x
1D RSV + Synflorix
6 – 7 months
N/A
x
x
x
1D RSV + Menveo
6 – 7 months
N/A
x
x
x
1D RSV + Placebo
6 – 7 months
N/A
x
x
x
2D RSV + Bexsero
50**
6 – 7 months
N/A
x
x
x
2D RSV + Nimenrix
6 – 7 months
N/A
x
x
x
2D RSV + Synflorix
6 – 7 months
N/A
x
x 
x
2D RSV + Menveo
6 – 7 months
N/A
x
x
x
2D RSV + Placebo
6– 7 months
N/A
x
x
x
Bexsero
50**
6 – 7 months
N/A
x
x
x
Nimenrix
6 – 7 months
N/A
x
x
x
Synflorix
6 – 7 months
N/A
x
x
x
Menveo
6 – 7 months
N/A
x
x
x
Placebo
6 – 7 months
N/A
x
x
x
1D: 1 Dose (1.5x1010 vp/dose); RSV: ChAd155-RSV vaccine; 2D: 2 Dose (5x1010 vp)./dose); N/A: Not Applicable.
* Note that across allfor both 1D and 2D RSV vaccine + active comparator/placebo groups the total number of 
subjects is 50100 and that for eachboth RSV vaccine + active comparator/placebo groups there will be a 1:1:1
ratio maintained with the samecorresponding active comparator./placebo group.)
** Note that these numbers of subjects anticipated to receive the control vaccines within participating countries 
are approximation ofnot yet known, but the distribution and supplies will be prepared to allow flexible enrolment 
across countries (for any comparator the range of subjects is 0 – 50 may be enrolled) but the overall total of 1500
subjects will be respected.
Old Study groups and treatment foreseen in the study Table 4
Treatment 
name
Vaccine/ 
Product name
Study Groups
RSV + 
Bexsero
RSV + 
Nimenrix
RSV + 
Menveo
RSV + 
NeisVac-C Bexsero Nimenrix Menveo
NeisVac-C
RSV ChAd ChAd155-RSV
x
x
x
x
Saline
FB
x
x
x
x
Bexsero
Bexsero
x
x
Nimenrix
Nimenrix
x
x
Menveo 
x
x
NeisVac-C
Neiss Vac-C
x
x
 
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New Study groups and treatment foreseen in the study Table 4
Treatment name
1D RSV ChAd
2D RSV ChAd
Bexsero
Nimenrix
Synflorix
Menveo
FB
Vaccine/ 
Product name
1D ChAd155-RSV 
1.5X1010vp/dose
2D ChAd155-RSV
5X1010 vp/dose
Bexsero
Nimenrix
Synflorix
Menveo
FB
Study Groups
1D RSV + Bexsero
x
x
x
1D RSV + Nimenrix
x
x
x
1D RSV + Synflorix
x
x
x
1D RSV + Menveo
x
x
x
1D RSV + Placebo
x
x
2D RSV + Bexsero
x
x
2D RSV + Nimenrix
x
x
2D RSV + Synflorix
x
x
2D RSV + Menveo
x
x
2D RSV + Placebo
x
Bexsero
x
x
Nimenrix
x
x
Synflorix
x
x
Menveo
x
x
Placebo
x
ChAd155-RSV: Chimpanzee Adenovirus Type 155 RSV vaccine (5x1010 vp); FB: Formulation buffer S9b; RSV ChAd: 
Treatment with ChAd155-RSV vaccine; 1D: 1 Dose (1.5x1010 vp/dose); 2D: 2 Dose (5x1010 vp)./dose).

Control: meningococcal vaccineControls: active controlscomparator vaccines
(Bexsero, or Nimenrix, or Synflorix, or Menveo, or NeisVac-C) and saline 
(Formulation buffer S9b).*Placebo (FB)*.
* The choice of active control comparator meningococcal vaccine (Bexsero,
Nimenrix, Synflorix, or Menveo) or NeisVac-C)Placebo is done at the country 
level. Refer to the ICF for the local choice of comparator/Placebo.

Vaccination schedules:

RSV investigational vaccine:
o
In the 1 Dose (1D) groups, a single lower dose of 1.5x1010 vp will be 
administered IM at Day 1 (Visit 1). Formulation buffer will be 
administered in the 1D groups at Day 31 (Visit 3). In the 2 Dose (2D) 
groups, two IM vaccine doses of 5x1010 vp will be administered IM 
according to a 0, 1-month schedule, (i.e., at Day 1 [Visit 1] and Day 31 
[Visit 3]) (see Figure 1 and Table 2) (Dose 1 will be administered before 
the first RSV season [and the second dose will be given one month after 
the first dose (RSV seasons will be determined for each country based on 
local epidemiological data. and documented in the Study Procedures 
Manual [SPM]. The RSV season is defined as the period of the year when 
70% of the RSV cases have occurred in previous years. For the calculation, 
where available, data from up to the ten previous years should be applied. If 
the data permit calculation of the actual date of the beginning of the season, 
rather than approximation to the nearest month, this is desirable. Refer to 
the SPM for RSV seasons per site.]).
 
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
Comparator or Placebo:
o
In countries where Bexsero or Nimenrix For Bexsero, Nimenrix, and 
NeisVac-C is used as a control, two primary doses will be administered IM 
with at least a 2 month interval with abetween these primary doses. A
booster dose will be administered IM in the second year of life (at Day 365
(Visit 7), with an interval of at least 2 months between the primary series 
and booster dose. The first Bexsero or Nimenrix dose will be administered 
at Day 1 (Visit 1) (in the groups receiving only Bexsero or Nimenrix, 
respectively). In the groups receiving only Bexsero or Nimenrix, the 
second dose will be at Day 61 (Visit 5). The first Bexsero or Nimenrix
dose to be administered to the 1D and 2D RSV groups will be at Day 61 
(Visit 5), following the 1 or 2 RSV vaccine doses, respectively. The second 
dose of Bexsero or Nimenrix in the 1D and 2D groups will be at Day 121 
(Visit 6). Formulation buffer will be administered, when neither RSV 
vaccine nor comparator is scheduled, at the 5 vaccination visits (see 
Figure 1 and Table 2).
o
In countries where Synflorix is used as a control, two doses will be 
administered IM with at least a 1 month interval between these primary 
doses. A booster dose will be administered IM in the second year of life at 
Day 365 (Visit 7). The first Synflorix dose will be administered at Day 31 
(Visit 3) (in the group receiving only Synflorix). In the group receiving 
only Synflorix, the second dose will be at Day 61 (Visit 5). The first 
Synflorix dose to be administered to the 1D and 2D RSV groups will be at 
Day 61 (Visit 5), following the 1 or 2 RSV vaccine doses, respectively. The 
second dose of Synflorix in the 1D and 2D groups will be at Day 121 
(Visit 6). Formulation buffer will be administered, when neither RSV 
vaccine nor comparator is scheduled, at the 5 vaccination visits (see
Figure 1 and Table 2).
o
In countries where Menveo is used as a control, two doses will be 
administered IM at least 3 months apart with the second dose in the second 
year of life. at Day 365 (Visit 7). The first Menveo dose will be 
administered as a comparator at Day 31 (Visit 3 (opposing the second RSV 
vaccine dose) from 7 months of age.) (in the group receiving only 
Menveo). The first Menveo dose to be administered to the 1D and 2D RSV 
groups will be at Day 61 (Visit 5), following the 1 or 2 RSV vaccine 
administrations.doses, respectively. Since the second Menveo dose has to be 
administered in the second year of life, at Day 365 (Visit 7), no 
administration will be performed at Day 121 and therefore in those 
countries the second Menveo dose(Visit 6). Formulation buffer will be at 
Visit 7, at the end of the first RSV season (refer toadministered, when 
neither RSV vaccine or comparator is scheduled, at the 4 vaccination 
visits (see Figure 1 and Table 2).
o
In countries where Placebo is used as a control, one dose will be 
administered IM at Day 31 (Visit 3) in the 1D RSV + Placebo group and 
two IM doses will be administered IM according to a 0, 1-month schedule
at Day 1 (Visit 1) and Day 31 (Visit 3) in the Placebo group (see Figure 1
and Table 2).
 
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
Treatment allocation: infants will be randomized using a centralized randomization 
system on internet (SBIR) before first vaccination and after assessment of eligibility 
(i.e., after screening conclusion) (refer to Section 6.2.2 for details about 
randomization of treatment). The randomization algorithm will use a minimization 
procedure accounting for country. as a minimization factor and the grouping 
comparator/placebo as a stratification factor.

Sampling schedule:

Nasal swab: there will be monthly nasal swab to detect asymptomatic RSV 
infections during the RSV season and if following active or a passive 
surveillance contacts, a subject presents symptoms of RTI, a nasal swab will be 
collected. (as well as a sample for local testing i.e., the type of sample to be 
determined locally [e.g., swab, etc.]) (Refer to the SPM).

Study visits: Other than the screening visit and assessment visits for active/passive 
surveillance, there will be 8 study visits except in countries where Menveo or 
Placebo is used as a control where there will be 7 study visits. 

In countries where Menveo is used as a comparator, no administration will be 
performed at Day 121 and therefore in those countries there will be no Visit 6 
and it will be administered at the end of the first RSV season at Visit 7 (refer to 
Table 2 and Table 7). Visit 2 (Day 8), Visit 4 (Day 38), and Visit 8 (Day 730) 
(no blood sampling for immune response and 

In countries where Placebo is used as a control, no vaccine administration) 
may take place will be performed after Visit 3 and therefore in the subject’s 
home orthose countries there will be no Visit 6. There will be a Visit 5 and 
Visit 7 for countries using Placebo and all other study procedures will occur at 
the investigators clinical facility as appropriate to the circumstances in the 
judgment of the investigator.these visits except vaccination.

Visit 2 (Day 8), Visit 4 (Day 38), and Visit 8 (Day 730) (no blood sampling for 
immune response and no vaccine administration) may take place in the 
subject’s home or at the investigators clinical facility as appropriate to the 
circumstances in the judgment of the investigator.
o
For the United Kingdom (UK) only, Visit 5 (Day 61) and Visit 7 (both with 
blood sampling) may also take place in the subject’s home or at the 
investigators clinical facility as appropriate to the circumstances in the 
judgment of the investigator.
Subjects’ parent(s)/LAR(s) will be instructed to contact the investigator/study staff if 
their child presents symptoms of spontaneous bleeding or easy bruising or if their child 
develops a rash, within 30 days after either vaccination, in order to detect any 
thrombocytopenic petechiae or purpura. The investigator will, based on his/her medical 
judgment, measure the total blood count and appropriately investigate infants with 
clinical suspicion of low platelets.
 
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In the Section 4.1. RTI case definitions, the Case definitions for data analysis Table 
6 was amended as follows:
Case
At sea level up to 2500 meters elevation
Above 2500 meters elevation
RSV-RTI
Runny nose OR blocked nose OR cough
AND 
Confirmed RSV infection 4
Same
RSV-LRTI
History of cough OR difficulty breathing 1
AND
SpO2 < 95% 2, OR RR increase 3
AND
Confirmed RSV infection 4
Same but with SpO2 <92%
RSV severe RSV-LRTI
Meeting the case definition of RSV-LRTI 
AND
SpO2 < 93% 2, OR lower chest wall in-
drawing
Same but with SpO2 <90%
RSV very severe RSV-
LRTI
Meeting the case definition of RSV-LRTI 
AND 
SpO2 < 90% 2, OR inability to feed, OR 
failure to respond / unconscious
Same but with SpO2 <88%
RSV hospitalization
Confirmed RSV infection 5
AND
Hospitalized for acute medical condition 6
Same
All-cause LRTI
History of cough OR difficulty breathing 1
AND 
SpO2 < 95% 2, OR RR increase 3
Same but with SpO2 <92%
LRTI = lower respiratory tract infections; RR = respiratory rate; RTI = respiratory tract infections; SpO2 = blood oxygen 
saturation.
Based on [Modjarrad, 2016]
1 Based on history reported by parents/LARs and includes difficulty breathing (e.g., showing signs of wheezing or 
stridor, tachypnoea, flaring [of nostrils], chest in-drawing, apnoea) associated with nasal obstruction.
In Section 5. STUDY COHORT, the Section 5.1. Number of subjects was amended as 
follows:
The target will be to enroll approximately 1500 infants (50 infants in the vaccine group 
and 50 infants in the control group) aged 6 and 7 months at the time of first vaccination, 
likely to be previously unexposed to RSV. with about 50 infants for each of three 
randomization groups. If necessary, the sample size will be increased through 
additional recruitment in order to achieve at least 5 RSV infected infants, with a 
negative RSV exposure status (at screening based on in-stream serological testing), in 
each RSV vaccine group. Dose 1 administration should be completed before the first 
RSV season and second dose will be given one month after the first dose (RSV seasons 
will be determined for each country based on local epidemiological data [and 
documented in the SPM. The RSV season is defined as the period of the year when 70% 
of the RSV cases have occurred in previous years. For the calculation, where available, 
data from up to the ten previous years should be applied. If the data permit calculation of 
the actual date of the beginning of the season, rather than approximation to the nearest 
month, this is desirable. Refer to the SPM for RSV seasons per site.]).country. Refer to 
Section 11.4 for the determination of sample size.
 
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In the Section 5.3. Exclusion criteria for enrolment the following changes have been 
made:

Chronic administration (defined as more than 14 days in total) of 
immunosuppressants or other immune-modifying drugs during the period starting six 
months prior to the first vaccine. For corticosteroids, this will mean prednisone 0.5 
mg/kg/day (for pediatric subjects), or equivalent. Inhaled and topicalTopical steroids 
are allowed.

History of recurrent wheezing. ((“Recurrent wheezing” is defined as ≥ 2 episodes of 
wheezing in the past 12 months). Wheezing should have been verified on 
auscultation by doctor).

History of any reaction or hypersensitivity likely to be exacerbated by any 
component of the vaccines (investigational or control) or placebo used in this study 
or any contraindication to them.

Concurrently participating in another clinical study, at any time during the study 
period, in which the subject or mother has been or will be exposed to an 
investigational or a non-investigational vaccine/product (pharmaceutical product or 
device).

For Thailand only, subjects who have received Synflorix prior to enrolment.)
In the Section 6.2.2.2. Treatment allocation to the subject the following change was
made:
The treatment numbers will be allocated by dose.components.
The Section 6.2.2.2.1. Study group and treatment number allocation was amended as 
follows:
The target will be to enroll approximately 1500 infants to ensure that 50 infants receive at 
least one dose of RSV investigational vaccine. Approximately 50 infants likely to be 
previously unexposed to RSV will be randomly assigned to receive 2 doses at 0, 1 month 
schedule of 0.5 mL of the ChAd155-RSV vaccine (5x1010 vp) [the 2D RSV + 
comparator group], approximately 50 infants likely to be previously unexposed to RSV 
will be randomly assigned to receive a single dose of 0.5 mL of ChAd155-RSV vaccine 
(1.5x1010 vp) [the 1D RSV + comparator group], and approximately 50 infants likely to 
be previously unexposed to RSV will be randomly assigned to receive 0.5 mL of the 
activecomparator/Placebo control comparator vaccine. [the comparator/Placebo control 
alone group].
Allocation of the subject to a study group at the investigator site will be performed using 
a randomization system on internet (SBIR) operated at the study level.
The randomization algorithm will assign each subject to either anthe 2 doses of RSV 
vaccine + comparator vaccine group, the single dose of RSV vaccine + comparator 
group, or its corresponding active control comparator group with the aim of keeping the 
ratio between the pooled 2 dose RSV group + comparator group, the pooled single dose 
RSV + comparator group and the pooled comparator group at 1:1:1 in the entire study 
(see Table 25 for a description of pooled groups).
 
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Countries will be grouped into fourfive levels according to the choice of comparator 
vaccine and the grouping factor will be applied as a single factor (the only factor) in the 
minimization or Placebo, the randomization algorithm will use a minimization 
procedure accounting for country as a minimization factor and the grouping 
comparator/placebo as a stratification factor to assure thatattempt to maintain a 1:1:1
ratio is maintainedas well within each level in the assignment of RSV + comparator 
vaccine versus comparator /Placebo control vaccine alone.
The actual randomization assignment the subject received (to one of four five 2 dose of
RSV + comparator vaccine groups or, to one of four active control five single dose of 
RSV + comparator vaccine groups, or to one of five comparator/Placebo control alone 
groups) will be able to be identified in SBIR.
 
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In Section 6.5. Outline of study procedures, the List of study procedures Table 7 had the following key changes:
Epoch
Epoch 001
Epoch 002
Epoch 003
Epoch 004
Age
6-7 months
6-9 months
Type of contact
Screening Visit 1 Visit 2 b Visit 3 Visit 4 b Visit 5 Visit 6 c
Visit 7
Visit 8 b 
Unscheduled 
visit for 
safety e
Contact for 
active/ 
passive 
surveillance f 
Surveillance 
for 
asymptomatic 
RSV-RTI g 
Assessment 
of potential 
RSV-RTI h 
Timepoints
D -30 to
D-1 a
D1
D8
D31
D38
D61
D121
D365 
end of the 
1st RSV 
season d
D730 
end of the 
2nd RSV 
season d
Monthly or 
Weekly
Monthly
30 minutes post-vaccination 
observation for additional 
comparator/salineFB vaccinations
O
O
O
Surveillance for RSV-RTI, difficulty in 
breathing and wheezing
O
O
O
O
O
O
O
O
●O
●O
Recording of AESI (spontaneous or 
excessive bleeding) z
●
●
●
●
●
●
Reporting of easy bruising, or
rash/petechiae monitored by 
parent(s)/LAR(s) z
O
O
O
O
O
AE: adverse event; AESI: Adverse Events of Special Interest; FB: Formulation buffer S9b; LRTI: lower respiratory tract infection; RSV: respiratory syncytial virus; RTI: respiratory 
tract infection, RVP: respiratory viral panel SAE: serious adverse event.
bVisit 2 (Day 8), Visit 4 (Day 38), and Visit 8 (Day 730) (no blood sampling for immune response and no vaccine administration) may take place in the subject’s home or at 
the investigators clinical facility as appropriate to the circumstances in the judgment of the investigator. Visit 5 (Day 61) and Visit 7 (both with blood sampling) may 
also take place in the subject’s home or at the investigators clinical facility as appropriate to the circumstances in the judgment of the investigator.
c In countries where Menveo or Placebo is used as a comparator, no administration will be performed at Day 121 and therefore in those countries there will be no Visit 6 and it will be 
administered at the end of the first RSV season at Visit 7 (refer to Figure 1 and ).Table 2).
d Refer to the SPM for RSV seasons per site.country.
rIf no blood sample was collected for humoral immunogenicity at the screening visit, an additional blood sample will be taken at Visit 1 that mustSamples to be taken 
before vaccination.
sSamples must be taken before vaccination.
z Subjects’ parent(s)/LAR(s) will be instructed to contact the investigator/study staff if their child presents symptoms of spontaneous bleeding or easy bruising or if their child develops a 
rash, within 30 days after either vaccination, in order to detect any thrombocytopenic petechiae or purpura. (see Table 19).
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The footnotes in the Intervals between study visits Table 8 have been amended as 
follows:
1 Visit 1 should take place no longer than 30 days after the Screening visit. When applicable, a re-screening visit may 
be scheduled at any time (but only once to assess eligibility; blood for humoral response will not be re-sampled).
All screening procedures need to be performed within 30 days of Visit 1.
2 In countries where Menveo or Placebo is used as a comparator, no administration will be performed at Day 121 and 
therefore in those countries there will be no Visit 6 and it will be administered at the end of the first RSV season at 
Visit 7 (refer to Figure 1and Table 2).
In Section 6.6.11. Study vaccines administration, the following change has been made:
The subjects will be observed closely (visual follow-up as well as measurement of resting 
vital signs) for at least 60 minutes following the administration of the vaccines at Visit 1 
and Visit 3, with appropriate medical treatment readily available in case of anaphylaxis. 
Vital signs are body temperature, HR and RR. Vital signs are preferably measured when 
the infant is calm. After administration of comparator vaccines or salineFB at Visit 5, 
Visit 6 and Visit 7, the subjects will be observed closely (visual follow-up as well as 
measurement of resting vital signs) for at least 30 minutes following the administration of 
the vaccines, with appropriate medical treatment readily available in case of anaphylaxis.
In Section 6.6.12.1. Blood sampling for humoral immunity, the following changes
have been made:

Blood sampling for humoral response will not be repeated in case of insufficient 
volume, at any timepoint. except if no blood sample for humoral 
immunogenicity was collected at the screening visit. In that case an additional 
blood sample will be taken at Visit 1 that must be taken before vaccination.
In Section 6.6.12.2. Blood sampling for hematology and biochemistry, the following 
changes have been made:
Note: Blood canmay be re-sampled for hematology and biochemistry assessment during 
a re-screening visit (as described above) or during an Unscheduled Visit where there is 
clinical indication for additional testing.
In Section 6.6.12.3. Nasal swab andor other specimen for localPCR assay, the 
following changes have been made:
Nasal swab andor other specimen for localPCR assay collected during assessment 
visit
Real time assessment of potential RSV-LRTI cases is important for the timely monitoring 
of safety.
If during passive or active surveillance contact, the investigator/study staff assesses that 
an infant presents a potential RSV-RTI (refer to Section 9.2), a nasal swab andor another 
specimen for local assay will be collected during an assessment visit:

The nasal swab will allow assessing the potential RSV infection by quantitative RT-
PCR and respiratory viral panel (RVP) at sponsor laboratory.
 
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
The specimen for local assay will allow assessing the potential RSV infection and 
respiratory viral panel (RVP) at a local routine laboratory, where available. The 
specimen type will depend on the assay run locally.
Nasal swab collected for PCR assay to detect asymptomatic RSV infections
During RSV season, there will be monthly nasal swabs to detect asymptomatic RSV 
infections. These nasal swabs will allow assessing the potential RSV infection by 
quantitative RT-PCR atperformed centrally at the sponsor laboratory. This swab may be 
omitted upon investigator discretion if a swab has been taken for a symptomatic episode 
in the previous 4 weeks.
In the Section 6.7.2. Biological samples the Biological samples Table 9 was amended 
as follows:
Sample
Timepoint
Type of sample†
Subject
Number of 
subjects
Quantity
Blood
Screening
Blood sample for hematology and biochemistry
All infants
150
2.3 mL
Blood sample for humoral response 
All infants
150
2.5 mL
Total volume of blood collected for each subject
4.8 mL
Visit 3 (Day 31)
Blood sample for humoral response
All infants
150
2.5 mL
Visit 5 (Day 61)
Blood sample for humoral response
All infants
150
2.5 mL
Total volume of blood collected for each subject from Screening to Visit 5 (Day 61)*
9.8 mL
Visit 7 (end of the 
first RSV 
transmission 
season)
Blood sample for humoral response
All infants
150
2.5 mL
Assessment of 
potential RSV-RTI
Blood sampling for assessment of mechanisms 
of illness (potential ERD)
Hospitalization 
for RSV-LRTI 
(only for RSV-
positive 
subjects using 
a locally 
available RSV 
test)
Hospitalization 
for RSV-LRTI 
(only for RSV-
positive 
subjects using 
a locally 
available RSV 
test)
2.5 mL
Unscheduled visit 
for safety
Blood sample for hematology and biochemistry
Event-driven Event-driven
2.3 mL
Total volume of blood collected for each subject from Screening to Visit 8 (end of the 
second RSV transmission season)*
12.3 mL
Nasal 
swab
Assessment of 
potential RSV-RTI
Nasal swab**
Event-driven Event-driven
-
Surveillance for 
asymptomatic 
RSV-RTI
Nasal swab***
All infants
150
-
† The priority ranking in blood sampling is hematology > biochemistry > humoral response.
Venipuncture will not be repeated for humoral response in case of insufficient volume, at any timepoint. except if no 
blood sample for humoral immunogenicity was collected at the screening visit. In that case an additional 
blood sample will be taken at Visit 1 that must be taken before vaccination.
* Total quantity of blood for each subject excludes any optional or unscheduled hematology and biochemistry blood 
sampling or blood sample for assessment of mechanism of illness collected if a subject has been hospitalized for 
RSV-LRTI.
 
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** If during passive or active surveillance contact, the investigator/study staff assesses that an infant presents a 
potential RSV-RTI (refer to Table 6 for definition), the potential RSV infection will be assessed by quantitative RT-
PCR of nasal swab specimens taken at an assessment visit.
*** During RSV season, there will be monthly nasal swabs to detect asymptomatic RSV infections. These swabs will be 
tested by quantitative RT-PCR at sponsor laboratory.
These assays will be performed only on enrolled infants. and samples from non-enrolled subjects will be 
discarded.
In Section 6.7.3. Laboratory assays, the following changes have been made:
Determination of a negative RSV exposure status in infants at 6 to 7 months of age will 
be based on RSV A and/or B neutralizing antibody titers present in serum at screening 
(before vaccination with the RSV vaccine) based on in-stream baseline serological 
testing. At birth, newborns do show positive for neutralizing antibodies due to maternal 
transfer during gestation. The titer of these antibodies declines over time. At the age of 
6 to 7 months a cut-off can be defined below which infants are considered to have a 
negative RSV exposure status. Infants that show neutralizing antibody titers above this 
cut-off are suspected to have experienced a recent RSV infection. This cut-off will thus 
allow the discrimination between a negative RSV exposure status versus RSV infected 
infants before start of vaccination.
The following laboratory assays are planned:

Functional (neutralizing) antibody titers against RSV-A will be measured by a 
neutralization assay on serum samples (Table 10).

RSV F protein antibody concentrations and palivizumab-competing antibody 
concentrations will be determined by in-house ELISA on serum sample.

RTI will be assessed by:

Quantitative RT-PCR that is able to discriminate RSV-A and RSV-B subtypes 
(Table 11).

Qualitative multiplex PCR for detection of a panel of viruses (Table 11).

Local RSV assay, and local RVP where available (Table 11).
Final confirmation of RSV presence will be obtained through the definitive results 
from the central test.
The Humoral Immunity (Antibody determination) Table 10 was amended as follows:
System Component
Method
Kit / Manufacturer
Unit
Cut-off*
Laboratory**
SERUM Respiratory 
Syncytial 
Virus A Ab
NEUTRALIZATION
In-house
ED60
To be defined
GSK Biologicals1 or 
NÉOMED-LABS 
SERUM Respiratory 
Syncytial 
Virus F 
protein 
Ab.IgG
(Anti-RSV 
PreF 
antibody)
ELISA
In-house
EU/ml
To be defined
GSK Biologicals1 or 
NÉOMED-LABS1
 
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System Component
Method
Kit / Manufacturer
Unit
Cut-off*
Laboratory**
SERUM Respiratory 
Syncytial 
Virus F 
protein 
Ab.IgG 
(Palivizumab 
competing 
Ab)
ELISA
In-house
µg/ml
To be defined
GSK Biologicals1 or 
NÉOMED-LABS
Ab: antibody; ELISA: enzyme-linked immunosorbent assay; IgG: immunoglobulin G; RSV: respiratory syncytial virus
* Assay cut-off and unit might be subject to change during the course of the study (e.g., in case of requalification, 
revalidation or standardization). In this case, this will be documented in the clinical report.
The Molecular Biology (PCR tests) Table 11 was amended as follows:
System
Component
Kit / 
Manufacturer
Method
Unit
Laboratory*
Nasal swab
RSV A RNA
RSV B RNA
In-house
Quantitative
RT-PCR 
Copies/ml
GSK Biologicals1 
or designated 
laboratory
Nasal swab
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 
(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) 2
Allplex
Respiratory 
Panel 
(Seegene) or 
equivalent 2
Multiplex PCR 
(Luminex)
Qualitative assay 
(positive/ 
negative)
GSK Biologicals1 
or designated 
laboratory
 
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Additional testing may include, but is not limited to, the following:

Anti-vector immunity: neutralization.

RSV F protein antibody concentrations and palivizumab-competing antibody 
concentrations will be determined by in-house ELISA on serum sample.
The Hematology and biochemistry tests Table 12 was amended as follows:
System
Discipline
Component
Timepoint
Method
Scale
Laboratory
Whole blood Hematology
Hemoglobin
Screening
As per 
local 
practice
Quantitative
Local 
laboratory
Leukocytes (White Blood Cells)
Lymphocytes
Neutrophils
Platelets
Serum
Biochemistry
Alanine Aminotransferase
Screening
As per 
local 
practice
Quantitative
Aspartate Aminotransferase
Creatinine
At screening repeat testing may be performed once according to Figure 2. At any time 
during the trial additional hematology and/or biochemistry testing may be performed for 
the further investigation of a potential AE.
Collected samples may be used for purposes related to the quality assurance of the 
laboratory tests described in this protocol. This may include the management of the 
quality of these current tests, the maintenance or improvement of these current tests, the 
development of new test methods for the markers described in this protocol, as well as 
making sure that new tests are comparable to previous methods and work reliably.
 
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The Immunological read-outs Table 13 was amended as follows:
Blood sampling timepoint
No. 
subjects
Component
Components 
priority rank
Type of contact and 
timepoint
Sampling 
timepoint
System
Screening 
(Day -30 to Day -1)
Pre-Vaccination
Serum 
~ 150
Anti-RSV A Neutralizing Antibody
1
Respiratory Syncytial Virus F protein 
Ab.IgG (Anti-RSV PreF antibody)
2
Respiratory Syncytial Virus F protein 
Ab.IgG (Palivizumab competing Ab) 
3
Visit 3 (Day 31)
Post-Vaccination 1
Serum
~ 150
Anti-RSV A Neutralizing Antibody 
1
Respiratory Syncytial Virus F protein 
Ab.IgG (Anti-RSV PreF antibody)
2
Respiratory Syncytial Virus F protein 
Ab.IgG (Palivizumab competing Ab) 
3
Visit 5 (Day 61)
Post-Vaccination 2
Serum
~ 150
Anti-RSV A Neutralizing Antibody 
1
Respiratory Syncytial Virus F protein 
Ab.IgG (Anti-RSV PreF antibody)
2
Respiratory Syncytial Virus F protein 
Ab.IgG (Palivizumab competing Ab)
3
Visit 7 (end of the first 
RSV transmission 
season)
Post-Vaccination 2
Serum
~ 150
Anti-RSV A Neutralizing Antibody
1
Respiratory Syncytial Virus F protein 
Ab.IgG (Anti-RSV PreF antibody)
2
Ab: Antibody; IgG: immunoglobulin G; RSV: respiratory syncytial virus.
In case of insufficient blood sample volume to perform assays for all antibodies, the 
samples will be analysed according to priority ranking provided in Table 13.
The RVP (Multiplex PCR) on specimens from all RSV-A/B positive and confirmed 
LRTI cases, according to case definition presented in Table 6 (Figure 3), will 
qualitatively assess the potential co-infections occurring in these subjects. The panel of 
viruses profiled is presented in Table 14.
The Molecular biology for nasal swab and specimen analysis Table 14 was amended 
as follows:
Blood samplingSampling timepoint
No. 
subjects
Component
Components 
priority rank
Type of contact and 
timepoint
Sampling 
timepoint
System
Surveillance for 
asymptomatic RSV-
RTI
Monthly contact 
during the RSV 
season
Nasal swab
~ 150
Quantitative RT-PCR
(RSV A RNA and RSV B RNA)
Not 
applicable
 
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In Section 7.1. Description of study vaccines, the Study vaccines Table 15 was 
amended as follows:
Treatment name
Vaccine name
Formulation
Presentation
Volume to be 
administered
Number of 
doses
1D RSV ChAd
1D ChAd155-RSV ChAd155-RSV=3*1010vp/mL
Liquid in 
monodose vial †
0.5 ml
1
2D RSV ChAd
2D ChAd155-RSV
ChAd155-RSV=1*10¹¹vp/mL
Liquid in 
monodose vial †
0.5 ml
2
Saline
Formulation 
buffer (FB)
Formulation 
buffer S9b
Na2HPO4=1.3mg; 
KH2PO4=186µg; 
NaCl=3.85mg; KCl=100µg; 
MgCl2=50µg
Clear liquid
0.5 ml
0, 1 or 2 ‡
Placebo
Formulation 
buffer S9b
Na2HPO4=1.3mg; 
KH2PO4=186µg; 
NaCl=3.85mg; KCl=100µg; 
MgCl2=50µg
Clear liquid
0.5 ml
2
Bexsero
Bexsero
Recombinant Neisseria 
meningitidis group B NHBA 
fusion protein=50µg; 
Recombinant Neisseria 
meningitidis group B NadA 
protein=50µg; Recombinant 
Neisseria meningitidis group B 
fHbp fusion protein=50µg; 
Outer membrane vesicles 
(OMV) from Neisseria 
meningitidis group B strain 
NZ98/254=25µg; 
Al(OH)3=500µg Al3+
White opalescent 
liquid suspension 
for injection in 
pre-filled syringe
0.5 ml
3
Nimenrix
Nimenrix §
MenACWY-TT
PSA=5µg TT; PSC=5µg TT; 
PSW135=5µg TT; PsY=5µg TT; 
TT~=44µg
White powder or 
cake in a single 
dose glass vial
0.5 ml
3
Nimenrix §
NaCl
NaCl=150mM
Sodium chloride 
as a clear liquid 
for suspension
Menveo
Menveo ¥
MenA lyo
MenA=10µg,CRM197=16.7-
33.3µg; KH2PO4=5mM; 
Sucrose=12.5mg
Lyophilized 
component in a 
vial
0.5 ml
2
Menveo ¥
MenCWY liquid
MenC=5µg,CRM197=7.1-
12.5µg; 
MenW=5µg,CRM197=3.3-
8.3µg; 
MenY=5µg,CRM197=5.6-
10µg; NaCl=4.5mg; 
Na3PO4=10mM; 
NaH2PO4=2.5mM; 
Na2HPO4=7.5mM; water=0.5ml
Liquid 
component in a 
vial
 
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Treatment name
Vaccine name
Formulation
Presentation
Volume to be 
administered
Number of 
doses
NeisVac-C
Synflorix
Neiss Vac-C
Synflorix
10Pn-PD-DiT 
MenC=10µg TT, TT=10-20µg; 
Al=500µg
PS1=1µg PD; PS4=3µg PD; 
PS5=1µg PD; PS6B=1µg PD; 
PS7F=1µg PD; PS9V=1µg 
PD; PS14=1µg PD; 
PS18C=3µg TT; PS19F=3µg 
DT; PS23F=1µg PD; PD=9-
16µg; DT=3-6µg; TT=5-10µg; 
AlPO4=500µg Al3+ 
Semi-opaque
Turbid white to 
off-white 
suspension
0.5 ml
3
† Clear, colorless solution free from visible particles.
‡ The number of SalineFormulation buffer doses depends on the study arm and study country (see Table 2).
§ MenACWY-TT, a white powder or cake, is resuspended with a NaCl solution, to make Nimenrix.
¥ MenA lyo, a lyophilized component, is resuspended with MenCWY liquid, to make Menveo.
* Formulation buffer will be administered, when neither RSV vaccine nor comparator is scheduled, at the 
vaccination visits (see Figure 1, Table 2 and Table 16).
In Section 7.2. Storage and handling of study vaccine, the following changes were
made:
For the salinePlacebo [Saline] (Formulation buffer S9b) and for the active control 
comparator meningococcal vaccines (Bexsero, Nimenrix, Synflorix and Menveo and 
NeisVac-C) any temperature excursion outside the range of 2.0 to +8.0C (for +2 to 
+8°C/+36 to +46°F label storage condition) and for the ChAd155-RSV vaccine any 
temperature excursion above -60°C (for -60°C/-76°F label storage condition) or 
below -80.0°C must be reported in the appropriate (electronic) temperature excursion 
decision form. The impacted investigational medicinal products (IMPs) must not be used 
and must be stored in quarantine at label temperature conditions until usage approval has 
been obtained from the sponsor.
Refer to the Module on Clinical Trial Supplies in the SPM for details and instructions on 
the temperature excursion reporting and usage decision process, packaging and 
accountability of the study vaccines.
Refer to the SPM for more details on aspects vaccine handling including disposal of 
waste and management of accidental spills.
In Section 7.3. Dosage and administration of study vaccines, the following changes
were made:
The first IM dose of ChAd155-RSV vaccine must be administered before the first RSV 
season (RSV seasons will be determined for each country based on local epidemiological 
data. while the second dose (when applicable) will be given one month after the first 
dose. The volume to be administered for each IM vaccination will be 0.5 mL in the 
anterolateral thigh. The preferable side for administration is the left side. If for some 
reason the left side cannot be used, please ensure the subsequent doses are 
administered on the same side as the first dose. In the second year of life at Day 365 
(Visit 7) if the muscle size is adequate, the site of administration can be the deltoid on 
the left side.
 
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The Dosage and administration Table 16 was amended as follows:
Old Dosage and administration Table 16
Type of 
contact and 
timepoint
Volume to be 
administered
Study group
Treatment name4 Route1
Site
Lo
ca
tio
n
Di
re
La
ter
li
Visit 1
(Day 1)
0.5 ml
RSV + Bexsero
RSV ChAd
IM
Antlat Thi
NA
Left
0.5 ml
RSV + Nimenrix
RSV ChAd
IM
Antlat Thi
NA
Left
0.5 ml
RSV + Menveo
RSV ChAd
IM
Antlat Thi
NA
Left
0.5 ml
RSV + NeisVac-C
RSV ChAd
IM
Antlat Thi
NA
Left
0.5 ml
Bexsero
Bexsero
IM
Antlat Thi
NA
Left
0.5 ml
Nimenrix
Nimenrix
IM
Antlat Thi
NA
Left
0.5 ml
Menveo
Saline
IM
Antlat Thi
NA
Left
0.5 ml
NeisVac-C
NeisVac-C
IM
Antlat Thi
NA
Left
Visit 3
(Day 31)
0.5 ml
RSV + Bexsero
RSV ChAd
IM
Antlat Thi
NA
Left
0.5 ml
RSV + Nimenrix
RSV ChAd
IM
Antlat Thi
NA
Left
0.5 ml
RSV + Menveo
RSV ChAd
IM
Antlat Thi
NA
Left
0.5 ml
RSV + NeisVac-C
RSV ChAd
IM
Antlat Thi
NA
Left
0.5 ml
Bexsero
Saline
IM
Antlat Thi
NA
Left
0.5 ml
Nimenrix
Saline
IM
Antlat Thi
NA
Left
0.5 ml
Menveo
Menveo
IM
Antlat Thi
NA
Left
0.5 ml
NeisVac-C
Saline
IM
Antlat Thi
NA
Left
Visit 5
(Day 61)
0.5 ml
RSV + Bexsero
Bexsero
IM
Antlat Thi
NA
Left
0.5 ml
RSV + Nimenrix
Nimenrix
IM
Antlat Thi
NA
Left
0.5 ml
RSV + Menveo
Menveo
IM
Antlat Thi
NA
Left
0.5 ml
RSV + NeisVac-C
NeisVac-C
IM
Antlat Thi
NA
Left
0.5 ml
Bexsero
Bexsero
IM
Antlat Thi
NA
Left
0.5 ml
Nimenrix
Nimenrix
IM
Antlat Thi
NA
Left
0.5 ml
Menveo
Saline
IM
Antlat Thi
NA
Left
0.5 ml
NeisVac-C
NeisVac-C
IM
Antlat Thi
NA
Left
Visit 6
(Day 121) 5
0.5 ml
RSV + Bexsero
Bexsero
IM
Antlat Thi
NA
Left
0.5 ml
RSV + Nimenrix
Nimenrix
IM
Antlat Thi
NA
Left
0.5 ml
RSV + NeisVac-C
NeisVac-C
IM
Antlat Thi
NA
Left
0.5 ml
Bexsero
Saline
IM
Antlat Thi
NA
Left
0.5 ml
Nimenrix
Saline
IM
Antlat Thi
NA
Left
0.5 ml
NeisVac-C
Saline
IM
Antlat Thi
NA
Left
Visit 7 (end of 
the first RSV 
transmission 
season)
0.5 ml
RSV + Bexsero
Bexsero
IM
Antlat Thi
NA
Left
0.5 ml
RSV + Nimenrix
Nimenrix
IM
Antlat Thi
NA
Left
0.5 ml
RSV + Menveo
Menveo
IM
Antlat Thi
NA
Left
0.5 ml
RSV + NeisVac-C
NeisVac-C
IM
Antlat Thi
NA
Left
0.5 ml
Bexsero
Bexsero
IM
Antlat Thi
NA
Left
0.5 ml
Nimenrix
Nimenrix
IM
Antlat Thi
NA
Left
0.5 ml
Menveo
Menveo
IM
Antlat Thi
NA
Left
0.5 ml
NeisVac-C
NeisVac-C
IM
Antlat Thi
NA
Left
 
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New Dosage and administration Table 16
Type of 
contact and 
timepoint
Study group
Treatment name1
Volume to be 
administered
(0.5 mL)
Route2
(IM)
Site
Location
(Anterolateral 
Thigh) 3
Laterality 4
(Left)
Visit 1
(Day 1)
1D RSV + Bexsero
1D RSV ChAd
0.5 mL
IM
Anterolateral 
Thigh
Left
1D RSV + Nimenrix
1D RSV ChAd
1D RSV + Synflorix
1D RSV ChAd
1D RSV + Menveo
1D RSV ChAd
1D RSV + Placebo
1D RSV ChAd
2D RSV + Bexsero
2D RSV ChAd
2D RSV + Nimenrix
2D RSV ChAd
2D RSV + Synflorix
2D RSV ChAd
2D RSV + Menveo
2D RSV ChAd
2D RSV + Placebo
2D RSV ChAd
Bexsero
Bexsero
Nimenrix
Nimenrix
Synflorix
FB
Menveo
FB
Placebo
FB
Visit 3
(Day 31)
1D RSV + Bexsero
FB
1D RSV + Nimenrix
FB
1D RSV + Synflorix
FB
1D RSV + Menveo
FB
1D RSV + Placebo
FB
2D RSV + Bexsero
2D RSV ChAd
2D RSV + Nimenrix
2D RSV ChAd
2D RSV + Synflorix
2D RSV ChAd
2D RSV + Menveo
2D RSV ChAd
2D RSV + Placebo
2D RSV ChAd
Bexsero
FB
Nimenrix
FB
Synflorix
Synflorix
Menveo
Menveo
Placebo
FB
Visit 5
(Day 61)
1D RSV + Bexsero
Bexsero
1D RSV + Nimenrix
Nimenrix
1D RSV + Synflorix 
Synflorix
1D RSV + Menveo
Menveo
2D RSV + Bexsero
Bexsero
2D RSV + Nimenrix
Nimenrix
2D RSV + Synflorix
Synflorix
2D RSV + Menveo
Menveo
Bexsero
Bexsero
Nimenrix
Nimenrix
Synflorix
Synflorix
Menveo
FB
 
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Type of 
contact and 
timepoint
Study group
Treatment name1
Volume to be 
administered
(0.5 mL)
Route2
(IM)
Site
Location
(Anterolateral 
Thigh) 3
Laterality 4
(Left)
Visit 6
(Day 121) 5
1D RSV + Bexsero
Bexsero
0.5 mL
IM
Anterolateral 
Thigh
Left
1D RSV + Nimenrix
Nimenrix
1D RSV + Synflorix
Synflorix
2D RSV + Bexsero
Bexsero
2D RSV + Nimenrix
Nimenrix
2D RSV + Synflorix
Synflorix
Bexsero
FB
Nimenrix
FB
Synflorix
FB
Visit 7 (end 
of the first 
RSV 
transmission 
season)
1D RSV + Bexsero
Bexsero
1D RSV + Nimenrix
Nimenrix
1D RSV + Synflorix
Synflorix
1D RSV + Menveo
Menveo
2D RSV + Bexsero
Bexsero
2D RSV + Nimenrix
Nimenrix
2D RSV + Synflorix
Synflorix
2D RSV + Menveo
Menveo
Bexsero
Bexsero
Nimenrix
Nimenrix
Synflorix
Synflorix
Menveo
Menveo
Antlat Thi: Anterolateral thigh; ChAd155-RSV: Chimpanzee Adenovirus Type 155 RSV vaccine (5x1010 vp); NA: not 
applicable; Saline: formulation buffer S9b.
1 IM: Intramuscular.
2 Directionality is a qualifier for further detailing the location of the vaccine administration location (e.g., Upper, Lower).
1D: 1 Dose (1.5x1010 vp/dose); 2D: 2 Dose (5x1010 vp/dose); RSV ChAd: Chimpanzee Adenovirus Type 155 RSV 
vaccine; NA: not applicable; FB: Formulation buffer S9b.
1 The choice of active comparator vaccine or Placebo control is done at the country level (see Table 2).
2 IM: Intramuscular.
3 In the second year of lifeon Day 365 (Visit 7) if the muscle size is adequate, the site of administration can be 
the deltoid on the left side.
4The preferable side for administration is the left side. If for some reason the left side cannot be used, please ensure 
the subsequent doses are administered on the same side as the first dose.
5 In countries where Menveo or Placebo is used as a comparator, no administration will be performed at Day 121 and 
therefore in those countries there will be no Visit 6 and it will be administered at the end of the first RSV season at 
Visit 7 (refer to Figure 1, Table 2 and Table 7).
Minimizing environmental contamination with genetically modified organisms
Each product will be used in accordance with the local applicable genetically modified 
organism regulations.
To minimize release of the recombinant vectored vaccine virus into the environment, 
each vaccine is produced under good manufacturing practice conditions with the handling 
of live material in appropriate laboratory facilities. This is to ensure that any release of 
modified organism is contained, inactivated and incinerated, using single use equipment 
as much as possible, to avoid release of modified genetic material into the environment.
Refer to the SPM for more details on aspects vaccine handling including disposal of 
waste and management of accidental spills.
 
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In Section 9.2. Surveillance for RSV-RTI, difficulty in breathing and wheezing 
episodes, the following cross-reference was added:
Refer to APPENDIX D for the symptoms and grading for assessment visits and 
worsening visits.
In Section 9.2.1. Passive surveillance, the following change was made:
All subjects’ parent(s)/LAR(s) will be instructed to contact investigator/study staff in 
case of any new or worsened RTI symptoms (cough, runny nose or blocked nose) or in 
case of any new difficulty in breathing or wheezing. They will be also reminded to record 
the start date and the end date of the RTI symptoms on the RTI episode card.
In Section 9.2.2. Surveillance for asymptomatic RSV-RTI, the following changes were
made:
In order to detect asymptomatic RSV-RTI, monthly nasal swabs for analysis at sponsor 
laboratory will be performed for all subjects during the RSV season. who are ‘RTI 
symptom free’ within an approximate 30 day period. Upon investigators discretion this, 
the asymptomatic visit may be omitted if a nasal swab has been taken for a potential 
disease episode in the previous 4 weeks. This (please refer to the SPM for an example 
of when to schedule the visit). The asymptomatic nasal swab will be tested by 
quantitative PCR.
In Section 9.2.3. Active surveillance, the following changes were made:
There will be contact between the investigator/study staff and subject’s parent(s)/LAR(s) 
on a regular basis (weekly during the RSV season and every month outside the RSV 
season). If there has not been a contact through a clinic visit (i.e., Visits 1, 2, 3, 4, 5, 6*, 
7, 8, 9), a passive surveillance contact (refer to Section 9.2.1), an assessment visit (refer 
to Section 9.2.4) or a surveillance for asymptomatic RSV infection (refer to Section 
9.2.2), then the investigator/study staff will contact the subject’s parent(s)/LAR(s). The 
active surveillance will be performed by phone, mobile phone or e-mail.
* In countries where Menveo or Placebo is used as a comparator, no administration will 
be performed at Day 121 and therefore in those countries there will be no Visit 6 and it 
will be administered at the end of the first RSV season at Visit 7 (refer to Table 2 and 
Table 7).
During each active follow-up contact, the investigator/study staff will:

Confirm with the subjects’ parent(s)/LAR(s), if the subject has developed new RTI 
symptoms (cough, runny nose or blocked nose) and if he/she has developed any 
symptoms of difficulty in breathing or wheezing (during and between contacts).

If there is any new or on-going difficulty in breathing, wheezing or parental 
concern, the investigator/study staff will schedule an assessment visit as soon as 
possible (refer to Section 9.2.4), but no later than 24 hours after the contact to 
ensure prompt assessment of the need for medical care. The investigator/study 
 
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staff will remind subjects’ parent(s)/LAR(s) to record the start date and the 
end date of the RTI symptoms on the RTI episode card.

If there is no suspicion of difficulty in breathing, nor wheezing, nor parental 
concern, but any new symptoms of an RTI (cough, runny nose or blocked nose) 
are present, the investigator/study staff will schedule an assessment visit as soon 
as possible (refer to Section 9.2.4), but no later than 72 hours after the contact.

Performing the visit as soon as possible is important to assess the need for medical 
care, to ensure that early symptoms are captured, and also to collect a nasal swab 
for the detection of RSV.

The investigator/study staff will remind subjects’ parent(s)/LAR(s) to record the 
start date and the end date of the RTI symptoms on the RTI episode card.
In Section 9.3.3.2.1. Assessment of intensity, the footnote of Table 20 Intensity scales 
for solicited symptoms in infants has been changed as follows:
* Fever is defined as temperature 38.0°C / 100.4° F by any route. The preferred location for measuring temperature 
in this study will be the axilla for subjects 1 and < 5 years of age and the rectum for subjects < 12 months of age.
The Section 9.3.3.2.2. Assessment of causality, the following change was made:
The investigator is obligated to assess the relationship between study vaccines and the 
occurrence of each AE/SAE using clinical judgement. In case of concomitant 
administration of multiple vaccines/products, if possible, the investigator should specify 
if the AE could be causally related to a specific vaccine/product administered (i.e., 
investigational, control or co-administered vaccine). When causal relationship to a 
specific vaccine(s)/product(s) cannot be determined the investigator should indicate the 
AE to be related to all products.
In Section 9.10.4. Holding rules, Table 23 Holding rules during the planned iSRC or 
IDMC evaluation has been amended as follows:
Holding 
Rule
Event
Number of infants
2a
Any Grade 3 solicited local AE lasting 48 hours or more following 
administration of an investigational RSV vaccine, within the 7-day (Days 
1-7) post-vaccination period.
≥ 25% &
≥ 2 infants in theany of two
pooled RSV vaccine groups
2b
Any Grade 3 solicited general AE lasting 48 hours or more following 
administration of an investigational RSV vaccine, that cannot reasonably 
be attributed to a cause other than vaccination, within the 7-day (Days 1-
7) post-vaccination period.
≥ 25% & 
≥ 2 infants in theany of two
pooled RSV vaccine groups
2c
Any Grade 3 unsolicited AE following administration of an 
investigational RSV vaccine, that cannot reasonably be attributed to a 
cause other than vaccination, within the 7-day (Days 1-7) post-
vaccination period
≥ 25% &
≥ 2 infants in theany of two
pooled RSV vaccine groups
2d
Infants hospitalized for RSV-LRTI
≥ 46 (in the combination of 
thetwo pooled RSV vaccine 
and the pooled 
comparator/Placebo groups)
 
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Figure 5 on the Evaluations based on 50 subjects per group - Risk assessment curve 
for one formulation based on the proposed safety holding rules during the planned 
IDMC evaluation has been changed:
Figure 5 gives the probability of not meeting holding rule assessed during the planned 
IDMC evaluation when 50 subjects are enrolled per study group and 150 subjects in the 
whole trial.
Old Figure 5
 
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New Figure 5
In Section 11. STATISTICAL METHODS, the following changes have been made:
In Section 11.2. Secondary endpoints, the following changes were made:

Occurrence of RSV-RTI, RSV-LRTI, severe RSV-LRTI and very severe RSV-LRTI 
(according to standardized case definitions) as from first vaccination (Day 1) up to 
the end of the second RSV transmission season.

Occurrence of very severe RSV-LRTI (according to standardized case definitions) 
among RSV infected infants with a negative RSV exposure status (at screening 
based on in-stream baseline serological testing) from first vaccination (Day 1) up 
to the end of the first RSV transmission season.

Humoral response to the investigational RSV vaccine, pre-vaccination (Screening), 
post-Dose 1 (Day 31) and post-Dose 2 (Day 61):

Palivizumab-competing antibody concentrations.
In Section 11.3. Tertiary endpoints, the following changes were made:

Humoral response to the investigational RSV vaccine, pre-vaccination 
(Screening), post-Dose 1 (Day 31) and post-Dose 2 (Day 61).

Palivizumab-competing antibody concentrations.
 
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In Section 11.4. Determination of sample size, the following changes have been made:
The sample size determination is based on the minimum number of subjects needed to 
allow detection of a serious ERD signal of ERD of the having a magnitude similar to 
that occurred in association withof the historic FI-RSVvaccine trials [Kim, 1969]. A 
total of 150 infants will be enrolled and randomized with 1:1:1 ratio intoto receive
either receiving1 dose of the 1.5x1010 vp/dose ChAd-155 RSV vaccine [the 1D RSV + 
comparator group], 2 doses of the 5x1010 vp/dose ChAd-155 RSV vaccine [the 2D RSV 
+ comparator group], or no ChAd-155 RSV vaccine [the comparator/Placebo control.
alone group].
An effect of vaccination on ERD will be monitored very closely. It is anticipated that 
prior to the transmission season approximately 70% of infants 6 monthsat least 50% of 
subjects [Dunn, 2013] will be RSV naïve i.e., have not experienced an RSV RTI 
previously [, 2014]. If the magnitude of ERD risk in RSV naïve children is as extreme as 
that observed in the FI trial (80% of RSV RTI progress to hospitalization), and in 
contrasta negative RSV experienced children follow a usual clinical course of infection 
(5% of RSV RTI require hospitalization) then in this cohort including RSV experienced 
and naive infants an overall rate of 60% RSV RTI requiring hospitalization is derived [,
1969]. RSV hospitalization is not an objective measure of RSV disease severity and so 
the progression of infection to very severe RSV LRTIexposure status (at screening
which will be assessed. by in-stream serological testing of baseline samples). While the 
rate of RSV infection could be highly variable by season, a conservative rate of 
infection of 20% in the first season is assumed [Kutsayataken. Therefore, a total of 10 
infected infants would be expected from 50 RSV vaccine recipients., 2016]. Therefore, 
with 50 infants in each RSV vaccine group, it is anticipated to observe at least 5 
infected infants with a negative RSV exposure status (at screening based on in-stream 
baseline serological testing) in each RSV vaccine group [50×0.5×0.2=5].
With a one-sided type I error of 0.05, and the assumption of thea 10% rate of 10% 
infection progressing to very severe RSV-LRTI, (which is a conservative assumption 
based on the rate in the natural history of disease), 105 infections can provide at least 
90% statistical power to demonstrate the progression rate from infection to very severe 
RSV-LRTI is less than 80%. That is less extreme than that observed in the historic FI-
RSV vaccine trial where 80% of RSV RTI cases progressed to hospitalization [Kim, 
1969]. During the 60%.course of the study, since the actual negative RSV exposure 
status (at screening based on in-stream baseline serological testing) and infection rates 
may be lower than 50% and 20%, respectively, the sample size will be adjusted as 
needed through additional recruitment in order to achieve at least 5 RSV infected 
infants with a negative RSV exposure status (at screening based on in-stream baseline 
serological testing) in each RSV vaccine group.
If a maximum of 21 out of 105 infections in infants receiving ChAd-155 RSV vaccine 
progress to very severe RSV-LRTI, then it can be concluded with 95% confidence that 
the expected progression rate of infection is less than the effect reported in previous FI-
RSV trials; if a minimum of 43 out of 105 infections progress to very severe RSV-LRTI 
then it can be concluded with 95% confidence that the expected progression rate of
 
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infection is more than the 10% observed in natural history of infection. The above power 
analysis is based on the procedure of inequality of one proportion in PASS 12.
With 50 subjects in each RSV vaccine group, the probability of observing at least one 
SAE would be about 92% if the true incidence rate of SAE is 5%. For estimating the 
proportion of subjects with AEs, the maximum width of exact 95% confidence interval 
(CI) would be under 30%, and it could be as large as 35% if attrition rate is 30%. Figure 
6 illustrates the precision on the estimate for the proportion of subjects with AEs 
following vaccination with each RSV formulation based on the number of subjects with 
AEs observed from 50 subjects.
In addition, relative risks for enhanced RSV-LRTI of RSV vaccine versus control will be 
monitored and evaluated. Under the assumption of 5% of annual LRTI event rate in 
control group, a one year follow up, and one-sided type I error of 0.1, the current sample 
size is able to provide about 80% statistical power to rule out the relative risk of at least 
8.5 (vaccine vs. control) in absence of vaccine efficacy. The power analysis is based on 
Two Independent Proportions (Superiority by a Margin) in PASS 12.
In Section 11.5. Cohorts for Analyses, the following changes have been made:
The Section 11.5.1. heading has been changed from Total vaccinated cohort to 
Exposed Set
The total vaccinated cohort (TVCExposed Set (ES) will include all subjects with at least 
one study vaccine administration documented.
A safety analysis based on the TVCES will include all vaccinated subjects.
An immunogenicity analysis basedwill be conducted on the TVCES and will include all 
vaccinated subjects for whom immunogenicity data are available.
The TVCES analysis will be performed per treatment actually administered at Dose 1.
The Section 11.5.2. Exposed Set of subjects with a negative RSV exposure status has 
been added:
The Exposed Set of subjects with a negative RSV exposure status will include all 
vaccinated subjects assessed as RSV unexposed at screening based on in-stream 
baseline serological testing.
The safety analysis of incidence of RSV-LRTI will be conducted on the cohort of 
subjects with a negative RSV exposure status (at screening based on in-stream baseline 
serological testing) as well as on the entire ES.
 
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The Section 11.5.3. Per-protocol cohortSet for analysis of immunogenicity (formerly 
Section 11.5.2.), has been amended as follows:
The per-protocol (PPset (PPS) cohort for analysis of immunogenicity will be defined by 
timepoint and will consist of all subjects from the TVCES who complied with eligibility 
criteria, study procedures up to the end of the study and had immunogenicity results in 
the epoch as described below.
More specifically, the PPS cohort for analysis of immunogenicity up to Day 61 (Visit 5
(Day 61)/) /at Day 365 (Visit 7) (end of the first RSV transmission season) will include 
all evaluable subjects:

Who met all eligibility criteria (i.e., no protocol violation linked to the 
inclusion/exclusion criteria, including age).

Who received at least one dose of study vaccine. as scheduled per protocol.

For whom the administration route and site of the vaccine was as according to 
protocol.

Who received the vaccine according to protocol procedures.

Who complied with the vaccination schedule, as specified in Table 7.

Who did not receive a concomitant medication/product/vaccine leading to exclusion 
from a PPS analysis, as described in Section 7.6.2, up to Day 61 (Visit 5 () /at 
Day61)/up to 365 (Visit 7) (end of the first RSV transmission season).

Who complied with the timings of the post vaccination blood sampling for immune 
response evaluation, up to Day 61 (Visit 5 (Day 61)/) /at Day 365 (Visit 7) (end of 
the first RSV transmission season), as specified in Table 7.

For whom post-vaccination immunogenicity results are available for at least one 
assay up to Day 61 (Visit 5 (Day 61)/) /at Day 365 (Visit 7) (end of the first RSV 
transmission season).
Table 24 presents the intervals between study visits that determine subjects’ eligibility 
for inclusion in the PPS analysis.
Footnote 3 of the Maximum allowed interval between study visits Table 24 was 
amended as follows:
3 In countries where Menveo or Placebo is used as a comparator, no administration will be performed at Day 121 and 
therefore in those countries there will be no Visit 6 and it will be administered at the end of the first RSV season at 
Visit 7 (refer to Table 2 and Table 7).
 
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The Pooled groups Table 25 was amended as follows:
Study groups
Pooled groups
1D RSV + Bexsero
Pooled 1D RSV
1D RSV + Nimenrix
1D RSV + Synflorix
1D RSV + Menveo
1D RSV + Placebo
2D RSV + NeisVac-
CBexsero
Pooled 2D RSV
2D RSV + Nimenrix
2D RSV + Synflorix 
2D RSV + Menveo
2D RSV + Placebo
Bexsero
Pooled comparator
Nimenrix
Synflorix
Menveo
NeisVac-CPlacebo
1D: 1 Dose (1.5x1010 vp/dose); RSV: ChAd155-RSV vaccine; 2D: 2 Dose (5x1010 vp/dose)
In the Section 11.6. Derived and transformed data, the Section 11.6.2. Safety had the 
following change:
For a given subject and the analysis of solicited AEs 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 TVCES will include only vaccinated 
subjects with documented safety data (i.e., symptom screen completed)
The Section 11.6.3. Immunogenicity was amended as follows:
Determination of a negative RSV exposure status in infants at 6 to 7 months of age will 
be based on RSV A and/or B neutralizing antibody titers present in serum at screening 
(before vaccination with the RSV vaccine) based on in-stream baseline serological 
testing. At birth, newborns do show positive for neutralizing antibodies due to maternal 
transfer during gestation. The titer of these antibodies declines over time. At the age of 
6 to 7 months a cut-off can be defined below which infants are considered to have a 
negative RSV exposure status. Infants that show neutralizing antibody titers above this 
cut-off are suspected to have experienced a recent RSV infection. This cut-off will thus 
allow the discrimination between a negative RSV exposure status versus RSV infected 
infants before start of vaccination.
The Section 11.6.4. RTI and LRTI, was amended as follows:
For the analysis of RTI and LRTI, all cases will be definitively classified as either RSV-
RTI, RSV-LRTI, severe RSV-LRTI or very severe RSV-LRTI according to the case 
definitions presented in Table 6, and the association to RSV infection will be assessed by 
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The Section 11.7. Analysis of demographics was amended as follows:
The analysis of demographics will be performed on the TVCES and on the PPS cohort 
for immunogenicity for each RSV + comparator vaccine group and each active control 
comparator group and also for the pooled RSV vaccine and pooled comparator groups.
Demographic characteristics (age at vaccination in months, sex, country and race) and 
vital signs), cohort description will be summarized by group using descriptive statistics:

Frequency tables will be generated for categorical variables such as race.
In the Section 11.8. Analysis of safety, the Section 11.8.1. Within groups assessment 
had the following changes:
The safety will be descriptively summarized based on the TVCES. The analysis of local 
AEs, general AEs and fever will be reported for each RSV + comparator vaccine group 
and each active control comparator group and also for the pooled RSV vaccine and 
pooled comparator groups. For the analysis of SAEs and AE of specific interest, the 
analysis will be performed only on the pooled RSV and pooled comparator groups.
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 vaccine dose and overall. The percentage of doses followed by at least one local AE 
(solicited and unsolicited), by at least one general AE (solicited and unsolicited) and by 
any AE during the 7-day or 30-day follow-up period will be tabulated, overall 
vaccination course, with exact 95% CI. The same computations will be done for Grade 3 
AEs, for any AEs considered related to vaccination and for any Grade 3 AEs considered 
related to vaccination. and AEs resulting in a medically attended visit.
The percentage of subjects with unsolicited AEs within 30 days (Day 1-30) after each 
vaccine dose (overall doses) with its exact 95% CI will be tabulated RSV + comparator 
vaccine group and each active control comparator group and also for the pooled RSV 
vaccine and pooled comparator groups and by 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 AEs 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 subject with episode of spontaneous or 
excessive bleeding (AE of specific interest), during a 30-day follow-up period after 
each vaccination will be tabulated according to associated Preferred Term code (to be 
identified in the Statistical Analysis Plan [SAP]).
The percentage of subjects with RSV-LRTI (AE of specific interest) from Dose 1 up to 
end of the first RSV transmission season and from Dose 1 up to end of second RSV 
season will be tabulated according to associated Preferred Term code presented in the 
SAP.
 
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The percentage of subjects with SAE within 30 days (Day 1-30) after each vaccine dose 
with its exact 95% CI will be tabulated and by MedDRA preferred term. Similar tables 
will be generated for SAEs from Dose 1 to end of first RSV season and from Dose 1 to 
end of the second RSV season.
The Section 11.9. Analysis of immunogenicity was amended as follows:
The primary analysis will be performed on the PP cohortPPS for immunogenicity and, if 
in any group the percentage of vaccinated subjects with serological results excluded from 
the PP cohortPPS for immunogenicity is more than 10%, a second analysis will be 
performed on the TVCES. The results from immunogenicity analysis will be reported by 
the pooled RSV vaccine group and the pooled comparator group.
For the final analysis, the Adapted PPS for immunogenicity analysis will be used 
which allows the summary of immunogenicity results by time point. In summary table 
on the Adapted PPS for immunogenicity, PPS for immunogenicity at Day 61 will be 
used for Pre, Day 31 and Day 61 immunogenicity summary and PPS for 
immunogenicity at Day 365 for Day 365 immunogenicity summary.
The infants are monitored for RSV infection starting from dose 1 and therefore 
immunogenicity analyses can be adjusted to exclude those infants with an infection 
prior to sampling.
In the Section 11.9.1. Within groups assessment, the Section 11.9.1.1. Analysis of 
secondary objectives had the following changes:
For boththree pooled groups, at each timepoint that blood samples are collected for 
humoral immune response against the investigational RSV vaccine (neutralizing antibody 
titers against RSV-A, RSV F antibody concentrations and palivizumab-competing 
antibody concentrations):).
An immunogenicity analysis will also be performed on the ES with a negative RSV 
exposure status (at screening based on in-stream baseline serological testing) for whom 
immunogenicity data are available.
The Section 11.9.1.2. Analysis of tertiary objective was amended as follows:
If available, any further exploratory immunology results (including, but not limited to 
anti-vector immunity and palivizumab-competing antibody concentrations) will be 
reported by timepoint for the two pooled RSV vaccine groups and the pooled comparator 
group and timepoint using descriptive summary statistics.
The Section 11.10. Analysis of RTI and LRTI was amended as follows:
The primary analysis will be performed on the TVCES of subjects with a negative RSV 
exposure status (at screening based on in-stream baseline serological testing) in the 
pooled single dose RSV vaccine group, the pooled two dose RSV vaccine group, and the 
pooled comparator group separately for first and second RSV seasons and overall. A 
similar analysis will be performed on the entire ES. As primary analysis, the assessment 
of RSV infection will be performed using the quantitative RT-PCR according to 
standardized case definitions (see Table 6) based on the available WHO case definitions.
 
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The number of RSV infections within each group and the maximum disease severity of 
the event will be tabulated. The rate (with 95% CI) of RSV-RTI and RSV-LRTI and 
infections progressing to hospitalization will be evaluated bothfor each of the three
pooled groups. RSV infection (symptomatic or asymptomatic) will be assessed by either 
central quantitative RT-PCR (RSV-A/B) or locally available test.
The rate of very severe RSV-LRTI among RSV infected infants with a negative RSV 
exposure status (at screening based on in-stream baseline serological testing) from first 
vaccination (Day 1) up to the end of the first RSV transmission season will be 
estimated as well as 95% one-sided lower CI.
The proportion and the relative risk of subjects with at least one RSV-associated RTI 
(with 95% CI) will be calculated.between each of two pooled RSV vaccine groups and 
the pooled control group will be calculated for both the cohort of subjects with a
negative RSV exposure status (at screening based on in-stream baseline serological 
testing) on the ES and on the entire ES. The same descriptive analysis will be performed 
for subjects with at least one RSV-associated LRTI and those with at least one RSV-
associated severe LRTI.
Descriptive analyses (mean, median, min, max) of viral load assessed by the quantitative 
RT-PCR (RSV-A/B) of RSV-RTI, RSV-associated LRTI and severe LRTIall cases as 
listed in Table 6 will be tabulated. by case category. This analysis will also be done on 
the twothree pooled groups.
The incidence rate of all-cause RTI cases as listed in Table 6 (with 95% CI) will be 
calculated by boththe three pooled groups. The same descriptive analysis will be 
performed for all cause LRTI and all cause severe LRTI. These will also be presented for 
each viral etiology identified by the multiplex PCR.
The incidence rate of asymptomatic RSV infections (with 95% CI) detected by the 
quantitative PCR (RSV-A/B), will be tabulated by the twothree pooled groups. 
Descriptive analyses (mean, median, min, max) of viral load assessed by the quantitative 
RT-PCR (RSV-A/B) of those asymptomatic RSV infections will also be done on the 
twothree pooled groups.
The RVP (Multiplex PCR) on specimens from all RSV-A/B positive and confirmed 
LRTI cases, according to case definition presented in Table 6 (Figure 3), will be 
tabulated as a qualitative assessment profiling the potential co-infections occurring in 
these subjects.
The Section 11.11. Interpretation of analyses was amended as follows:
For the occurrence of very severe RSV-LRTI among RSV infected infants with a 
negative RSV exposure status (at screening based on in-stream baseline serological 
testing) from first vaccination (Day 1) up to the end of the first RSV transmission 
season, if the upper boundary of the 95% one-sided lower CI of the rate is under 80%, 
it indicates that the very severe RSV-LRTI rate is less than that of the historic RSV-FI 
trials [Kim, 1969].
 
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The Section 11.12.1. Sequence of analyses was amended as follows:
In preparation of the planned iSRC and IDMC evaluations, analyses of all available 
safety data (i.e., data that are as clean as possible) will be performed (see Section 9.10 for 
more information). These analyses will be done by an unblinded statistician outside GSK 
to maintain the blinding of the study blind, and will be documented in a statistical 
analysis report. Only the outcome of the iSRC and IDMC reviews will be communicated 
to the RSV study team (no safety signal or safety signal). No clinical study report will be 
written.
In the Section 12. ADMINISTRATIVE MATTERS, the Section 12.1. electronic Case 
Report Form instructions had the following change:
The investigator will be provided with a CD-ROM ofstorage device containing 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.
In the new Section 13. COUNTRY SPECIFIC REQUIREMENTS, the new Section 
13.1. Requirements for Belgium had the following statement:
Belgium will not use placebo, and will only use Bexsero.
The Section 14. REFERENCES (formely Section 13.) was amended as follows:
Chu HY, Steinhoff MC, Magaret A, et al. Respiratory syncytial virus transplacental 
antibody transfer and kinetics in mother-infant pairs in Bangladesh. J Infect Dis. 2014; 
210(10): 1582-9. 
Dunn SR, Ryder AB, Tollefson et al. Seroepidemiologies of human metapneumovirus 
and respiratory syncytial virus in young children, determined with a new recombinant 
fusion protein enzyme-linked immunosorbent assay. Clin Vaccine Immunol. 2013; 
(10): 1654-6.
Kutsaya A, Teros-Jaakkola T, Kakkola L, et al. Prospective clinical and serological 
follow-up in early childhood reveals a high rate of subclinical RSV infection and a 
relatively high reinfection rate within the first 3 years of life. Epidemiol Infect. 2016; 
144(8): 1622-33.
Pierantoni A, Esposito ML, Ammendola V et al. Mucosal delivery of a vectored RSV 
vaccine is safe and elicits protective immunity in rodents and nonhuman primates. Mol 
Ther Methods Clin Dev. 2015; 2, 15018.
Taylor G, Thom M, Capone S, et al. Efficacy of a virus-vectored vaccine against human 
and bovine respiratory syncytial virus infections. Sci Transl Med. 2015; 7: 300.
The Section APPENDIX A LABORATORY ASSAYS was amended as follows:
RSV A Neutralization assay
The serum neutralization assay is a functional assay that measures the ability of serum 
antibodies to neutralize RSV entry and replication in a host cell line.
 
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First, v Virus neutralization is performed by incubating a fixed amount of RSV-A long 
strain (Long, ATCC No. VR-26) 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 three 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 fluorescein isothiocyanate,horse-radish peroxidase (HRP), allowing the 
visualization of plaques by immunofluorescence.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].
ELISA

Anti-RSV protein F ELISA
The anti-F protein IgG ELISA is an indirect ELISA allowing the detection and the 
quantitation of specific IgG antibodies directed against the RSV F protein in human 
serum samples. PreF 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 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-preF IgG antibodies present in the serum sample. The optical 
density of each sample dilution is then interpolated on the reference standard. The 
corresponding antibody concentration, corrected for the dilution factor, is 
expressed in arbitrary ELISA Laboratory Units per milliliter (ELU/mL).
PCR Reverse Transcription Polymerase Chain Reaction (RT-PCR)

Quantitative RT-PCR able to discriminate RSV-A and RSV-B subtypes:
Briefly, RSV A and RSV B RNAs extracted from the nasal 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 RT-PCR for detection of a panel of viruses:
 
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The APPENDIX D, indicating THE SYMPTOMS AND GRADING FOR 
ASSESSMENT VISITS AND WORSENING VISITS, was added:
HISTORY FROM PARENT OR CARER - PART 1
Symptoms of RTI
Cough
Yes/No (if Yes: start date and end date)
Runny nose
Yes/No (if Yes: start date and end date)
Blocked nose
Yes/No (if Yes: start date and end date)
Wheezing
Yes/No (if Yes: start date and end date)
Difficulty in breathing
Yes/No (if Yes: start date and end date)
Parental/Carer concern
Parental concern
Yes/No 
MEDICAL OBSERVATION - PART 2a*
Temperature
Record temperature and route of measurement
Heart rate
Beats per minute when child is settled
Respiratory rate
Breaths per minute counted over one minute
Lower chest wall indrawing (subcostal recession)
Yes/No
SpO2
% measured in room air when quiet and not feeding (NB 
altitude is collected for each participating site)
Nasal swab taken for testing at central laboratory
Yes/No
Specimen taken for RSV and RVP testing at local 
laboratory
Yes/No (If Yes specify type of specimen test and result: 
positive/negative)
Has a blood sample been taken for assessment of 
mechanism of illness?
Yes/No/ Not available
MEDICAL OBSERVATION - PART 2b*
Must be completed in full if:

The parent or carer reports wheezing or difficulty in breathing

The respiratory rate is > 40/minute for subject 12-30 months of age

Lower chest wall indrawing is observed

SpO2 measured in room air by pulse oximetry is < 95%
N.B. May be completed in part or in full for any child attending an assessment visit
Signs of 
increased 
respiratory 
effort
Audible wheeze
Yes/No/Not available
Grunting
Yes/No/Not available
Nasal flaring
Yes/No/Not available
Intercostal recession
Yes/No/Not available
Signs 
associated with 
severity
Apnea outside medical facility Has an episode of apnea > 20 seconds occurred outside a 
medical facility? Yes/No/Not available (if Yes provide all 
details [free text field])
Apnea under medical 
observation
Has an episode of apnea > 20 seconds occurred during 
medical observation? Yes/No/Not available (if Yes provide all 
details [free text field])
Peripheral cyanosis
Yes/No/Not available
Central cyanosis 
Yes/No/Not available
Irritability/agitation
0 = content, happy, interactive
1 = mildly irritable when touched, occasional crying, can be 
comforted, is interactive
2 = moderately irritable, intermittently crying, resists 
comforting, less interactive
3 = extremely irritable, cannot be comforted, crying 
throughout examination or not interactive
Not available
Lethargy/excessive 
sleepiness
0 = interactive
1 = mildly lethargic/sleepy is normally interactive when 
roused
2 = moderately lethargic/ sleepy, less interactive than normal 
when roused
3 = extremely lethargic/sleepy, is not interactive when roused
Not available
 
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Conscious level
A = The child is awake, alert, and interactive with parents and 
care providers
V =The child responds only if the care provider or parents 
call the child’s name or speak loudly
P =The child responds only to painful stimuli, such as 
pinching the nail bed of a toe or finger.
U = The child is unresponsive to all stimuli
Not available
Assessment of feeding ability 0 = Normal feeding
1 = Reduced ability to feed
2 = Unable to feed
Not available
Skin turgor
Yes → > 2 seconds
No → 2 seconds
Not available
Findings on 
auscultation
Wheeze on auscultation with 
stethoscope
Yes/No/Not available
Crackles
Yes/No/Not available
Investigations
Chest X-ray if available**
Collected? Yes/No/Not available (If Yes: specify date and 
specify the presence or absence of the following features: 
hyperexpansion, peribronchial thickening, interstitial 
infiltrates, segmental or lobar consolidation, pleural effusion, 
atelectasis, other:  please specify)
Blood culture if available**
Collected? Yes/No (If Yes, specify date and  coded results as 
1. Pneumococcus, 2. Haemophilus influenza 3. 
Meningococcus, 4. Salmonella, 5. Other pathogenic 
organism, 6. Contaminant, 7. No isolate, 8. No result [missing 
confirmed] and note if 1 to 6: was the period of incubation to 
positivity detection > 48 hours? Yes/No, if 1, 2, 3 or 4 specify 
serotype/group, if 5 or 6 specify organism and if 8 comment)
Complete blood count If 
available**
Collected? Yes/No/Not available (if Yes specify date of 
collection or tick box if date is same as visit date and specify 
laboratory name, record results for hematology blood count: 
hemoglobin, platelets, total white cell count, neutrophil 
count, lymphocyte count)
Inpatient care
Hospitalization indicated? 
Hospitalization?
Yes/No (if Yes, specify start date of hospitalization and total 
number of calendar days on which the child was hospitalized 
for at least one hour)
If yes: Requirement for 
monitoring/nursing 
observation
Yes/No (if Yes total number of calendar days on which the 
requirement for monitoring/nursing observation was done for 
at least one hour)
If yes: Requirement for 
nasogastric or intravenous 
fluids
Yes/No (if Yes specify start date of fluids and specify total 
number of calendar days on which nasogastric or 
intravenous fluids were given for at least one hour)
If yes: Requirement for 
supplemental oxygen
Yes/No (if Yes specify start date of oxygen and specify total 
number of calendar days on which oxygen was administered 
for at least one hour)
If yes: Requirement for 
respiratory support excluding 
mechanical ventilation (e.g. 
high flow, continuous 
positive airway pressure 
[CPAP])
Yes/No (if Yes specify start date of respiratory support and 
specify total number of calendar days on which respiratory 
support [excluding mechanical support] was given for at 
least one hour)
If yes: Requirement of 
mechanical ventilation 
Yes/No (if Yes specify start date of mechanical ventilation 
and specify total number of calendar days on which 
mechanical ventilation was given for at least one hour)
 
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If yes: Requirement for 
pediatric intensive care unit 
management
Yes/No (if Yes specify start date of pediatric care and specify 
total number of calendar days on which the child was cared 
for on pediatric intensive care unit for at least one hour)
Was the primary reason for 
hospitalization social in 
nature?
Yes/No
In the opinion of the principal 
investigator and the RSV 
local result, was RSV-LRTI 
the principal reason for 
admission to hospital?
Yes/No (If No, comment)
WORSENING INFORMATION OF RTI EPISODE (Worsening episode) - PART 3*
If in the investigator’s judgment a deterioration in the clinical status has occurred during the same RTI 
episode, then the most extreme value of all deteriorated clinical symptoms and signs (as listed in Part 2a and 
2b) must be captured 
N.B. May be completed in part or in full for any child experiencing a deterioration during the course of a 
disease episode
Maximum temperature***
Record temperature and route of measurement
Maximum respiratory rate***
Breaths per minute counted over one minute
Lower chest wall indrawing  (subcostal recession)***
Yes/No/Not available
Minimum SpO2 recorded***
%  measured in room air (NB altitude is collected 
for each participating site)
Nasal swab taken for testing at central laboratory
Yes/No
Specimen taken for RSV and RVP testing at local 
laboratory 
(optional sample if the previous swab from the 
same RTI episode was RSV-positive)
Yes/No (If Yes specify type of specimen test and result: 
positive/negative)
Not available
Signs of increased 
respiratory effort 
Audible wheeze***
Yes/No/Not available
Grunting***
Yes/No/Not available
Nasal flaring***
Yes/No/Not available
Intercostal recession***
Yes/No/Not available
Signs associated with 
severity observed 
Apnea outside medical 
facility observed during 
disease episode*** 
Has an episode of apnea > 20 seconds occurred outside a 
medical facility? Yes/No/Not available (if Yes provide all 
details [free text field])
Apnea under medical 
observation*** 
Has an episode of apnea > 20 seconds occurred during 
medical observation? Yes/No/Not available (if Yes provide 
all details [free text field])
Peripheral cyanosis***
Yes/No/Not available
Central cyanosis*** 
Yes/No/Not available
Irritability/agitation (record 
highest score)***
0 = content, happy, interactive
1 = mildly irritable when touched, occasional crying, can 
be comforted, is interactive
2 = moderately irritable, intermittently crying, resists 
comforting, less interactive
3 = extremely irritable, cannot be comforted, crying 
throughout examination or not interactive
Not available
Lethargy/excessive 
sleepiness (record highest 
score)***
0 = interactive
1 = mildly lethargic/sleepy is normally interactive when 
roused
2 = moderately lethargic/ sleepy, less interactive than 
normal when roused
3 = extremely lethargic/sleepy, is not interactive when 
roused
Not available
 
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Conscious level (record 
lowest level of 
consciousness)***
A = The child is awake, alert, and interactive with parents 
and care providers
V =The child responds only if the care provider or parents 
call the child’s name or speak loudly
P =The child responds only to painful stimuli, such as 
pinching the nail bed of a toe or finger.
U = The child is unresponsive to all stimuli
Not available
Assessment of feeding 
ability (record highest 
score)***
0 = Normal feeding
1 = Reduced ability to feed
2 = Unable to feed
Not available
Skin turgor*** 
Yes → > 2 seconds
No → 2 seconds
Not available
Findings on 
auscultation 
Wheeze on auscultation*** Yes/No/Not available
Crackles***
Yes/No/Not available
* Observation done by qualified medical/nursing personnel
** Test not required per protocol but if taken as part of clinical management result should be recorded
*** Record if a deterioration in this parameter has occurred relative to that documented at the assessment 
visit during the course of this disease episode
 
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GlaxoSmithKline Biologicals SA
Vaccines R &D
Protocol Amendment 2
eTrack study number 
and Abbreviated Title
204894 (RSV PED-011)
IND number
16999
EudraCT number
2018-000431-27
Amendment number:
Amendment 2
Amendment date:
24 January 2019
Co-ordinating author:

(Scientific Writer)
Rationale/background for changes:

In response to a request received from the English Competent Authority (MHRA) 
on 2 January 2019, added clarification that hypersensitivity to any component of 
comparator or control vaccines used in this study or contraindication to them is an 
exclusion criterion. 
Amended text has been included in bold italics and deleted text in strikethrough in 
the following sections:
In the Section 5.3. Exclusion criteria for enrolment the following changes have been 
made:

History of any reaction or hypersensitivity likely to be exacerbated by any 
component of the vaccines (investigational or control) or placebo used in this study 
or any contraindication to them.
 
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GlaxoSmithKline Biologicals SA
Vaccines R &D
Protocol Amendment 3
eTrack study number 
and Abbreviated Title
204894 (RSV PED-011)
IND number
16999
EudraCT number
2018-000431-27
Amendment number:
Amendment 3
Amendment date:
21 March 2019
Co-ordinating author:

(Scientific Writer)
Rationale/background for changes:

The indication of pneumonia was added for Synflorix (Sections 1.3.2 and 1.3.3).

References to Day 365 and Day 730 for Visits 7 and 8, respectively, were removed 
in Tables 8 and 24 and throughout.

Clarification was added to the exclusion criterion on recurrent wheezing to specify 
in the subject’s lifetime. 

A hyperlink reference was added to include World Health Organization (WHO) 
weight percentile guidelines for girls and boys ages 5 years and under
(https://www.who.int/childgrowth/standards/weight_for_age/en/). 

The exclusion criterion related to mothers participating in another clinical study 
was clarified to specify if breastfeeding. 

The cut-off for the neutralization assay was added (Table 10). 

Revised Section 9.10.3 to reflect that an additional analysis may be conducted 
after subjects complete a full RSV season when there are 5 infections among 
subjects with a negative RSV exposure status (at screening) in each randomization 
group. 

Section 9.10.5 was revised to clarify the roles of the iSRC and VSMB.

In addition, some typographical errors have been corrected throughout the 
protocol.
Amended text has been included in bold italics and deleted text in strikethrough in 
the following sections:
On the protocol cover page the Coordinating author has been added:
Co-ordinating authors 

(Scientific Writer)
 
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On the protocol cover page the Contributing author has been added.
Contributing authors

(Study Delivery Lead)
In the Synopsis, the following changes were made:
Synopsis Table 1
Study groups and epochs foreseen in the study (Amended 21 
March 2019) 
Study groups
Target
Numbers of 
subjects*
Age (Min/Max)
Epochs
Epoch 001
Epoch 002
Epoch 003
Epoch 004
1D RSV + Bexsero
50**
6 – 7 months
N/A
x
x
x
1D RSV + Nimenrix
6 – 7 months
N/A
x
x
x
1D RSV + Synflorix
6 – 7 months
N/A
x
x
x
1D RSV + Menveo
6 – 7 months
N/A
x
x
x
1D RSV + Placebo
6 – 7 months
N/A
x
x
x
2D RSV + Bexsero
50**
6 – 7 months
N/A
x
x
x
2D RSV + Nimenrix
6 – 7 months
N/A
x
x
x
2D RSV + Synflorix
6 – 7 months
N/A
x
x 
x
2D RSV + Menveo
6 – 7 months
N/A
x
x
x
2D RSV + Placebo
6– 7 months
N/A
x
x
x
Bexsero
50**
6 – 7 months
N/A
x
x
x
Nimenrix
6 – 7 months
N/A
x
x
x
Synflorix 
6 – 7 months
N/A
x
x
x
Menveo
6 – 7 months
N/A
x
x
x
Placebo
6 – 7 months
N/A
x
x
x
1D: 1 Dose (1.5x1010 vp/dose); RSV: ChAd155-RSV vaccine; 2D: 2 Dose (5x1010 vp/dose); N/A: Not Applicable. 
* Note that for both 1D and 2D RSV vaccine + active comparator/placebo groups the total number of subjects is 100 
and that for both RSV vaccine + active comparator/placebo groups there will be a 1:1:1 ratio maintained with the 
corresponding active comparator/placebo group.
** Note that the numbers of subjects anticipated to receive the control vaccines within participating countries are not 
yet known, but the distribution and supplies will be prepared to allow flexible enrolment across countries (for any 
comparator the range of subjects is 0 – 50 may be enrolled) but the overall total of 150 subjects will be respected

Vaccination schedules:
RSV investigational vaccine:

In the 1 Dose (1D) groups, a single lower dose of 1.5x1010 vp will be 
administered IM at Day 1 (Visit 1). Formulation buffer will be administered in 
the 1D groups at Day 31 (Visit 3). In the 2 Dose (2D) groups, two doses of 
5x1010 vp will be administered IM according to a 0, 1-month schedule, (i.e., at 
Day 1 [Visit 1] and Day 31 [Visit 3]) (see Synopsis Table 3). Dose 1 will be 
administered before the first RSV season and the second dose will be given 
one month after the first dose (RSV seasons will be determined for each 
country based on local epidemiological data and documented in the Study 
Procedures Manual [SPM]. The RSV season is defined as the period of the 
year when 70% of the RSV cases have occurred in previous years. For the 
calculation, where available, data from up to the ten previous years should be 
applied. If the data permit calculation of the actual date of the beginning of the 
 
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season, rather than approximation to the nearest month, this is desirable. 
(Amended 21 March 2019)
Comparator or Placebo:

In countries where Bexsero or Nimenrix is used as a control, two doses will be 
administered IM with at least a 2 month interval between these primary doses. 
A booster dose will be administered IM in the second year of life at Day 365 
(Visit 7), with an interval of at least 2 months between the primary series and 
booster dose. The first Bexsero or Nimenrix dose will be administered at 
Day 1 (Visit 1) (in the groups receiving only Bexsero or Nimenrix, 
respectively). In the groups receiving only Bexsero or Nimenrix, the second 
dose will be at Day 61 (Visit 5). The first Bexsero or Nimenrix dose to be 
administered to the 1D and 2D RSV groups will be at Day 61 (Visit 5), 
following the 1 or 2 RSV vaccine doses, respectively. The second dose of 
Bexsero or Nimenrix in the 1D and 2D groups will be at Day 121 (Visit 6). 
Formulation buffer will be administered, when neither RSV vaccine nor 
comparator is scheduled, at the 5th vaccination visits (see Synopsis Table 3)
(Amended 21 March 2019). 

In countries where Synflorix is used as a control, two doses will be 
administered IM with at least a 1 month interval between these primary doses. 
A booster dose will be administered IM in the second year of life at Day 365 
(Visit 7). The first Synflorix dose will be administered at Day 31 (Visit 3) (in 
the group receiving only Synflorix). In the group receiving only Synflorix, the 
second dose will be at Day 61 (Visit 5). The first Synflorix dose to be 
administered to the 1D and 2D RSV groups will be at Day 61 (Visit 5), 
following the 1 or 2 RSV vaccine doses, respectively. The second dose of
Synflorix in the 1D and 2D groups will be at Day 121 (Visit 6). Formulation 
buffer will be administered, when neither RSV vaccine nor comparator is 
scheduled, at the 5 vaccination visits (see Synopsis Table 3) (Amended 21
March 2019).

In countries where Menveo is used as a control, two doses will be 
administered IM at least 3 months apart with the second dose in the second 
year of life at Day 365 (Visit 7). The first Menveo dose will be administered 
at Day 31 (Visit 3) (in the group receiving only Menveo). The first Menveo 
dose to be administered to the 1D and 2D RSV groups will be at Day 61 (Visit 
5), following the 1 or 2 RSV vaccine doses, respectively. Since the second 
Menveo dose has to be administered in the second year of life at Day 365 
(Visit 7), no administration will be performed at Day 121 (Visit 6). 
Formulation buffer will be administered, when neither RSV vaccine nor 
comparator is scheduled, at the 4 vaccination visits (see Synopsis Table 3)
(Amended 21 March 2019). 

In countries where Placebo is used as a control, one dose will be administered 
IM at Day 31 (Visit 3) in the 1D RSV + Placebo group and two IM doses will 
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
administered IM according to a 0, 1-month schedule at Day 1 (Visit 1) and 
Day 31 (Visit 3) in the Placebo group (see Synopsis Table 3). 
Synopsis Table 3
Vaccines administered and vaccination schedules (Amended 
21 March)
Groups
Age* (Months) / (Visit, Day)
6-7 / (V1, D1)
7-8 / (V3, D31) 8-9 / (V5, D61)
10-11 / (V6, D121)**
14-18 / (V7, 
D365)
1D RSV + Bexsero
1D RSV ChAd FB
Bexsero
Bexsero
Bexsero
2D RSV + Bexsero
2D RSV ChAd 2D RSV ChAd Bexsero
Bexsero
Bexsero
Bexsero
Bexsero
FB
Bexsero
FB
Bexsero
1D RSV + Nimenrix
1D RSV ChAd FB
Nimenrix
Nimenrix
Nimenrix
2D RSV + Nimenrix
2D RSV ChAd 2D RSV ChAd Nimenrix
Nimenrix
Nimenrix
Nimenrix
Nimenrix
FB
Nimenrix
FB
Nimenrix
1D RSV + Synflorix
1D RSV ChAd FB
Synflorix
Synflorix
Synflorix
2D RSV + Synflorix
2D RSV ChAd 2D RSV ChAd Synflorix
Synflorix
Synflorix
Synflorix
FB
Synflorix
Synflorix
FB
Synflorix
1D RSV + Menveo
1D RSV ChAd FB
Menveo
Menveo
2D RSV + Menveo
2D RSV ChAd 2D RSV ChAd Menveo
Menveo
Menveo
FB
Menveo
FB
Menveo
1D RSV + Placebo
1D RSV ChAd FB
2D RSV + Placebo
2D RSV ChAd 2D RSV ChAd
Placebo
FB
FB
V: Visit; D: Day; 1D: 1 Dose (1.5x1010 vp/dose); 2D: 2 Dose (5x1010 vp/dose); RSV ChAd: ChAd155-RSV vaccine;
FB: Formulation buffer S9b.
* Assumes enrolled at 6 and 7 months of age for the vaccine Dose 1 to be administered before the first RSV season 
(RSV seasons will be determined for each country based on local epidemiological data).
** In countries where Menveo or Placebo is used as a comparator, no administration will be performed at Day 121 
and therefore in those countries there will be no Visit 6 and it will be administered at the end of the first RSV 
season at Visit 7. 

For the United Kingdom (UK)authorized sites only, Visit 5 (Day 61) and Visit 7 
(both with blood sampling) may also take place in the subject’s home or at the 
investigators clinical facility as appropriate to the circumstances in the judgment 
of the investigator (Amended 21 March 2019).

Surveillance for spontaneous or excessive bleeding.
Subjects’ parent(s)/LAR(s) will be instructed to contact the investigator/study staff if 
their child presents symptoms of spontaneous bleeding or easy bruising or if their child 
develops a rash, within 30 days after either vaccination (Visit 1 and Visit 3), in order to 
detect any thrombocytopenic petechiae or purpura. The investigator will, based on his/her 
medical judgment, measure the total blood count and appropriately investigate infants 
with clinical suspicion of low platelets (Amended 21 March 2019).
 
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Section 1.2.2.1, Study Population was amended as follows: 
The immunogenicity, safety and reactogenicity of the pediatric candidate RSV vaccine 
(ChAd155-RSV vaccine) has been evaluated in healthy adults aged 18 to 45 years (study 
201974 [RSV PED-001; NCT02491463]). A clinical study is currently being conducted 
in RSV-seropositive infants aged 12 to 23 months (study 204838 [RSV PED-002]). The 
safety profile of the ChAd155-RSV vaccine in adults (study 201974 [RSV PED-001; 
NCT02491463]) has been evaluated deemed satisfactory by GSK and an Independent 
Data Monitoring Committee (IDMC). Should there be a satisfactory safety profile of the 
ChAd155-RSV vaccine in RSV-seropositive infants, as evaluated by an IDMC on Day 60 
data (i.e., 30 days post-Dose 2 of the highest dose level) of the study RSV PED-002, the 
present study will be performed. This study will be conducted on infants aged 6 and 7 
months (having a low chance of natural exposure to RSV before inclusion in the study). 
Although potentially both RSV-exposed and RSV-unexposed subjects will be enrolled, 
Tthe primary analysis for incidence of LRTI will be conducted in infants with a negative 
RSV exposure status (at screening based on in-stream serological testing). This study will 
support the decision to age de-escalate to the targeted population (infants as from 6 weeks 
of age) (Amended 21 March 2019). 
Section 1.2.4, Rationale for safety monitoring plan was amended as follows: 
During this study, safety evaluations will be performed by an internal safety review 
committee (iSRC) (refer to Section 9.10.2) and an independent data monitoring 
committee (IDMC) (refer to Section 9.10.3), with specific holding rules. Data of LRTI 
associated with RSV infection will be received by the IDMC within 48 hours upon GSK 
becoming aware (refer to Section 9.10.3 for more detailed information). Any holding 
rules met during the study will be escalated to the Vaccine Safety Monitoring Board 
(VSMB; refer to Sections 9.10.4 and 9.10.5) (Amended 21 March 2019).
Section 1.2.4.2, Rationale for monitoring for spontaneous or excessive bleeding was
revised as follows: 
During a study carried out in adult subjects (RSV001), a mild non-clinically significant 
drop in hemoglobin was noted following vaccination with another adenoviral vector 
(PanAd3-RSV) without clinical signs and with a reversal towards baseline values over 
time [RSV001 Interim Study Report, 2014]. In the repeat dose toxicology study in rabbits 
using the ChAd155-RSV vaccine, a transient non-clinically significant drop in platelets 
was noted post IM vaccination (maximal drop of platelet observed 24 hours after 
vaccination; refer to the current IB for further details). In light of these data, subjects’ 
parent(s)/ legally acceptable representative(s) (LAR[s]) will be instructed to contact the 
investigator/study staff if their child presents symptoms of spontaneous bleeding or easy 
bruising or if their child develops a rash, within 30 days after either vaccination (Visit 1 
and Visit 3), in order to detect any thrombocytopenic petechiae or purpura. The 
investigator will, based on his/her medical judgment, measure the total blood count and 
appropriately investigate infants with clinical suspicion of low platelets (Amended 21 
March 2019).
 
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Section 1.2.7, Rationale for ChAd155 RSV vaccine recipients receiving active 
comparator vaccine was amended as follows: 
To provide potential benefit to all trial participants and to maintain the study blind until 
the end of follow up, the ChAd155-RSV vaccine recipients will also receive 
immunization with the selected active comparator vaccine (Amended 21 March 2019).
Section 1.3.1, Risk Assessment was amended as follows: 
As with all injectable vaccines, immediate systemic allergic reactions to vaccination can 
occur. In order to be able to treat infants with an immediate systemic allergic reaction to 
vaccination, all infants across all stepsgroups will need to remain under observation 
(visual follow-up as well as measurement of vital signs) at the study site for at least 
60 minutes after vaccination for Visit 1 and Visit 3 and 30 minutes for all remaining 
vaccination visits (Amended 21 March 2019).
Section 1.3.2, Benefit Assessment was amended as follows: 
The choice of active comparator vaccine (Bexsero, Nimenrix, Synflorix, or Menveo) for 
each participating country ensures that the vaccine may be given according to the local 
label and provides potential medical benefit in the country that chose active comparator. 
Within a given participating country, all infants in both groups of this study will receive 
the full locally recommended vaccination course of active comparator vaccine where 
possible and may be immunized against either invasive meningococcal disease caused by 
Neisseria meningitidis (with the meningococcal vaccines Bexsero, Nimenrix or Menveo);
or against invasive pneumococcal disease, pneumonia, and acute otitis media caused by 
Streptococcus pneumoniae (with the pneumococcal vaccine Synflorix) (Amended 21
March 2019).
Section 1.3.2, Overall Benefit: Risk Conclusion was amended as follows: 
The investigational ChAd155-RSV vaccine is currently in Phase I/II stage of clinical 
development and no vaccine efficacy has been demonstrated. Taking into account the 
measures taken to minimize the risk to infants participating in this study, the potential 
risks to the subjects are justified by the potential benefits linked to the development of 
this pediatric RSV vaccine.
The four control vaccines administered to all participants in this study as active 
comparators, are licensed for infants in the particular country where possible, and 
therefore have demonstrated medical benefit in the prevention of invasive meningococcal 
disease caused by Neisseria meningitidis (for the meningococcal vaccines Bexsero,
Nimenrix, Menveo); or against invasive pneumococcal disease, pneumonia, and acute 
otitis media caused by Streptococcus pneumoniae (for the pneumococcal vaccine 
Synflorix) (Amended 21 March 2019).
Section 3 has been amended as follows: 
 
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STUDY DESIGN OVERVIEW (AMENDED 21 MARCH 2019)
Figure 7
Study design 
D: Day; FU: follow-up; IDMC: Independent Data Monitoring Committee; iSRC: internal Safety Review Committee; RSV: respiratory syncytial virus; RTI: respiratory tract infection; SE: 
solicited events; V: Visit 1D: 1 Dose (1.5x1010 vp/dose); 2D: 2 Dose (5x1010 vp/dose); FB: Formulation buffer S9b. 
* Vaccine Dose 1 at Day 1 will be administered before the first RSV season (refer to Section 5.1 for definition of RSV season).
End of RSV 
season 2
SE to D8
= Blood sample for safety
BSS
BSS
Surveillance period for RSV RTI a
BSH
BSH
BSH
= Blood sample for humoral immunogenicity
BSH
Nasal swab, as applicable c
BSH
Vaccination phase
FU phase
Screening
Epoch 002
Epoch 003
Epoch 004
Epoch 001
D121
V6 ‡
D61
V5
End of RSV 
season 1
V7
V8 †
D1
D8
D31
D38
V1*
V2 †
V3
V4 †
Visit
Day
SCREENING
D-30 to D-1
IDMC/iSRC review b
SE to D8
2D RSV+Bexsero
2D RSV
Dose 1
Dose 2
Bexsero
Bexsero
Bexsero
Bexsero
Bexsero
FB
Bexsero
Bexsero
FB
2D RSV+Nimenrix
2D RSV
2D RSV
Nimenrix
Nimenrix
Nimenrix
Nimenrix
Nimenrix
FB
Nimenrix
Nimenrix
FB
2D RSV+Menveo
2D RSV
2D RSV
Menveo
Menveo
Menveo
FB
Menveo
FB
Menveo
2D RSV+Synflorix
2D RSV
2D RSV
Synflorix 
Synflorix
Synflorix
Synflorix
FB
Synflorix
Synflorix
Synflorix
FB
2D RSV
1D RSV+Bexsero
1D RSV
Bexsero
Bexsero
Bexsero
FB
1D RSV+Nimenrix
1D RSV
FB
Nimenrix
Nimenrix
Nimenrix
1D RSV+Menveo
1D RSV
FB
Menveo
Menveo
1D RSV+Synflorix
1D RSV
FB
Synflorix
Synflorix
Synflorix
IDMC review b
2D RSV+ Placebo
2D RSV
2D RSV
Placebo   
FB
FB
1D RSV+ Placebo
1D RSV
FB
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† Visit 2 (Day 8), Visit 4 (Day 38), and Visit 8 (no blood sampling for immune response and no vaccine administration) may take place in the subject’s home or at the investigators 
clinical facility as appropriate to the circumstances in the judgment of the investigator. For the United Kingdom (UK)authorized sites only, Visit 5 (Day 61) and Visit 7 (both with 
blood sampling) may also take place in the subject’s home or at the investigators clinical facility as appropriate to the circumstances in the judgment of the investigator (Amended 
21 March 2019).
‡ In countries where Menveo or Placebo is used as a comparator, no administration will be performed at Day 121 and therefore in those countries there will be no Visit 6 and it will be 
administered at the end of the first RSV season at Visit 7 (refer to Table 2 and Table 7). 
a Surveillance for RSV-RTI comprises monthly nasal swab collected to detect asymptomatic RSV infections during RSV season and active and passive surveillance contacts for RSV 
symptomatic RTI. Of note the swab may be omitted if a nasal swab has been taken at a symptomatic visit in the same month (see Section 9.2). Data about RSV–RTI incidence 
will be reviewed monthly by an IDMC.
b An iSRC will review all accumulating safety data monthly until the IDMC reviews has reviewed all safety data up to 30 days after administration of Dose 2 (i.e., Day 61). The IDMC will 
review all accumulating safety data monthly throughout the period of vaccination and accumulating SAEs until the end of the second RSV transmission season. Refer to Sections 
9.10.2 and 9.10.3.
c Refer to Section 6.6.12.3
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Table 2
Vaccines administered and vaccination schedules (Amended 
21 March 2019)
Groups
Age* (Months) / (Visit, Day)
6-7 / (V1, D1)
7-8 / (V3, D31) 8-9 / (V5, D61)
10-11 / (V6, D121)**
14-18 / (V7, D365)
1D RSV + Bexsero
1D RSV ChAd FB
Bexsero
Bexsero
Bexsero
2D RSV + Bexsero
2D RSV ChAd 2D RSV ChAd Bexsero
Bexsero
Bexsero
Bexsero
Bexsero
FB
Bexsero
FB
Bexsero
1D RSV + Nimenrix
1D RSV ChAd FB
Nimenrix
Nimenrix
Nimenrix
2D RSV + Nimenrix
2D RSV ChAd 2D RSV ChAd Nimenrix
Nimenrix
Nimenrix
Nimenrix
Nimenrix
FB
Nimenrix
FB
Nimenrix
1D RSV + Synflorix
1D RSV ChAd FB
Synflorix
Synflorix
Synflorix
2D RSV + Synflorix
2D RSV ChAd 2D RSV ChAd Synflorix
Synflorix
Synflorix
Synflorix
FB
Synflorix
Synflorix
FB
Synflorix
1D RSV + Menveo
1D RSV ChAd FB
Menveo
Menveo
2D RSV + Menveo
2D RSV ChAd 2D RSV ChAd Menveo
Menveo
Menveo
FB
Menveo
FB
Menveo
1D RSV + Placebo
1D RSV ChAd FB
2D RSV + Placebo
2D RSV ChAd 2D RSV ChAd
Placebo
FB
FB
V: Visit; D: Day; 1D: 1 Dose (1.5x1010 vp/dose); 2D: 2 Dose (5x1010 vp/dose); RSV ChAd: ChAd155-RSV vaccine;
FB: Formulation buffer S9b. 
* Assumes enrolled at 6 and 7 months of age for the vaccine Dose 1 to be administered before the first RSV season; 
the second dose will be given one month after the first dose. (RSV seasons will be determined for each country 
based on local epidemiological data [The RSV season is defined as the period of the year when 70% of the RSV 
cases have occurred in previous years. For the calculation, where available, data from up to the ten previous 
years should be applied. If the data permit calculation of the actual date of the beginning of the season, rather 
than approximation to the nearest month, this is desirable. Refer to the SPM for RSV seasons per country.])
** In countries where Menveo or Placebo is used as a comparator, no administration will be performed at Day 121 and 
therefore in those countries there will be no Visit 6 and it will be administered at the end of the first RSV season at 
Visit 7. 
 
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Table 3
Study groups and epochs foreseen in the study (Amended 21 
March 2019) 
Study groups
Target Number 
of subjects
Age (Min/Max)
Epochs
Epoch 001
Epoch 002
Epoch 003
Epoch 004
1D RSV + Bexsero
50
6 – 7 months
N/A
x
x
x
1D RSV + Nimenrix
6 – 7 months
N/A
x
x
x
1D RSV + Synflorix
6 – 7 months
N/A
x
x
x
1D RSV + Menveo
6 – 7 months
N/A
x
x
x
1D RSV + Placebo
6 – 7 months
N/A
x
x
x
2D RSV + Bexsero
50
6 – 7 months
N/A
x
x
x
2D RSV + Nimenrix
6 – 7 months
N/A
x
x
x
2D RSV + Synflorix
6 – 7 months
N/A
x
x 
x
2D RSV + Menveo
6 – 7 months
N/A
x
x
x
2D RSV + Placebo
6– 7 months
N/A
x
x
x
Bexsero
50
6 – 7 months
N/A
x
x
x
Nimenrix
6 – 7 months
N/A
x
x
x
Synflorix 
6 – 7 months
N/A
x
x
x
Menveo
6 – 7 months
N/A
x
x
x
Placebo
6 – 7 months
N/A
x
x
x
1D: 1 Dose (1.5x1010 vp/dose); RSV: ChAd155-RSV vaccine; 2D: 2 Dose (5x1010 vp/dose); N/A: Not Applicable. 

Vaccination schedules:
RSV investigational vaccine:

In the 1 Dose (1D) groups, a single lower dose of 1.5x1010 vp will be 
administered IM at Day 1 (Visit 1). Formulation buffer will be administered in 
the 1D groups at Day 31 (Visit 3). In the 2 Dose (2D) groups, two doses of 
5x1010 vp will be administered IM according to a 0, 1-month schedule, (i.e., at 
Day 1 [Visit 1] and Day 31 [Visit 3]) (see Figure 1 and Table 2). Dose 1 will be 
administered before the first RSV season and the second dose will be given one 
month after the first dose (RSV seasons will be determined for each country 
based on local epidemiological data and documented in the Study Procedures 
Manual [SPM]. The RSV season is defined as the period of the year when 70% 
of the RSV cases have occurred in previous years. For the calculation, where 
available, data from up to the ten previous years should be applied. If the data 
permit calculation of the actual date of the beginning of the season, rather than 
approximation to the nearest month, this is desirable. (Amended 21 March 
2019). 
Comparator or Placebo:

In countries where Bexsero or Nimenrix is used as a control, two doses will be 
administered IM with at least a 2 month interval between these primary doses. A 
booster dose will be administered IM in the second year of life at Day 365 
(Visit 7), with an interval of at least 2 months between the primary series and 
booster dose. The first Bexsero or Nimenrix dose will be administered at Day 1 
(Visit 1) (in the groups receiving only Bexsero or Nimenrix, respectively). In the 
groups receiving only Bexsero or Nimenrix, the second dose will be at Day 61 
(Visit 5). The first Bexsero or Nimenrix dose to be administered to the 1D and 
 
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2D RSV groups will be at Day 61 (Visit 5), following the 1 or 2 RSV vaccine 
doses, respectively. The second dose of Bexsero or Nimenrix in the 1D and 2D 
groups will be at Day 121 (Visit 6). Formulation buffer will be administered, 
when neither RSV vaccine nor comparator is scheduled, at the 5 vaccination 
visits (see Figure 1 and Table 2). (Amended 21 March 2019)

In countries where Synflorix is used as a control, two doses will be administered 
IM with at least a 1 month interval between these primary doses. A booster dose 
will be administered IM in the second year of life at Day 365 (Visit 7). The first
Synflorix dose will be administered at Day 31 (Visit 3) (in the group receiving 
only Synflorix). In the group receiving only Synflorix, the second dose will be at 
Day 61 (Visit 5). The first Synflorix dose to be administered to the 1D and 2D 
RSV groups will be at Day 61 (Visit 5), following the 1 or 2 RSV vaccine doses, 
respectively. The second dose of Synflorix in the 1D and 2D groups will be at 
Day 121 (Visit 6). Formulation buffer will be administered, when neither RSV 
vaccine nor comparator is scheduled, at the 5 vaccination visits (see Figure 1 
and Table 2). (Amended 21 March 2019)

In countries where Menveo is used as a control, two doses will be administered 
IM at least 3 months apart with the second dose in the second year of life at 
Day 365 (Visit 7). The first Menveo dose will be administered at Day 31
(Visit 3) (in the group receiving only Menveo). The first Menveo dose to be 
administered to the 1D and 2D RSV groups will be at Day 61 (Visit 5), 
following the 1 or 2 RSV vaccine doses, respectively. Since the second Menveo 
dose has to be administered in the second year of life at Day 365 (Visit 7), no 
administration will be performed at Day 121 (Visit 6). Formulation buffer will 
be administered, when neither RSV vaccine or comparator is scheduled, at the 4 
vaccination visits (see Figure 1 and Table 2). (Amended 21 March 2019)
Section 5.3, Exclusion criteria for enrolment has been amended as follows:

History of recurrent wheezing. (“Recurrent wheezing” is defined as ≥ 2 episodes of 
wheezingin the subject´s lifetime.in the past 12 months). Wheezing should have 
been verified on auscultation by doctor (Amended 21 March 2019).

Weight below the fifth percentile according to the World Health Organization 
(WHO) weight-for-age tables 
(https://www.who.int/childgrowth/standards/weight_for_age/en/)

(Amended 21 March 2019).

Concurrently pParticipating in another clinical study, at any time during the study 
period, in which the subject or mother (if breastfeeding) has been or will be exposed 
to an investigational or a non-investigational vaccine/product (pharmaceutical 
product or device) (Amended 21 March 2019).
Section 6.2.2.2.1, Study group and treatment number allocation 
After obtaining the signed and dated ICF from the subject’s parent(s)/LAR(s) and having 
checked the eligibility of the subject, the delegated study staff in charge of the vaccine 
administration will access SBIR. Upon providing the subject identification number and 
 
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the age, the randomization system will determine the study group and will provide the 
treatment number to be used for the first dose (Amended 21 March 2019).
Section 6.2.2.2.2, Treatment number allocation for subsequent doses
For each dose subsequent to the first dose, the delegated 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 
(Amended 21 March 2019).
Section 6.6.5, Medical History was amended as follows:
6.6.5       Medical History
Obtain the subject’s medical history by interview and/or review of the subject’s medical 
records and record weight at birth and gestation in weeks at birth as well as any pre-
existing conditions or signs and/or symptoms present in a subject prior to the first study 
vaccination in the eCRF. For World Health Organization (WHO) weight percentile
standards for girls and boys, refer to the following link: 
https://www.who.int/childgrowth/standards/weight_for_age/en/ (Amended 21 March 
2019).
Section 6.6.9 was revised as follows:
6.6.9       Assess pre-vaccination body temperature
The rectal (preferred route) body temperature of each subject needs to be measured prior 
to any study vaccines administration. If the subject has fever (fever is defined as 
temperature 38.0°C/100.4°F regardless the location of measurement) on the day of 
vaccination, the vaccination visit will be rescheduled within the allowed interval for this 
visit (see Table 24) (Amended 21 March 2019).
Section 6.6.15 was amended as follows: 
6.6.15       Recording of AEs, AEs of special interest and SAEs

Subjects’ parent(s)/LAR(s) will be instructed to contact the investigator/study staff if 
their child presents symptoms of spontaneous bleeding or easy bruising or if their 
child develops a rash, within 30 days after either vaccination (Visit 1 and Visit 3), in 
order to detect any thrombocytopenic petechiae or purpura after each vaccination 
from Visit 1 [Day 1] to Visit 5 Day 61 (Amended 21 March 2019).
 
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Table 7
List of study procedures
Epoch
Epoch 001
Epoch 002
Epoch 003
Epoch 004
Age
6-7 months
6-9 months
Type of contact
Screening Visit 1 Visit 2 b Visit 3 Visit 4 b Visit 5 Visit 6 c
Visit 7
Visit 8 b 
Unscheduled 
visit for 
safety e
Contact for 
active/ 
passive 
surveillance f 
Surveillance 
for 
asymptomatic 
RSV-RTI g 
Assessment 
of potential 
RSV-RTI h 
Timepoints
D -30 to
D-1 a
D1
D8
D31
D38
D61
D121
D365
End of the 
1st RSV 
season d
D730
End of the 
2nd RSV 
season d
Monthly or 
Weekly
Monthly
Informed consent
●
Check inclusion/exclusion criteria
●
O
Collect demographic data
●i
Medical history j
●
Physical examination k
●
O
O
O
O
O
O
O
O
O
●
Growth monitoring l
●
●
●
●
●
Check contraindications and 
warnings and precautions
O
O
O
O
O
(Pre-vaccination) body temperature
●
●
●
●
●
Randomization
O
Vaccine administration m
●
●
●
● c
●
Recording of administered treatment 
number
●
●
●
●
●
60 minutes post-vaccination 
observation n
O
O
30 minutes post-vaccination 
observation for additional 
comparator/FB vaccinations 
O
O
O
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Epoch
Epoch 001
Epoch 002
Epoch 003
Epoch 004
Age
6-7 months
6-9 months
Type of contact
Screening Visit 1 Visit 2 b Visit 3 Visit 4 b Visit 5 Visit 6 c
Visit 7
Visit 8 b 
Unscheduled 
visit for 
safety e
Contact for 
active/ 
passive 
surveillance f 
Surveillance 
for 
asymptomatic 
RSV-RTI g 
Assessment 
of potential 
RSV-RTI h 
Timepoints
D -30 to
D-1 a
D1
D8
D31
D38
D61
D121
D365
End of the 
1st RSV 
season d
D730
End of the 
2nd RSV 
season d
Monthly or 
Weekly
Monthly
Blood sampling for assessment of 
mechanisms of illness (potential 
ERD; ~2.5 mL)
● o
Blood sampling for hematology and 
biochemistry (~2.3 mL)
● p
● q
Blood sampling for humoral response 
(~2.5 mL)
● r
● s
●
●
Surveillance for RSV-RTI, difficulty in 
breathing and wheezing
O
O
O
O
O
O
O
O
O
O
Documentation of symptoms and 
signs of RTI t
●
Nasal swab for central testing (RSV 
and RVP)
● u
● v
Specimen for local testings (RSV and 
RVP)
● w
Distribution of RTI episode card x
O
O
O
O
O
O
O
Collection of RTI episode card x
O
O
O
O
O
O
O
O
O
O
Transcription of RTI episode card
●
●
●
●
●
●
●
O
●
●
Record any concomitant 
medications/vaccinations
●
●
●
●
●
●
●
●
●
●
●
Distribution of the subject card
O
Distribution of diary card
O
O
O
O
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Epoch
Epoch 001
Epoch 002
Epoch 003
Epoch 004
Age
6-7 months
6-9 months
Type of contact
Screening Visit 1 Visit 2 b Visit 3 Visit 4 b Visit 5 Visit 6 c
Visit 7
Visit 8 b 
Unscheduled 
visit for 
safety e
Contact for 
active/ 
passive 
surveillance f 
Surveillance 
for 
asymptomatic 
RSV-RTI g 
Assessment 
of potential 
RSV-RTI h 
Timepoints
D -30 to
D-1 a
D1
D8
D31
D38
D61
D121
D365
End of the 
1st RSV 
season d
D730
End of the 
2nd RSV 
season d
Monthly or 
Weekly
Monthly
Return of diary card
O
O
O
O
Diary card transcription by 
investigator
●
●
●
●
Recording of solicited AEs (Day 1–7)
●
● 
●
●
● y
Recording of unsolicited AEs (Day 1-
30)
●
●
●
●
●
● y
Recording of AE leading to study 
withdrawal
●
●
●
●
●
●
●
●
●
●
●
●
Recording of AESI (RSV-LRTI)
●
●
●
●
●
●
●
●
●
●
●
●
Recording of AESI (spontaneous or 
excessive bleeding) z
●
●
●
●
●
●
Reporting of easy bruising, or 
rash/petechiae monitored by 
parent(s)/LAR(s) z
O
O
O
O
O
Recording of SAEs
●
●
●
●
●
●
●
●
●
●
●
●
Recording of SAEs related to study 
participation, or to a concurrent GSK 
medication/vaccine
●
●
●
●
●
●
●
●
●
●
●
●
●
Screening conclusion
●
Study conclusion
●
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Epoch
Epoch 001
Epoch 002
Epoch 003
Epoch 004
Age
6-7 months
6-9 months
Type of contact
Screening Visit 1 Visit 2 b Visit 3 Visit 4 b Visit 5 Visit 6 c
Visit 7
Visit 8 b 
Unscheduled 
visit for 
safety e
Contact for 
active/ 
passive 
surveillance f 
Surveillance 
for 
asymptomatic 
RSV-RTI g 
Assessment 
of potential 
RSV-RTI h 
Timepoints
D -30 to
D-1 a
D1
D8
D31
D38
D61
D121
D365
End of the 
1st RSV 
season d
D730
End of the 
2nd RSV 
season d
Monthly or 
Weekly
Monthly
Signing of investigator signature form 
by investigator after Screening and 
before each analysis
●
●
●
●
AE: adverse event; AESI: Adverse Events of Special Interest; FB: Formulation buffer S9b; LRTI: lower respiratory tract infection; RSV: respiratory syncytial virus; RTI: respiratory tract 
infection, RVP: respiratory viral panel SAE: serious adverse event.
● is used to indicate a study procedure that requires documentation in the individual eCRF.
O is used to indicate a study procedure that does not require documentation in the individual eCRF.
Note: the double-bordered lines following Visit 5 (Day 61), Visit 7 (end of the first RSV transmission season) and Visit 8 (end of the second RSV transmission season) indicate the 
statistical analyses which will be performed. After Visit 5 (Day 61) the study will be conducted in a single blind manner, with patients remaining blinded up to the last study visit 
(end of the second RSV transmission season). The investigator will not have access to the treatment allocation up to the last study visit (end of the second RSV transmission 
season), except in case of emergency unblinding.
a For vaccination done on the same day as screening, it must be ensured that screening procedures only begin after signing consent and that all the screening procedures confirming 
eligibility, including the laboratory results, are made available prior to vaccination (see Section 6.6.2).
bVisit 2 (Day 8), Visit 4 (Day 38), and Visit 8 (Day 730) (no blood sampling for immune response and no vaccine administration) may take place in the subject’s home or at the 
investigators clinical facility as appropriate to the circumstances in the judgment of the investigator. For the UK onlyFor authorized sites only; screening, Visit 5 (Day 61) and 
Visit 7 (both with blood sampling) may also take place in the subject’s home or at the investigators clinical facility as appropriate to the circumstances in the judgment of the 
investigator (Amended 21 March 2019). 
c In countries where Menveo or Placebo is used as a comparator, no administration will be performed at Day 121 and therefore in those countries there will be no Visit 6 and it will be 
administered at the end of the first RSV season at Visit 7 (refer Figure 1 and Table 2).
d Refer to the SPM for RSV seasons per country.
e This visit is applicable for infants with hematological/biochemical values out of normal range or for further evaluation of clinical suspicion of low platelet count.
f Active contacts for surveillance of RSV-RTI will take place weekly during each RSV season and every month outside the RSV season. Passive phone contacts from the carers to the 
investigator will take place when symptoms occur.
gIn order to detect asymptomatic RSV infection, monthly visits will be performed during the RSV season.
hThis visit is only applicable for infants with potential RSV-RTI.
i Recording of demographic data includes date of birth, sex, race, ethnicity and comparator group.
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jMedical history is collected by interview and/or review of the subject’s medical records and includes recording the subject’s weight at birth and gestation in weeks at birth as well as 
any pre-existing conditions or signs and/or symptoms present in a subject prior to the first study vaccination in the eCRF.
kAt screening, perform a complete physical examination, including assessment of vital signs (body temperature, heart rate [HR], and RR). At subsequent study visits, perform a 
physical examination only if the subject’s parent(s)/LAR(s) indicate(s) during questioning that there might be some underlying pathology(ies) or if deemed necessary.
lGrowth monitoring includes weight and length (for infants < 24 months of age) or height (for subjects 24 months of age).
mRefer to Table 2 and to the SPM for the comparator vaccine selection for each country.
n Infants will need to remain under observation (visual follow-up as well as measurement of resting vital signs) at the study site for at least 60 minutes after vaccination. Vital signs are 
body temperature, HR and RR. Vital signs are measured preferably when the infant is calm.
oBlood sample collected for subjects hospitalized for LRTI (only for RSV-positive subjects using a locally available RSV test). Refer to Section 6.7.3
p At Screening, for infants with hematological/biochemical values out of normal range which are expected to be temporary, a re-screening visit may be scheduled during which blood 
sample collection for hematology/biochemistry will be repeated (maximum one re-screening visit per infant is allowed).
q If any Grade 1 abnormality with potential clinical relevance (according to investigator judgment) or any ≥ Grade 2 abnormality is detected, or for further evaluation of clinical suspicion 
of low platelet count, refer to Section 6.6.12.2 and Figure 2 for re-test.
rIf no blood sample was collected for humoral immunogenicity at the screening visit, an additional blood sample will be taken at Visit 1 that must be taken before vaccination.
sSamples must be taken before vaccination.
t Signs and symptoms to be recorded in the eCRF are listed in the SPM.
u Nasal swab collected at the monthly surveillance for asymptomatic RSV-RTI will be tested by quantitative RT-PCR. This swab may be omitted upon investigator discretion if a swab 
has been taken for a symptomatic episode in the previous 4 weeks (see Section 6.6.12.3).
v If during passive or active surveillance contact, the investigator/study staff assesses that an infant presents a potential RSV-RTI (refer to Table 6 for definition), the potential RSV 
infection will be assessed by quantitative RT-PCR.
w At a local routine laboratory (Amended 21 March 2019).
x Subject’s parent(s)/LAR(s) will be instructed to record on the RTI episode card symptoms the start date and the end date of the following symptoms (cough, runny nose, blocked 
nose, difficulty in breathing, or wheezing) and to return it to the investigator at the next visit or by mail (e-mail or postal mail).
y Only when the unscheduled visit occurs within the AE reporting time frame, i.e., from Day 1 to Day 7 for solicited AEs and from Day 1 to Day 30 for unsolicited AEs.
z Subjects’ parent(s)/LAR(s) will be instructed to contact the investigator/study staff if their child presents symptoms of spontaneous bleeding or easy bruising or if their child develops a 
rash, within 30 days after either vaccination, in order to detect any thrombocytopenic petechiae or purpura (see Table 19). 
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Table 8 was amended as follows:
Table 8
Target intervals between study visits (Amended 21 March 
2019)
Interval
Length of interval
Screening Visit 1 (Day 1)
30 days 1
Visit 1 (Day 1) Visit 2 (Day 8)
7 days
Visit 1 (Day 1) Visit 3 (Day 31)
30 days
Visit 1 (Day 1) Visit 5 (Day 61)
60 days
Visit 3 (Day 31) Visit 4 (Day 38)
7 days
Visit 3 (Day 31) Visit 5 (Day 61)
30 days
Visit 5 (Day 61) Visit 6 (Day 121) 2
60 days
Visit 1 (Day 1) Visit 7 (end of the first RSV transmission 
season)
365 days
(From vaccination to the defined end of the first RSV 
transmission season)
Visit 1 (Day 1) Visit 8 (end of the second RSV 
transmission season)
730 days
(From vaccination to the defined end of the second 
RSV transmission season)
1 Visit 1 should take place no longer than 30 days after the Screening visit. When applicable, a re-screening visit may 
be scheduled at any time (but only once to assess eligibility). All screening procedures need to be performed 
within 30 days of Visit 1.
2 In countries where Menveo or Placebo is used as a comparator, no administration will be performed at Day 121 and 
therefore in those countries there will be no Visit 6 and if applicable it will be administered at the end of the first 
RSV season at Visit 7 (refer to Figure 1 and Table 2). 
Table 10 was amended as follows: 
Table 10
Humoral Immunity (Antibody determination) (Amended 21 March 
2019)
System
Component
Method
Kit / Manufacturer
Unit
Cut-off*
Laboratory**
SERUM
Respiratory 
Syncytial Virus A 
Ab
NEUTRALIZATION
In-house
ED60 18 ED60To be 
defined
GSK Biologicals1
SERUM
Respiratory 
Syncytial Virus F 
protein Ab.IgG
(Anti-RSV PreF 
antibody)
ELISA
In-house
EU/ml To be defined
NÉOMED-LABS1
Ab: antibody; ELISA: enzyme-linked immunosorbent assay; IgG: immunoglobulin G; RSV: respiratory syncytial virus
* Assay cut-off and unit might be subject to change (e.g., in case of requalification, revalidation or standardization). In 
this case, this will be documented in the clinical report. 
**Refer to APPENDIX B for the laboratory addresses.
1 GSK Biologicals laboratory refers to the CLS in Rixensart, Belgium; Wavre, Belgium
Section 9.1.5.1, Spontaneous or excessive bleeding was amended as follows:
9.1.5.1       Spontaneous or excessive bleeding
Subjects’ parent(s)/ legally acceptable representative(s) (LAR[s]) will be instructed to 
contact the investigator/study staff if their child presents symptoms of spontaneous 
bleeding or easy bruising or if their child develops a rash, within 30 days after either 
vaccination (Visit 1 and Visit 3), in order to detect any thrombocytopenic petechiae or 
 
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purpura. The investigator will, based on his/her medical judgment, measure the total 
blood count and appropriately investigate infants with clinical suspicion of low platelets.
Any episode of spontaneous or excessive bleeding occurring within 30 days after each 
vaccination should be fully investigated with a full range of hematological tests to 
identify the underlying cause and reported as an AE of special interest (Amended 21
March 2019).
Section 9.10.2, Internal safety review committee (iSRC) oversight was amended as 
follows: 
9.10.2   Internal safety review committee (iSRC) oversight
This study will be overseen by an iSRC operating under a charter. An iSRC was already 
involved in study RSV PED-002 (204838). Core members of the iSRC will include a 
GSK Biologicals’ safety physician, a CRDL, and a biostatistician who are not otherwise 
involved in the conduct of the project. The iSRC safety reviews will be conducted using 
unblinded data. The iSRC has access to the subject randomization and reviews unblinded 
data.
The iSRC will review all accumulating safety and reactogenicity data four weeks after 
the start of vaccination and then every 4 weeks until all dosing with ChAd155-RSV 
vaccine is complete on the study. The iSRC members will determine if a safety signal 
should be escalated to the VSMB. The iSRC members will determine whether any of the 
predefined holding rules are met (refer to Section 9.10.4) or if there is any other safety 
signal. In this case, vaccination in the study will be immediately put on hold (refer to 
Section 9.10.5) (Amended 21 March 2019).
Section 9.10.3, Independent Data Monitoring Committee (IDMC) oversight was 
amended as follows:
9.10.3   Independent Data Monitoring Committee (IDMC) oversight
This study will be overseen by an IDMC operating under a charter. The IDMC involved 
in the present study was already involved in study RSV PED-002 (204838). Overall, the 
role of the IDMC includes the review and protection of data integrity and rights and 
safety of study participants throughout the study period. It will provide initial, regular, 
and closing advice to GSK Biologicals on medical, ethical, scientific and safety-related 
issues. Its advice will be based on the interpretation of study data with reference to the 
study protocol.
The IDMC will review the protocol and statistical analysis plan. 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 the principal investigators and GSK Biologicals’ designated 
project representatives at any stage of the study.
The IDMC may recommend to the sponsor to suspend the enrolment to the study and/or 
vaccination based on their review of safety data arising in this study (refer to Section 
9.10.4)
 
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The IDMC safety reviews will be conducted using unblinded data. The IDMC will 
review all available safety data while taking into account any other findings that could 
have an impact on the safety of the subjects.
The IDMC members will determine whether any of the predefined study holding rules 
are met (refer to Section 9.10.4) or if there is any other safety signal. If this is the case, 
vaccination in the study will be immediately put on hold. If no safety signal is observed, 
the favorable outcome of the safety evaluation authorizing the investigator to proceed 
with vaccination of infants as outlined in Figure 1 will be also documented and provided 
in writing.

The IDMC will receive the following safety data within 48 hours upon GSK 
becoming aware of:

Fatal SAEs occurring from Day 1 to the end of the second RSV transmission 
season.

Life-threatening SAEs occurring from Day 1 to the end of the second RSV 
transmission season.

Related SAEs occurring from Day 1 to the end of the second RSV transmission 
season.

SAEs occurring within 30 days of vaccination.

LRTI associated with RSV infection (AE of special interest) occurring from Day 
1 to the end of the second RSV transmission season.

Spontaneous or excessive bleeding (AE of special interest) occurring within 30 
days after each vaccination.
The IDMC will receive the following safety data monthly:

Summary reports of solicited and unsolicited AEs. (during the period of 
vaccination).

Cumulative reports of the incidence of RSV RTI, RSV-LRTI, severe RSV-
LRTI, very severe RSV-LRTI and RSV-RTI leading to hospitalization based on 
Table 6 by using local test results until the quantitative PCR results are 
available.

Cumulative tables of incidence of all SAEs.
Additionally, an analysis on occurrence of the progression from infection to very 
severe RSV-LRTI from first vaccination (Day 1) up to the end of the first RSV 
transmission season will be conducted on all subjects who have completed Visit 7 (end 
of the first RSV transmission season) by independent Data Analysis Center if there are 
minimum of 5 infections among subjects with a negative RSV exposure status (at 
screening which will be assessed by in-stream serological testing of baseline samples) 
in each randomized group. (Amended 21 March 2019)
 
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In addition, the IDMC will receive from GSK Biologicals:

New information that may adversely affect the safety of the subjects or the conduct 
of the study.

All subsequent protocol amendments, informed consent changes or revisions or other 
documents originally submitted for review.

All subsequent protocol administrative changes (for information).
Table 22 was amended as follows:
Table 22
Holding rules assessed by the investigator (Amended 21 
March 2019)
Holding 
Rule
Event
Number of 
infants/group
1a
Death or any life-threatening serious adverse event (SAE) that can be causally related 
to vaccination, according to investigator’s assessment.
≥ 1
1b
Any withdrawal from the study (by investigator or parent(s)/LAR(s) of the subject 
request) following a Grade 3 AE that cannot reasonably be attributed to a cause other 
than vaccination.
≥ 1
1c
Any local or general solicited AE leading to hospitalization that cannot reasonably be 
attributed to a cause other than vaccination.
≥ 1
1d
Within 30 days post-vaccination (Visit 1 and Visit 3),
Any spontaneous local or general bleeding
AND Thrombocytopenia < 50000/mm3
≥ 1
If an investigator detects one of the holding rules mentioned above, he/she will 
immediately put the enrolment or the vaccination on hold (refer to Section 9.10.4) and 
he/she will immediately inform the sponsor and enter the data in the eCRF. It is sponsor’s 
responsibility to put the enrolment or the vaccination on hold at all sites.
Section 9.10.5 was amended as follows:
9.10.5      Procedure if the trial is put on hold
If the trial is put on hold by the investigator or iSRC or IDMC because a pre-defined 
holding rule is met or because of a safety concern, then all enrolment in the study and all 
vaccination will cease immediately, but all other procedures relating to safety, 
immunology and disease monitoring will continue. The iSRC/IDMC will review all 
available safety information and may ask for additional information to be provided by the 
investigators or the sponsorstudy team. The iSRC/IDMC will make a recommendation to 
the sponsorstudy team whether the study should be stopped permanently, modified or 
continued unchanged (Amended 21 March 2019).
The sponsor VSMB will review all data and iSRC/IDMC recommendation and will 
decide whether to stop permanently, modify or continue the conduct of the study. The 
decision of the VSMB regarding the further conduct of the study will be documented and 
provided in writing to the investigators (Amended 21 March 2019).
 
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Table 24 was amended as follows: 
Table 24
Maximum allowed interval between study visits (Amended 21 
March 2019)
Interval
Allowed length of interval1
Screening Visit 1 (Day 1)
0 - 30 days
Visit 1 (Day 1) Visit 2 (Day 8)
7 - 10 days
Visit 1 (Day 1) Visit 3 (Day 31)
23 - 44 days
Visit 1 (Day 1) Visit 5 (Day 61)
60 - 81 days
Visit 3 (Day 31) Visit 4 (Day 38)
7 - 10 days
Visit 3 (Day 31) Visit 5 (Day 61)
28 - 37 days 2
Visit 5 (Day 61) Visit 6 (Day 121) 3
60 - 81 days
Visit 5 (Day 61) Visit 7
(end of the first RSV transmission season)
90 days to the defined end of transmission season or 
up to 4 weeks after
Visit 6 (Day 121) 3 Visit 7
(end of the first RSV transmission season)
60 days to the defined end of transmission season or 
up to 4 weeks after
Visit 1 (Day 1) Visit 7
(end of the first RSV transmission season)
180 days to the Defined end of first RSV transmission 
season or up to 4 weeks after
Visit 1 (Day 1) Visit 8
(end of the second RSV transmission season)
from the dDefined end of second RSV transmission 
season or up 
to 4 weeks after
1 Subjects will not be eligible for inclusion in the PP cohort for analysis of immunogenicity if they make the study visit 
outside this interval.
2 The interval between Visit 1 and Visit 5 must be a minimum of 60 days to be in line with the active comparator 
vaccination schedules as per the respective approved labels.
3 In countries where Menveo or Placebo is used as a comparator, no administration will be performed at Day 121 and 
therefore in those countries there will be no Visit 6 and Menveo will be administered at the end of the first RSV 
season at Visit 7 (refer to Table 2 and Table 7). For those countries where there is no Visit 6, should 
consider the interval from Visit 5 - Visit 7.
Section 11.5.3 was amended as follows: 
11.5.3    Per-protocol Set for analysis of immunogenicity (Amended 21 
March 2019)
The per-protocol set (PPS) cohort for analysis of immunogenicity will be defined by 
timepoint and will consist of all subjects from the ES who complied with eligibility 
criteria, study procedures up to the end of the study and had immunogenicity results in 
the epoch as described below. 
More specifically, the PPS cohort for analysis of immunogenicity up to Day 61 (Visit 5) 
/at Visit 7 (end of the first RSV transmission season) will include all evaluable subjects: 

Who met all eligibility criteria (i.e., no protocol violation linked to the 
inclusion/exclusion criteria, including age).

Who received study vaccine as scheduled per protocol. 

For whom the administration route and site of the vaccine was as according to 
protocol.

Who received the vaccine according to protocol procedures.

Who complied with the vaccination schedule, as specified in Table 7. 
 
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
Who did not receive a concomitant medication/product/vaccine leading to exclusion 
from a PPS analysis, as described in Section 7.6.2 up to Day 61 (Visit 5) /at Day 365 
(Visit 7) (end of the first RSV transmission season). 

Who complied with the timings of the post vaccination blood sampling for immune 
response evaluation, up to Day 61 (Visit 5) /at Day 365 (Visit 7) (end of the first 
RSV transmission season), as specified in Table 7. 

For whom post-vaccination immunogenicity results are available for at least one 
assay up to Day 61 (Visit 5) /at Day 365 (Visit 7) (end of the first RSV transmission 
season). 
Section 11.8.1 was amended as follows: 
11.8.1        Within groups assessment 
The safety will be descriptively summarized based on the ES. The analysis of local AEs, 
general AEs and fever will be reported for each RSV + comparator vaccine group and 
each active control comparator group and also for the pooled RSV vaccine and pooled 
comparator groups. For the analysis of SAEs and AE of specific interest, the analysis will 
be performed only on the pooled RSV and pooled comparator groups.
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 vaccine dose and overall. The percentage of doses followed by at least one local AE 
(solicited and unsolicited), by at least one general AE (solicited and unsolicited) and by 
any AE during the 7-day or 30-day follow-up period will be tabulated, overall 
vaccination course, with exact 95% CI. The same computations will be done for Grade 3 
AEs, for any AEs considered related to vaccination for any Grade 3 AEs considered 
related to vaccination and AEs resulting in a medically attended visit.
The percentage of subjects reporting each individual solicited local AE (any grade, Grade 
2, Grade 3, resulting in a medically attended visit) and solicited general AE (any grade, 
Grade 2, Grade 3, any related, Grade 2 related, Grade 3 related, resulting in medically 
attended visit) during the 7-day follow-up period (Day 1-7) will be tabulated for each 
RSV + comparator vaccine group and each active control comparator group and also for 
the pooled RSV vaccine and pooled comparator groups after each vaccine dose and 
overall. Similarly, the percentage of doses followed by each individual solicited local and 
general AE and their sub-categories, will be tabulated, overall vaccination course, with 
exact 95% CI.
For fever, the number and percentage of subjects reporting fever by half degree (°C) 
cumulative increments during the 7-day follow-up period (Day 1-7) will be tabulated for 
each RSV + comparator vaccine group and each active control comparator group and also 
for the pooled RSV vaccine and pooled comparator groups after each vaccine dose and 
overall. Similar tabulations will be performed for any fever with a causal relationship to 
vaccination, Grade 3 (> 40.0°C) causally related fever and for any fever resulting in a 
medically attended visit. In addition, the prevalence of any and Grade 3 fever will be 
presented graphically over time after vaccination.
 
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For each group and for each hematology and biochemistryclinical safety laboratory 
parameters: a listing of laboratory value outside the normal range for the unscheduled 
visits will be provided as per the toxicity scale refered in the protocol. The percentage of 
subjects having hematology and biochemistry results below or above the local laboratory 
normal ranges will be tabulated by timepoint. The maximum grading during the study 
will be tabulated (Refer to APPENDIX C) Laboratory values will be classified 
according to toxicity criteria. Laboratory values that are outside the normal range will 
also be flagged in the data listings, along with corresponding normal ranges and 
assessment of clinical significance (Amended 21 March 2019)
Section 11.12.1 was amended as follows:
Section 11.12.1   Sequence of analyses
In preparation of the planned iSRC and IDMC evaluations, analyses of all available 
safety data (i.e., data that are as clean as possible) will be performed (see Section 9.10 for 
more information). These analyses will be done by an unblinded statistician outside GSK 
to maintain the blinding of the study, and will be documented in a statistical analysis 
report. Only the outcome of the iSRC and IDMC reviews will be communicated to the 
RSV study team (no safety signal or safety signal). No clinical study report will be 
written. 
The statistical analyses will be performed in 3 steps:

An analysis will be performed when all data up to Day 61 (i.e., data that are as clean 
as possible) are available. Additional safety data available at the time of this analysis 
will be described. At this point, the statistician will be unblinded (i.e., individual 
subject treatment assignments will be available) and the study will be conducted in a 
single blind manner, with patients remaining blinded up to the last study visit (end of 
the second RSV transmission season). Summary results may unblind some specific 
subjects but no individual listings will be provided and the investigator will not have 
access to the treatment allocation up to the last study visit (end of the second RSV 
transmission season), except in case of emergency unblinding (see Section 9.8). 
(Amended 21 March 2019)

An analysis will be performed when all data up to Visit 7 (end of the first RSV 
transmission season) are available. No individual listings will be provided.

The final analysis will be performed when all data up to study conclusion (end of the 
second RSV transmission season) are available. An integrated clinical study report 
containing all data will be written and made available to the investigators at that 
time.
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.
 
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GlaxoSmithKline Biologicals SA
Vaccines R &D
Protocol Amendment 4
eTrack study number 
and Abbreviated Title
204894 (RSV PED-011)
IND number
16999
EudraCT number
2018-000431-27
Amendment number:
Amendment 4
Amendment date:
01 August 2019
Co-ordinating author:

(Scientific Writer)
Rationale/background for changes:

The per protocol set definition in the synopsis was updated. 

Clarification was added on recruiting sufficient subjects with negative RSV 
exposure status. 

Clarification was added to RTI and LRTI episode definitions. 

Table 24 was updated to clarify the visit window intervals.

Additional wording was added to indicate that for countries where it is not 
acceptable to provide copies of medical records to the sponsors, the investigator 
will transcribe the required information in a manner that respects the subject’s 
anonymization.

In addition, some typographical errors have been corrected throughout the 
protocol.
Amended text has been included in bold italics and deleted text in strikethrough in 
the following sections:
On the protocol cover page, a Contributing author has been added.
Contributing authors 
(Amended 1 August
2019)

 (Clinical Research and 
Development Lead)

 (Clinical Research and 
Development Lead)

 (Lead Statistician)

 (Project Statistician
 
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Number of subjects
The target will be to enroll approximately 150 infants 
likely to be previously unexposed to RSV with about 50 
infants for each of three randomization groups. If 
necessary, the sample size will may be increased through 
additional recruitment in order to achieve at least 5 a 
sufficient number of RSV infected infants, with a negative 
RSV exposure status (at screening based on in-stream 
baseline serological testing), in each RSV vaccine group. 
Dose 1 of the ChAd155-RSV vaccine should be 
administered before the first RSV season and second dose 
will be given one month after the first dose (RSV seasons 
will be determined for each country based on local 
epidemiological data and documented in the SPM. The 
RSV season is defined as the period of the year when 70% 
of the RSV cases have occurred in previous years. For the 
calculation, where available, data from up to the ten 
previous years should be applied. If the data permit 
calculation of the actual date of the beginning of the 
season, rather than approximation to the nearest month, 
this is desirable.) (Amended 1 August 2019).
Per Protocol Set
Subset of subjects in the exposed set (ES) who have 
complied with eligibility criteria, study procedures up to 
the time point of analysis and who have availability of 
measurement(s) for the analysis variable(s) of interest
(Amended 1 August 2019). All subjects who received at 
least 1 dose of the study treatment to which they are 
randomised and have post-vaccination data (Full Analysis 
Set) minus subjects with protocol deviations that lead to 
exclusion.
Section 1.2.2.3 was updated as follows:
1.2.2.3 In-stream serological testing of baseline samples to determine exposure 
status (Amended 1 August 2019)
Subjects will not be screened for serostatus as criterion for enrolment in the study, due to 
the potential presence and detection of residual maternal antibodies (Refer to Section 
6.7.3 for more details on the determination of a negative RSV exposure status). The 
assumption is that the majority of infants are previously unexposed (see Section 1.2.2.2). 
Serological testing of baseline samples to determine exposure status will be performed in-
stream to ensure at least 50% of infants with a negative RSV exposure status (at 
screening based on in-stream baseline serological testing) and the sample size will may
be adjusted as needed through additional recruitment (Section 11.4). 
Section 5.1 was updated as follows: 
5.1 Number of subjects 
 
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The target will be to enroll approximately 150 infants likely to be previously unexposed 
to RSV with about 50 infants for each of three randomization groups. If necessary, the 
sample size will may be increased through additional recruitment in order to achieve at 
least 5 a sufficient number of RSV infected infants, with a negative RSV exposure status 
(at screening based on in-stream serological testing), in each RSV vaccine group. Dose 1 
administration should be completed before the first RSV season and second dose will be 
given one month after the first dose (RSV seasons will be determined for each country 
based on local epidemiological data and documented in the SPM). The RSV season is 
defined as the period of the year when 70% of the RSV cases have occurred in previous 
years. For the calculation, where available, data from up to the ten previous years should 
be applied. If the data permit calculation of the actual date of the beginning of the season, 
rather than approximation to the nearest month, this is desirable. Refer to the SPM for 
RSV seasons per country. Refer to Section 11.4 for the determination of sample size 
(Amended 1 August 2019). 
Section 6.7.3 was updated for clarification as follows: 
Section 6.7.3     Laboratory assays
Please refer to APPENDIX A for a detailed description of the assays performed in the 
study. Please refer to APPENDIX B for the address of the clinical laboratories for sample 
analysis.
Determination of a negative RSV exposure status in infants at 6 to 7 months of age will 
be based on RSV A and/or B neutralizing antibody titers present in serum at screening 
(before vaccination with the RSV vaccine) based on in-stream baseline serological 
testing. At birth, newborns do show positive for neutralizing antibodies due to maternal 
transfer during gestation. The titer of these antibodies declines over time. At the age of 6 
to 7 months a cut-off can be defined below which infants are considered to have a 
negative RSV exposure status. Infants that show neutralizing antibody titers above this 
cut-off are suspected to have experienced a recent RSV infection. This cut-off will thus 
allow the discrimination between a negative RSV exposure status versus RSV infected 
infants before start of vaccination. 
The following laboratory assays are planned:

Functional (neutralizing) antibody titers against RSV-A will be measured by a 
neutralization assay on serum samples (Table 10).

RTI will be assessed by:

Quantitative RT-PCR that is able to discriminate RSV-A and RSV-B subtypes 
(Table 11).

Qualitative multiplex PCR for detection of a panel of viruses (Table 11).

Local RSV assay, and/or local RVP where available (Table 11) (Amended 1 
August 2019).
Table 19 was updated to slign the shading for “Unsolicited AEs” and “AE of special 
interest (spontaneous or excessive bleeding) so that both end around V5 D6.
 
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Table 19
Reporting periods for collecting safety information (Amended 1 August 
2019)
Visit
SCR
V1
V2
V3
V4
V5
V
6
V7
V8
Days
-30 to 
-1
1 7 8
30
31
37 38
60
61
12
1
end 
of 
the 
1st
RSV 
seas
on
end of the 
2nd RSV 
season
Solicited local and 
general AEs
Unsolicited AEs
AEs/SAEs leading to 
withdrawal from the 
study
AE of special interest 
(RSV-LRTI)
AE of special interest 
(spontaneous or 
excessive bleeding)*
SAEs**
SAEs related to study 
participation (start at 
signature of informed 
consent form) or 
concurrent GSK 
medication/ vaccine
AE: Adverse Event; RSV-LRTI: Respiratory Syncytial Virus-Lower Respiratory Tract Infection; SAE: Serious Adverse 
Event; SCR: Screening; V: Visit.
* Subjects’ parent(s)/LAR(s) will be instructed to contact the investigator/study staff if their child presents symptoms of 
spontaneous bleeding or easy bruising or if their child develops a rash, within 30 days after either vaccination, in 
order to detect any thrombocytopenic petechiae or purpura.
** Each subject’s parent(s)/LAR(s) will be instructed to contact the investigator immediately should they/the subject 
    manifest any signs or symptoms they perceive as serious
Section 3.3.1 was updated as follows:
Section 3.3.1    Active questioning to detect adverse events and serious adverse 
events
As a consistent method of collecting AEs, the subject’s parent(s)/LAR(s) should be asked 
a non-leading question such as:
 
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‘Has your child acted differently or felt different in any way since receiving the vaccine 
or since the last 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. For 
countries where it is not acceptable to provide copies of medical records to the sponsor, 
the required information will be transcribed by the investigator and provided to GSK 
respecting the subject’s anonymization (Amended 1 August 2019).
Section 11.4 was revised as follows: 
11.4  Determination of sample size
The sample size determination is based on the minimum number of subjects needed to 
allow detection of a serious ERD signal having a magnitude similar to that of the historic 
FI-RSV vaccine trials [Kim, 1969]. A total of 150 infants will be enrolled and 
randomized with 1:1:1 ratio to receive either 1 dose of the 1.5x1010 vp/dose ChAd-155 
RSV vaccine [the 1D RSV + comparator group], 2 doses of the 5x1010 vp/dose ChAd-
155 RSV vaccine [the 2D RSV + comparator group], or no ChAd-155 RSV vaccine [the 
comparator/Placebo control alone group].
An effect of vaccination on ERD will be monitored very closely. It is anticipated that at 
least 50% of subjects [Dunn, 2013] will have a negative RSV exposure status (at 
screening which will be assessed by in-stream serological testing of baseline samples). 
While the rate of RSV infection could be highly variable by season, a conservative rate of 
infection of 20% in the first season is assumed [Kutsaya, 2016]. Therefore, with 50 
infants in each RSV vaccine group, it is anticipated to observe at least 5 infected infants 
with a negative RSV exposure status (at screening based on in-stream baseline 
serological testing) in each RSV vaccine group [50×0.5×0.2=5].
With a one-sided type I error of 0.05, and the assumption of a 10% rate of infection 
progressing to very severe RSV-LRTI (which is a conservative assumption based on the 
rate in the natural history of disease), 5 infections can provide at least 90% statistical 
power to demonstrate the progression rate from infection to very severe RSV-LRTI is 
less than 80%. That is less extreme than that observed in the historic FI-RSV vaccine trial 
where 80% of RSV RTI cases progressed to hospitalization [Kim, 1969]. During the 
course of the study, since the actual negative RSV exposure status (at screening based on 
in-stream baseline serological testing) and infection rates may be lower than 50% and 
20%, respectively, the sample size will may be adjusted as needed through additional 
recruitment in order to achieve at least 5 a sufficient number of RSV infected infants
with a negative RSV exposure status (at screening based on in-stream baseline 
serological testing) in each RSV vaccine group (Amended 1 August 2019). 
 
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Tabe 24 was updated to clarify window intervals as follows: 
Table 24
Maximum allowed interval between study visits (Amended 1 August 
2019)
Interval
Allowed length of interval
Screening Visit 1 (Day 1)
0 - 30 days
Visit 1 (Day 1) Visit 2 (Day 8)
7 - 10 days
Visit 1 (Day 1) Visit 3 (Day 31) 
23 - 44 days1
Visit 1 (Day 1) Visit 5 (Day 61)
60 - 81 days1
Visit 3 (Day 31) Visit 4 (Day 38)
7 - 10 days
Visit 3 (Day 31) Visit 5 (Day 61) 2
30 - 37 days 1,3
Visit 5 (Day 61) Visit 6 (Day 121)4
60 - 81 days
Visit 7
(end of the first RSV transmission season)
Defined end of first RSV transmission season5
Visit 8
(end of the second RSV transmission season)
Defined end of second RSV transmission season5
1 Subjects will not be eligible for inclusion in the PP cohort for analysis of immunogenicity if they make the study visit 
outside this interval.
2 Where Synflorix is used as the comparator, a minimum of 30 days between Visit 3 and Visit 5 must be 
maintained to align with the active comparator vaccination schedule.
3 The interval between Visit 1 and Visit 5 must be a minimum of 60 days to be in line with the active comparator 
vaccination schedules as per the respective approved labels.
4 In countries where Menveo or Placebo is used as a comparator, no administration will be performed at Day 121 and 
therefore in those countries there will be no Visit 6 and Menveo will be administered at the end of the first RSV 
season at Visit 7 (refer to Table 2 and Table 7). 
5 As soon as possible after the end of the RSV season (approximately within 4 weeks) and in accordance with 
the active comparator vaccination schedule if applicable. If the active comparator dosing for V7 is later 
than 4 weeks after the end of the first RSV transmission season, then the recommended timing of the 
active comparator takes precedence.
Section 11.6.3 was updated as follows: 
11.6.3  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 timepoint will exclude subjects with a missing or non-evaluable measurement. 
Kinetics will be plotted on subjects with results available at all timepoints. The geometric 
mean titers/concentrations (GMTs/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.
Determination of a negative RSV exposure status in infants at 6 to 7 months of age will
be based on RSV A and/or B neutralizing antibody titers present in serum at screening 
(before vaccination with the RSV vaccine) based on in-stream baseline serological 
testing. At birth, newborns do show positive for neutralizing antibodies due to maternal 
transfer during gestation. The titer of these antibodies declines over time. At the age of 6 
to 7 months a cut-off can be defined below which infants are considered to have a 
 
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negative RSV exposure status. Infants that show neutralizing antibody titers above this 
cut-off are suspected to have experienced a recent RSV infection. This cut-off will thus 
allow the discrimination between a negative RSV exposure status versus RSV infected 
infants before start of vaccination. 
Vaccine response in terms of RSV neutralizing antibodies will be defined in the statistical 
analysis plan.
The description of the handling of data below the lower limit of quantification for GMC 
calculation and fold increase will be described in the statistical analysis plan.
Section 11.6.4 was updated as follows: 
11.6.4   RTI and LRTI
For the analysis of RTI and LRTI, all cases will be definitively classified as either RSV-
RTI, RSV-LRTI, severe RSV-LRTI or very severe RSV-LRTI according to the case 
definitions presented in Table 6, and the association to RSV infection will be assessed by 
quantitative PCR as primary analysis.
All confirmed LRTI will also be investigated for a panel of respiratory viruses (multiplex 
PCR; refer to Table 11, as a supplementary analysis of the occurrence of RSV-LRTI 
diagnosed upon the multiplex PCR.
For the analysis of RTI episode, a new RTI episode will be defined as any occurrence of 
cough, runny nose, blocked nose wheezing or difficulty breathing with an interval of at 
least 7 symptom free days since the last episode of RTI that was diagnosed. For the 
analysis of LRTI episode, a new LRTI episode will be defined as a history of cough or 
difficulty breathing and blood oxygen saturation < 95%, or respiratory rate increase 
and confirmed RSV infection with an interval of at least 7 symptom free days since the 
last episode of LRTI that was diagnosed (Amended 1 August 2019).
Section 11.8.1 was updated as follows: 
For clinical safety laboratory parameters: a listing of laboratory value outside the normal 
range for the unscheduled visits will be provided as per the toxicity scale refered in the 
protocol. The maximum grading during the study will be tabulated (Refer to APPENDIX 
C) Laboratory values will be classified according to toxicity criteria. Laboratory values
that are outside the normal range will also be flagged in the data listings, along with 
corresponding normal ranges and assessment of clinical significance (Amended 1 
August 2019).
Section 11.10 was updated as follows: 
11.10. Analysis of RTI and LRTI 
The primary analysis will be performed on the ES of subjects with a negative RSV 
exposure status (at screening based on in-stream baseline serological testing) in the 
pooled single dose RSV vaccine group, the pooled two dose RSV vaccine group, and the 
pooled comparator group separately for first and second RSV seasons and overall. A 
 
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similar analysis will be performed on the entire ES. As primary analysis, the assessment 
of RSV infection will be performed using the quantitative RT-PCR according to 
standardized case definitions (see Table 6) based on the available WHO case definitions. 
The number of RSV infections within each group and the maximum disease severity of 
the event will be tabulated. The rate (with 95% CI) of RSV-RTI and RSV-LRTI and 
infections progressing to hospitalization will be evaluated for each of the three pooled 
groups. 
The incidence rate of very severe RSV-LRTI among RSV infected infants with a 
negative RSV exposure status (at screening based on in-stream baseline serological 
testing) from first vaccination (Day 1) up to the end of the first RSV transmission season 
will be estimated as well as 95% one-sided lower CI.
The proportion incidence rate and the relative risk of subjects with at least one RSV-
associated RTI (with 95% CI) between each of two pooled RSV vaccine groups and the 
pooled control group will be calculated for both the cohort of subjects with a negative 
RSV exposure status (at screening based on in-stream baseline serological testing) on the 
ES and on the entire ES. The same descriptive analysis will be performed for subjects 
with at least one RSV-associated LRTI and those with at least one RSV-associated severe 
LRTI (Amended 1 August 2019). 
Section 11.12.1 was updated as follows:
11.12.1 Sequence of analyses
In preparation of the planned iSRC and IDMC evaluations, analyses of all available 
safety data (i.e., data that are as clean as possible) will be performed (see Section 9.10 for 
more information). These analyses will be done by an unblinded statistician outside GSK
independent data analysis center to maintain the blinding of the study, and will be 
documented in a statistical analysis report. Only the outcome of the iSRC and IDMC 
reviews will be communicated to the RSV study team (no safety signal or safety signal). 
No clinical study report will be written (Amended 1 August 2019). 
 
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SAP_001.pdf: 
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Statistical Analysis Plan 
Detailed Title: 
A Phase 1/2, randomized, observer-blind, controlled, 
multi-center study to evaluate safety, reactogenicity 
and immunogenicity of GSK Biologicals’ (RSV) 
investigational vaccine based on the RSV viral 
proteins F, N and M2-1 encoded by chimpanzee-
derived adenovector (ChAd155-RSV) 
(GSK3389245A), when administered intramuscularly 
as a single dose or as two doses according to a 0, 1-
month schedule, to infants aged 6 and 7 month 
eTrack study number and 
Abbreviated Title 
204894 (RSV PED-011) 
Scope: 
All data pertaining to the above study 
Date of Statistical Analysis 
Plan 
Final: 27 March 2019 
Co-ordinating author: 
 (Statistician)  
Reviewed by: 
 (Clinical and Epidemiology 
Project Lead);  
 (Clinical Research and Development 
Lead);  
 (Lead statistician); 
 (Lead 
statistical analyst);  
 (Scientific writer);  
 (Regulatory Affairs); 
 (SERM physician);  
 – safety scientist;  
 (Public disclosure representative)  
Approved by: 
 (Clinical and Epidemiology 
Project Lead);  
 (Lead statistician);  
 (Study Statistician);  
 (Lead Scientific writer);  
 (Lead statistical Analyst)  
APP 9000058193 Statistical Analysis Plan Template (Effective date: 5th March 2019) 
 
 
 
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TABLE OF CONTENTS 
PAGE 
LIST OF ABBREVIATIONS ........................................................................................... 13 
1. 
DOCUMENT HISTORY .......................................................................................... 14 
2. 
STUDY DESIGN .................................................................................................... 14 
3. 
OBJECTIVES/ENDPOINTS ................................................................................... 21 
3.1. 
Objectives ................................................................................................... 21 
3.1.1. 
Primary Objective ........................................................................ 21 
3.1.2. 
Secondary Objective .................................................................... 21 
3.1.3. 
Tertiary objective ......................................................................... 22 
3.2. 
Endpoints.................................................................................................... 22 
3.2.1. 
Primary endpoints ........................................................................ 22 
3.2.2. 
Secondary endpoints ................................................................... 22 
3.2.3. 
Tertiary endpoints ........................................................................ 23 
4. 
ANALYSIS SETS ................................................................................................... 23 
4.1. 
Definition..................................................................................................... 23 
4.1.1. 
Exposed Set ................................................................................ 23 
4.1.2. 
Exposed Set of subjects with a negative RSV exposure 
status ........................................................................................... 23 
4.1.3. 
Per-protocol Set for analysis of immunogenicity........................... 24 
4.2. 
Criteria for eliminating data from Analysis Sets ........................................... 25 
4.2.1. 
Elimination from Exposed Set (ES) .............................................. 25 
4.2.2. 
Elimination from Exposed Set (ES) subjects with a 
negative RSV exposure status ..................................................... 25 
4.2.3. 
Elimination from Per-protocol analysis Set (PPS) ........................ 25 
4.2.3.1. 
Excluded subjects ...................................................... 25 
5. 
STATISTICAL ANALYSES ..................................................................................... 27 
5.1. 
Demography ............................................................................................... 27 
5.1.1. 
Analysis of demographics/baseline characteristics planned 
in the protocol .............................................................................. 27 
5.1.2. 
Additional considerations ............................................................. 28 
5.2. 
Immunogenicity........................................................................................... 28 
5.2.1. 
Analysis of immunogenicity planned in the protocol ..................... 28 
5.2.1.1. 
Within groups assessment .......................................... 29 
5.2.1.1.1. 
Analysis of secondary objectives ............ 29 
5.2.1.1.2. 
Analysis of tertiary objective ................... 29 
5.2.2. 
Additional considerations ............................................................. 29 
5.3. 
Analysis of safety and reactogenicity .......................................................... 30 
5.3.1. 
Analysis of safety and reactogenicity planned in the 
protocol ........................................................................................ 30 
5.3.1.1. 
Within groups assessment .......................................... 30 
5.3.1.2. 
Between groups assessment ...................................... 32 
5.3.2. 
Additional considerations ............................................................. 32 
5.3.2.1. 
Combined Solicited and Unsolicited Adverse 
Events ........................................................................ 33 


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5.3.2.2. 
Exclusion of implausible solicited Adverse 
Event .......................................................................... 33 
5.3.2.3. 
Solicited Adverse Events ............................................ 33 
5.3.2.4. 
Unsolicited Adverse Events ........................................ 34 
5.4. 
Analysis of RTI and LRTI ............................................................................ 35 
5.4.1. 
Analysis of RTI and LRTI planned in protocol .............................. 35 
5.4.2. 
Additional consideration ............................................................... 36 
6. 
ANALYSIS INTERPRETATION .............................................................................. 36 
7. 
CONDUCT OF ANALYSES .................................................................................... 36 
7.1. 
Sequence of analyses................................................................................. 36 
7.2. 
Statistical considerations for interim analyses ............................................. 37 
8. 
CHANGES FROM PLANNED ANALYSES ............................................................. 37 
9. 
NON-STANDARD DATA DERIVATION RULES AND STATISTICAL 
METHODS ............................................................................................................. 38 
9.1. 
Immunogenicity........................................................................................... 38 
9.2. 
RTI and LRTI .............................................................................................. 38 
9.3. 
Hematology and Biochemistry parameters .................................................. 39 
9.4. 
Coding for the AE of specific interest .......................................................... 40 
10. ANNEXES .............................................................................................................. 46 
10.1. 
Business rules for standard data derivations and statistical methods .......... 46 
10.1.1. 
Attributing events to vaccine doses .............................................. 46 
10.1.2. 
Handling of missing data .............................................................. 46 
10.1.2.1. Dates .......................................................................... 46 
10.1.2.2. Laboratory data .......................................................... 47 
10.1.2.3. Daily recording of solicited symptoms ......................... 47 
10.1.2.3.1. Studies with paper diaries ....................... 47 
10.1.2.4. Unsolicited adverse events ......................................... 48 
10.1.3. 
Data derivation ............................................................................ 48 
10.1.3.1. Age at vaccination in days .......................................... 48 
10.1.3.2. Age at vaccination in months ...................................... 48 
10.1.3.3. Age at vaccination in years ......................................... 48 
10.1.3.4. Weight ........................................................................ 49 
10.1.3.5. Height ......................................................................... 49 
10.1.3.6. Body mass index (BMI) .............................................. 49 
10.1.3.7. Temperature ............................................................... 49 
10.1.3.8. Numerical serology results ......................................... 49 
10.1.3.9. Geometric mean titers (GMTs) and 
concentrations (GMCs) ............................................... 50 
10.1.3.10. Onset day ................................................................... 50 
10.1.3.11. Duration of events ...................................................... 50 
10.1.3.12. Counting rules for combining solicited and 
unsolicited adverse events ......................................... 50 
10.1.3.13. Counting rules for occurrences of solicited 
adverse events ........................................................... 50 
10.1.3.14. Display of decimals..................................................... 51 
10.1.3.15. Percentages ............................................................... 51 
10.1.3.16. Differences in percentages ......................................... 51 


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10.1.3.17. Demographic/baseline characteristics statistics .......... 51 
10.1.3.18. Serological summary statistics ................................... 52 
10.1.3.19. Statistical methodology ............................................... 52 
10.1.3.20. Exact confidence intervals around proportions ........... 52 
10.1.3.21. Standardized asymptotic confidence intervals 
around differences in proportions ............................... 52 
10.2. 
TFL and/or TFL ToC ................................................................................... 53 
11. REFERENCES ....................................................................................................... 54 
12. LIST OF LISTINGS FOR THE FINAL ANALYSIS ................................................... 55 
13. MOCK TABLES ...................................................................................................... 56 
 


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LIST OF TABLES 
PAGE 
Table 1 
Vaccines administered and vaccination schedules ................................. 15 
Table 2 
Study groups and epochs foreseen in the study ..................................... 16 
Table 3 
Study groups and treatment foreseen in the study ................................. 17 
Table 4 
Maximum allowed interval between study visits for PPS ........................ 24 
Table 5 
Implausible Solicited Adverse Events ..................................................... 33 
Table 6 
Case definitions for data analysis ........................................................... 38 
Table 7 
Toxicity grading scales for hematology and biochemistry 
parameters applicable for this study ....................................................... 39 
 


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LIST OF FIGURES 
PAGE 
Figure 1 
Study design .......................................................................................... 14 
 


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LIST OF TEMPLATES 
PAGE 
Template 1 
Number of subjects by country and center - <RSV 1D, RSV 2D, 
Comparator/Placebo> groups (Exposed Set) ......................................... 56 
Template 2 
Summary of study completion with reasons for withdrawal <RSV 
1D, RSV 2D, Comparator/Placebo> <groups> < pooled RSV 1D, 
RSV 2D, Comparator/Placebo groups> (Exposed Set) .......................... 56 
Template 3 
Summary of visit attendance/phone contact completion <RSV 
1D, RSV 2D, Comparator/Placebo> groups (Exposed Set) .................... 57 
Template 4 
Summary of important protocol deviations leading to elimination 
from any analyses <RSV 1D, RSV 2D, Comparator/Placebo> 
<groups>< -pooled RSV 1D, RSV 2D, Comparator/Placebo 
groups> .................................................................................................. 58 
Template 5 
Summary of subject disposition from enrolled set to randomized 
set (Exposed Set) ................................................................................... 58 
Template 6 
Summary of subject disposition from randomized set to exposed 
set .......................................................................................................... 59 
Template 7 
Summary of subject disposition from Exposed Set to Per 
Protocol Set at <Day 31/Day 61/end of first RSV season> <RSV 
1D, RSV 2D, Comparator/Placebo> groups (Exposed set)..................... 59 
Template 8 
Summary of subject disposition from Exposed Set to End of 
study <RSV 1D, RSV 2D, Comparator/Placebo> groups 
(Exposed set) ......................................................................................... 60 
Template 9 
Deviations from protocol for age and intervals between study 
visits <RSV 1D, RSV 2D, Comparator/Placebo> groups 
(Exposed Set) ........................................................................................ 61 
Template 10 Minimum and maximum visit dates <RSV 1D, RSV 2D, 
Comparator/Placebo> groups (Exposed Set) ......................................... 61 
Template 11 Summary of demographic characteristics - <RSV 1D, RSV 2D, 
Comparator/Placebo> <groups>< -pooled RSV 1D, RSV 2D, 
Comparator/Placebo groups> (Exposed Set, PPS for 
immunogenicity at <Day 31/Day 61/end of first RSV season>) ............... 62 
Template 12 Summary of vital signs characteristics - <RSV 1D, RSV 2D, 
Comparator/Placebo> <groups>< pooled RSV 1D, RSV 2D, 
Comparator/Placebo groups> (Exposed set, PPS for 
immunogenicity at <Day 31/Day 61/end of first RSV season>) ............... 63 
Template 13 Number of enrolled subjects by age category <RSV 1D, RSV 2D, 
Comparator/Placebo> groups ................................................................ 64 


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Template 14 Compliance in completing solicited adverse events information 
<RSV 1D, RSV 2D, Comparator/Placebo> groups (Exposed Set) .......... 64 
Template 15 Summary of <grade 3> adverse events (solicited and unsolicited) 
<with causal relationship to vaccination, with medically attend 
visit> within <7, 30> days following first and second vaccination 
and overall <RSV 1D, RSV 2D, Comparator/Placebo> 
<groups>< pooled RSV 1D, RSV 2D, Comparator/Placebo 
groups> (Exposed Set) .......................................................................... 65 
Template 16 Percentage of subjects with solicited local adverse events by 
maximum intensity within the 7-day (Days 1-7) following first and 
second vaccination and overall - <RSV 1D, RSV 2D, 
Comparator/Placebo> <groups> < pooled RSV 1D, RSV 2D, 
Comparator/Placebo groups>(Exposed Set) .......................................... 66 
Template 17 Duration in days of solicited <general, local> adverse events 
within 7 days following first and second vaccination and overall 
<RSV 1D, RSV 2D, Comparator/Placebo> groups (Exposed Set) .......... 67 
Template 18 Percentage of subjects with solicited general adverse events by 
maximum intensity within the 7-day (Days 1-7) following first and 
second vaccination and overall - <RSV 1D, RSV 2D, 
Comparator/Placebo> <groups> < pooled RSV 1D, RSV 2D, 
Comparator/Placebo groups >(Exposed Set) ......................................... 68 
Template 19 Percentage of subjects reporting solicited local adverse events 
(any grade /grade 2,3/ grade 3) within 7-days following first and 
second vaccination by maximum intensity for pooled RSV 1D, 
RSV 2D, Comparator/Placebo groups (Exposed Set) ............................ 69 
Template 20 Percentage of subjects reporting fever (any and grade 3) and 
other solicited general adverse events (any grade /grade 2,3/ 
grade 3) within 7-days following first and second vaccination by 
maximum intensity for pooled RSV 1D, RSV 2D and 
Comparator/Placebo groups (Exposed Set) ........................................... 70 
Template 21 Summary of subjects with at least one <Ø/grade 3/ related/ 
grade 3 related/serious/ medically attended> unsolicited adverse 
event <episode of spontaneous or excessive bleeding> classified 
by MedDRA Primary System Organ Class and Preferred Term 
<with onset within 30 days of first and second vaccination><from 
vaccination dose 1 up to Day 61> <pooled> <RSV 1D, RSV 2D, 
Comparator/Placebo> groups (Exposed Set) ......................................... 71 
Template 22 Summary of subjects with at least one <episode of RSV-LRTI 
(AE of specific interest)/serious adverse event> classified by 
MedDRA Primary System Organ Class and Preferred Term 
<from vaccination dose 1 up to end of <first/second> RSV 
season for pooled RSV 1D, RSV 2D and Comparator/Placebo 
groups (Exposed Set) ............................................................................ 72 


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Template 23 Listing of SAE from vaccination dose 1 up to <Day 61/end of first 
RSV season/study end> (Exposed Set) ................................................. 73 
Template 24 Listing of AEs related to LRTI and association to RSV infection 
from vaccination dose 1 up to <Day 61/end of first RSV 
season/study end> (Exposed Set) .......................................................... 73 
Template 25 Listing of AEs related to spontaneous or excessive bleeding 
together with hemoglobin and platelet count results with 30 days 
of first and second vaccination (Exposed Set) ........................................ 74 
Template 26 Listing of adverse events, SAEs and solicited symptoms leading 
to study or treatment discontinuation from vaccination dose 1 up 
to <Day 61/end of first RSV season/end of second RSV 
season>(Exposed Set) ........................................................................... 74 
Template 27 Listing of unscheduled safety visit from vaccination dose 1 up to 
<Day 61/end of first RSV season/study end> (Exposed Set) .................. 74 
Template 28 Summary of subjects taking a concomitant medication within 
<7/30> days following each vaccination and overall <RSV 1D, 
RSV 2D, Comparator/Placebo> <groups>< for pooled RSV 1D, 
RSV 2D and Comparator/Placebo groups> (Exposed Set) ..................... 75 
Template 29 Summary of occurrences and subjects with at least one solicited 
and unsolicited adverse event classified by MedDRA Primary 
System Organ Class and Preferred Term with onset within 30 
days of first and second vaccination – SAE excluded <RSV 1D, 
RSV 2D, Comparator/Placebo> groups (Exposed Set) .......................... 76 
Template 30 Number (%) of subjects with serious adverse events <from Day 1 
up to <Day 61/end of second RSV season>, including number of 
events reported for pooled RSV 1D, RSV 2D and 
Comparator/Placebo> groups (Exposed Set) ......................................... 77 
Template 31 Number and percentage of subjects with <anti-RSV A antibody 
titre, anti-RSV F concentration> equal to or above <cut-off 
><unit>  and gm<t,c> for pooled RSV 1D, RSV 2D and 
Comparator/Placebo> groups (<Adapted>PPS of 
immunogenicity at <Day X, end of 1st RSV season>) ............................. 77 
Template 32 Distribution of <RSV-A neutralising antibody titre, RSV-F 
antibody concentration> for pooled RSV 1D, RSV 2D and 
Comparator/Placebo> groups (<Adapted>PPS for 
immunogenicity <at Day X, end of 1st RSV season>) ............................. 78 
Template 33 Vaccine response for anti-RSV-A neutralising antibody titre at 
each post-vaccination timepoint for pooled RSV 1D, RSV 2D and 
Comparator/Placebo> groups (PPS for analysis of 
immunogenicity at <Day X, End of 1st RSV season>) ............................. 79 
Template 34 Number and percentage of subjects with <anti-RSV A antibody 
titre, anti-RSV F concentration> equal to or above <cut-off 


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204894 (RSV-PED-011) 
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><unit> and GMR for pooled RSV 1D, RSV 2D and 
Comparator/Placebo> groups (PPS of immunogenicity at <Day 
X, End of 1st RSV season>) .................................................................... 80 
Template 35 Distribution of fold of anti-RSV-A neutralising antibody titer by 
<cumulative> pre-vaccination titer category for pooled RSV 1D, 
RSV 2D and Comparator/Placebo> groups (PPS for analysis of 
immunogenicity at <Day X, end of first RSV season>) ........................... 81 
Template 36 Descriptive statistics of <anti-RSV A neutralizing antibody titre, 
anti-RSV F antibody concentration>at pre-vaccination, Day <31, 
61,> <and end of 1st RSV transmission season> for pooled RSV 
1D, RSV 2D and Comparator/Placebo> groups (<Adapted> PPS 
for immunogenicity) ................................................................................ 82 
Template 37 Reverse cumulative distribution curves for anti-RSV-A 
neutralising antibody titres in each group at baseline and <Day 
31, Day 61, End of first RSV season> for pooled RSV 1D, RSV 
2D and Comparator/Placebo> group <PPS for analysis of 
immunogenicity at <Day X, End of 1st RSV season> .............................. 83 
Template 38 Individual results of anti-RSV-A neutralising antibody titre at Day 
<61/end of first RSV season> versus pre-vaccination in <each 
pooled <RSV 1D, RSV 2D> group> and Comparator/placebo 
group> (PPS for analysis of immunogenicity at <Day X>) ...................... 83 
Template 39 Number and percentage of subjects with at least one RSV 
infection, RSV-RTI, RSV-LRTI, RSV-severe LRTI, RSV-very 
severe LRTI, All-cause LRTI and RSV hospitalization (based on 
WHO case definition) from vaccination dose 1 up to end of <first, 
second> RSV season for pooled RSV 1D, RSV 2D and 
Comparator/Placebo group (<Exposed Set, Exposed Set with a 
negative RSV exposure status>) ............................................................ 84 
Template 40 Proportion of subjects with at least one RSV hospitalization over 
the number of subjects with at least one RSV infection 
(symptomatic or asymptomatic*) from vaccination dose 1 up to 
end of <first, second> RSV season for pooled RSV 1D, RSV 2D 
and Comparator/Placebo group <Exposed Set, Exposed Set with 
negative RSV baseline status> .............................................................. 84 
Template 41 Number and percentage of subjects reporting the RSV infection 
of different severity (based on WHO case definition) by number 
of events experienced between vaccination dose 1 up to end of 
<first, second> RSV season for pooled RSV 1D, RSV 2D and 
Comparator/Placebo group <Exposed Set, Exposed Set with 
negative RSV baseline status> .............................................................. 85 
Template 42 Number and percentage of RSV infections and associated 
disease severity (based on WHO case definition) and relative 
risk from  vaccination dose 1 up to end of <first, second> RSV 
season for pooled RSV 1D, RSV 2D and Comparator/Placebo 


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204894 (RSV-PED-011) 
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group <Exposed Set, Exposed Set with negative RSV baseline 
status> ................................................................................................... 86 
Template 43 Number and percentage of RSV infections (based on WHO case 
definition) requiring hospitalization between vaccination dose 1 
up to end of <first, second> RSV season for pooled RSV 1D, 
RSV 2D and Comparator/Placebo group <Exposed Set, Exposed 
Set with negative RSV baseline status> ................................................. 86 
Template 44 Descriptive statistics of viral load calculated on all qRT-PCR 
confirmed RSV infection episodes with varying disease severity 
(based on WHO case definition) from vaccination dose 1 up to 
end of <first, second> RSV season for pooled RSV 1D, RSV 2D 
and Comparator/Placebo group <Exposed Set, Exposed Set with 
negative RSV baseline status> .............................................................. 87 
Template 45 Descriptive statistics of maximum viral load per subjects based 
on qRT-PCR confirmed episode with varying disease severity 
(based on WHO case definition) form vaccination dose 1 up to 
end of <first, second> RSV season for pooled RSV 1D, RSV 2D 
and Comparator/Placebo group <Exposed Set, Exposed Set with 
negative RSV baseline status> .............................................................. 88 
Template 46 Frequency of multiple respiratory pathogen for qRT-PCR 
confirmed RSV-RTI episodes from vaccination dose 1 up to end 
of <first, second> RSV season for pooled RSV 1D, RSV 2D and 
Comparator/Placebo groups <Exposed Set, Exposed Set with 
negative RSV baseline status> .............................................................. 89 
Template 47 Frequency of multiple respiratory pathogen for confirmed LRTI 
episodes from vaccination dose 1 up to end of <first, second> 
RSV season for pooled RSV 1D, RSV 2D and 
Comparator/Placebo groups <Exposed Set, Exposed Set with 
negative RSV baseline status> .............................................................. 90 
Template 48 Listing of RSV-RTI cases identified according to WHO case 
definitions from vaccination dose 1 up to end of second RSV 
season <Exposed Set, Exposed Set with negative RSV baseline 
status> ................................................................................................... 90 
Template 49 Listing of RSV-RTI requiring hospitalization and type of inpatient 
facility required from vaccination dose 1 up to end of second 
RSV season <Exposed Set, Exposed Set with negative RSV 
baseline status> ..................................................................................... 91 
Template 50 Number and percentage of subjects with highest associated 
severity of RSV infection (based on WHO case definition) from 
vaccination dose 1 up to <first, second> RSV season for pooled 
RSV 1D, RSV 2D and Comparator/Placebo groups <Exposed 
Set, Exposed Set with negative RSV baseline status> ........................... 91 
Template 51 Number and percentage of subjects reporting the RSV infection 
of maximum severity (based on WHO case definition) by number 


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204894 (RSV-PED-011) 
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27-MAR-2019 
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of events experienced between vaccination dose 1 up to end of 
<first, second> RSV season for pooled RSV 1D, RSV 2D and 
Comparator/Placebo groups <Exposed Set, Exposed Set with 
negative RSV baseline status > ............................................................. 92 
Template 52 Number and percentage of subjects with <anti-RSV A antibody 
titre, anti-RSV F concentration> equal to or above <cut-off 
><unit>  and gm<t,c> for pooled RSV 1D, RSV 2D and 
Comparator/Placebo> groups – by RSV baseline status 
(<Adapted>PPS of immunogenicity at <Day X, end of 1st RSV 
season>) ................................................................................................ 93 
Template 53 Distribution of <RSV-A neutralising antibody titre, RSV-F 
antibody concentration> for pooled RSV 1D, RSV 2D and 
Comparator/Placebo> groups – by RSV baseline 
status(<Adapted>PPS for immunogenicity <at Day X, end of 1st 
RSV season>) ........................................................................................ 94 
Template 54 Number and percentage of subjects with <anti-RSV A antibody 
titre, anti-RSV F concentration> equal to or above <cut-off 
><unit> and GMR for pooled RSV 1D, RSV 2D and 
Comparator/Placebo> groups – by RSV baseline status (PPS of 
immunogenicity at <Day X, End of 1st RSV season>) ............................. 95 
Template 55 Descriptive statistics of <anti-RSV A neutralizing antibody titre, 
anti-RSV F antibody concentration>at pre-vaccination, Day <31, 
61,> <and end of 1st RSV transmission season> for pooled RSV 
1D, RSV 2D and Comparator/Placebo> groups – by RSV 
baseline status (<Adapted> PPS for immunogenicity) ............................ 96 
Template 56 Summary of subjects by unsolicited adverse event category with 
onset within 30 days of first and second vaccination (Exposed 
Set) ........................................................................................................ 96 
Template 57 Number and percentage of subjects with at least one RSV-RTI 
progressing to RSV-LRTI, RSV-severe LRTI, RSV-very severe 
LRTI and RSV hospitalization from vaccination dose 1 up to end 
of <first, second> RSV season for pooled RSV 1D, RSV 2D and 
Comparator/Placebo groups <ES, Exposed Set with negative 
RSV exposure status> ........................................................................... 97 
 


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204894 (RSV-PED-011) 
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LIST OF ABBREVIATIONS 
AE 
Adverse event 
AESI 
Adverse Events of Special Interest 
ChAd155-
RSV 
Investigational recombinant chimpanzee adenovirus Type 155-
vectored RSV vaccine 
CI 
Confidence Interval 
ERD 
Enhanced Respiratory Disease 
ES 
Exposed Set 
GMC 
Geometric mean antibody concentration 
GMT 
Geometric mean antibody titre 
GSK 
GlaxoSmithKline 
LL 
Lower Limit of the confidence interval 
LLOQ 
Lower Limit of Quantification 
LRTI 
Lower respiratory tract infection 
MedDRA 
Medical Dictionary for Regulatory Activities 
NA 
Not Applicable 
PD 
Protocol Deviation 
PPS 
Per-Protocol Set 
RR 
Relative Risk 
RSV 
Respiratory Syncytial Virus 
RTI 
Respiratory Tract Infection 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SDTM 
Study Data Tabulation Model 
SPM 
Study Procedure Manual 
SR 
Study Report 
TFL 
Tables Figures and Listings  
ToC 
Table of Content 
UL 
Upper Limit of the confidence interval 
ULOQ 
Upper Limit of Quantification 
 


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204894 (RSV-PED-011) 
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1. 
DOCUMENT HISTORY 
Date 
Description 
Protocol Version 
27 MAR 2019 
Final 
Amendment 3: 21 MAR 2019 
2. 
STUDY DESIGN 
Figure 1 
Study design  
 
D: Day; FU: follow-up; IDMC: Independent Data Monitoring Committee; iSRC: internal Safety Review Committee; RSV: 
respiratory syncytial virus; RTI: respiratory tract infection; SE: solicited events; V: Visit 1D: 1 Dose (1.5x1010 vp/dose); 
2D: 2 Dose (5x1010 vp/dose); FB: Formulation buffer S9b.  
* Vaccine Dose 1 at Day 1 will be administered before the first RSV season (refer to Section 5.1 of the protocol for 
definition of RSV season). 
† Visit 2 (Day 8), Visit 4 (Day 38), and Visit 8 (no blood sampling for immune response and no vaccine administration) 
may take place in the subject’s home or at the investigators clinical facility as appropriate to the circumstances in the 
judgment of the investigator. For authorized sites only, Visit 5 (Day 61) and Visit 7 (both with blood sampling) may 
also take place in the subject’s home or at the investigators clinical facility as appropriate to the circumstances in the 
judgment of the investigator 
‡ In countries where Menveo or Placebo is used as a comparator, no administration will be performed at Day 121 and 
therefore in those countries there will be no Visit 6 and it will be administered at the end of the first RSV season at 
Visit 7 (refer to Table 2 and Table 7 of the protocol). 
a Surveillance for RSV-RTI comprises monthly nasal swab collected to detect asymptomatic RSV infections during RSV 
season and active and passive surveillance contacts for RSV symptomatic RTI. Of note the swab may be omitted if a 
nasal swab has been taken at a symptomatic visit in the same month (see Section 9.2 of the protocol). Data about 
RSV–RTI incidence will be reviewed monthly by an IDMC. 
b An iSRC will review all accumulating safety data monthly until the IDMC reviews has reviewed all safety data up to 30 
days after administration of Dose 2 (i.e., Day 61). The IDMC will review all accumulating safety data monthly 
throughout the period of vaccination and accumulating SAEs until the end of the second RSV transmission season. 
Refer to Sections 9.10.2 and 9.10.3 of the protocol. 
c Refer to Section 6.6.12.3 of the protocol 
End of RSV 
season 2
SE to D8
= Blood sample for safety
BSS
BSS
Surveillance period for RSV RTI a
BSH
BSH
BSH
= Blood sample for humoral immunogenicity
BSH
Nasal swab, as applicable c
BSH
Vaccination phase
FU phase
Screening
Epoch 002
Epoch 003
Epoch 004
Epoch 001
D121
V6 ‡
D61
V5
End of RSV 
season 1
V7
V8 †
D1
D8
D31
D38
V1*
V2 †
V3
V4 †
Visit
Day
SCREENING
D-30 to D-1
IDMC/iSRC review b
SE to D8
2D RSV+Bexsero
2D RSV
Dose 1
Dose 2
Bexsero
Bexsero
Bexsero
Bexsero
Bexsero
FB
Bexsero
Bexsero
FB
2D RSV+Nimenrix
2D RSV
2D RSV
Nimenrix
Nimenrix
Nimenrix
Nimenrix
Nimenrix
FB
Nimenrix
Nimenrix
FB
2D RSV+Menveo
2D RSV
2D RSV
Menveo
Menveo
Menveo
FB
Menveo
FB
Menveo
2D RSV+Synflorix
2D RSV
2D RSV
Synflorix 
Synflorix
Synflorix
Synflorix
FB
Synflorix
Synflorix
Synflorix
FB
2D RSV
1D RSV+Bexsero
1D RSV
Bexsero
Bexsero
Bexsero
FB
1D RSV+Nimenrix
1D RSV
FB
Nimenrix
Nimenrix
Nimenrix
1D RSV+Menveo
1D RSV
FB
Menveo
Menveo
1D RSV+Synflorix
1D RSV
FB
Synflorix
Synflorix
Synflorix
IDMC review b
2D RSV+ Placebo
2D RSV
2D RSV
Placebo   
FB
FB
1D RSV+ Placebo
1D RSV
FB


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204894 (RSV-PED-011) 
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Page 15 of 97 
Table 1 
Vaccines administered and vaccination schedules 
Groups 
Age* (Months) / (Visit, Day) 
6-7 / (V1, D1) 7-8 / (V3, D31) 8-9 / (V5, D61) 
10-11 / (V6, D121)** 
14-18 / (V7) 
1D RSV + Bexsero 
1D RSV ChAd FB 
Bexsero 
Bexsero 
Bexsero 
2D RSV + Bexsero 
2D RSV ChAd 2D RSV ChAd Bexsero 
Bexsero 
Bexsero 
Bexsero 
Bexsero 
FB 
Bexsero 
FB 
Bexsero 
1D RSV + Nimenrix 
1D RSV ChAd FB 
Nimenrix 
Nimenrix 
Nimenrix 
2D RSV + Nimenrix 
2D RSV ChAd 2D RSV ChAd Nimenrix 
Nimenrix 
Nimenrix 
Nimenrix 
Nimenrix 
FB 
Nimenrix 
FB 
Nimenrix 
1D RSV + Synflorix 
1D RSV ChAd FB 
Synflorix 
Synflorix 
Synflorix 
2D RSV + Synflorix 
2D RSV ChAd 2D RSV ChAd Synflorix 
Synflorix 
Synflorix 
Synflorix 
FB 
Synflorix 
Synflorix 
FB 
Synflorix 
1D RSV + Menveo 
1D RSV ChAd FB 
Menveo 
 
Menveo 
2D RSV + Menveo 
2D RSV ChAd 2D RSV ChAd Menveo 
 
Menveo 
Menveo 
FB 
Menveo 
FB 
 
Menveo 
1D RSV + Placebo 
1D RSV ChAd FB 
 
 
 
2D RSV + Placebo 
2D RSV ChAd 2D RSV ChAd  
 
 
Placebo 
FB 
FB 
 
 
 
V: Visit; D: Day; 1D: 1 Dose (1.5x1010 vp/dose); 2D: 2 Dose (5x1010 vp/dose); RSV ChAd: ChAd155-RSV vaccine; FB: 
Formulation buffer S9b. 
* Assumes enrolled at 6 and 7 months of age for the vaccine Dose 1 to be administered before the first RSV season; 
the second dose will be given one month after the first dose. (RSV seasons will be determined for each country 
based on local epidemiological data [The RSV season is defined as the period of the year when 70% of the RSV 
cases have occurred in previous years. For the calculation, where available, data from up to the ten previous years 
should be applied. If the data permit calculation of the actual date of the beginning of the season, rather than 
approximation to the nearest month, this is desirable. Refer to the SPM for RSV seasons per country.])  
** In countries where Menveo or Placebo is used as a comparator, no administration will be performed at Day 121 and 
therefore in those countries there will be no Visit 6 and it will be administered at the end of the first RSV season at 
Visit 7. 
• 
Experimental design: Phase I/II, observer-blind, randomized, controlled, multi-
centric study with three parallel groups 
• 
Duration of the study: approximately 24 months. 
− 
Epoch 001: Screening Visit starting up to 30 days before first vaccination and 
ending on Day -1. 
− 
Epoch 002: primary starting at Visit 1 (Day 1) and ending at Visit 5 (Day 61). 
− 
Epoch 003: follow-up starting after Visit 5 (Day 61)* and ending at Visit 7 (end 
of the first RSV transmission season). 
− 
Epoch 004: follow-up starting after Visit 7 (end of the first RSV transmission 
season)* and ending at Visit 8 (end of the second RSV transmission season).  
*Any safety, immunogenicity and disease surveillance data collected beyond Visit 5 
(Day 61) will be collected in Epoch 003. Any safety, immunogenicity and disease 
surveillance data collected beyond Visit 7 (end of the first RSV transmission season) 
will be collected in Epoch 004. Refer to the SPM for RSV transmission seasons per 
country. 
• 
Primary Completion Date (PCD): Visit 5 (Day 61). 


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204894 (RSV-PED-011) 
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Page 16 of 97 
• 
End of Study (EoS): Last testing results released of samples collected at Visit 8 (end 
of the second RSV transmission season) related to primary and secondary 
endpoints.*  
* Up to Visit 8 (end of the second RSV season), there will be monthly nasal swab to 
detect asymptomatic RSV infections during the RSV season or if following active or 
a passive surveillance contacts, a subject presents symptoms of respiratory tract 
infection (RTI), a nasal swab will be collected. 
• 
Study groups: 
Table 2 
Study groups and epochs foreseen in the study 
Study groups 
Target Number 
of subjects 
Age (Min/Max) 
Epochs 
Epoch 001 
Epoch 002 
Epoch 003 
Epoch 004 
1D RSV + Bexsero 
50 
6 – 7 months 
N/A 
x 
x 
x 
1D RSV + Nimenrix 
6 – 7 months 
N/A 
x 
x 
x 
1D RSV + Synflorix 
6 – 7 months 
N/A 
x 
x 
x 
1D RSV + Menveo 
6 – 7 months 
N/A 
x 
x 
x 
1D RSV + Placebo 
6 – 7 months 
N/A 
x 
x 
x 
2D RSV + Bexsero 
50 
6 – 7 months 
N/A 
x 
x 
x 
2D RSV + Nimenrix 
6 – 7 months 
N/A 
x 
x 
x 
2D RSV + Synflorix 
6 – 7 months 
N/A 
x 
x  
x 
2D RSV + Menveo 
6 – 7 months 
N/A 
x 
x 
x 
2D RSV + Placebo 
6– 7 months 
N/A 
x 
x 
x 
Bexsero 
50 
6 – 7 months 
N/A 
x 
x 
x 
Nimenrix 
6 – 7 months 
N/A 
x 
x 
x 
Synflorix  
6 – 7 months 
N/A 
x 
x 
x 
Menveo 
6 – 7 months 
N/A 
x 
x 
x 
Placebo 
6 – 7 months 
N/A 
x 
x 
x 
1D: 1 Dose (1.5x1010 vp/dose); RSV: ChAd155-RSV vaccine; 2D: 2 Dose (5x1010 vp/dose); N/A: Not Applicable.  


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204894 (RSV-PED-011) 
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27-MAR-2019 
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Table 3 
Study groups and treatment foreseen in the study 
Treatment name 1D RSV ChAd  
2D RSV ChAd 
Bexsero  Nimenrix  Synflorix 
Menveo  
FB 
Vaccine/ 
Product name 
1D ChAd155-RSV 
1.5X1010 vp/dose 
2D ChAd155-RSV 
5X1010 vp/dose 
Bexsero Nimenrix Synflorix 
Menveo 
FB 
Study Groups 
 
 
 
 
 
 
 
1D RSV + Bexsero 
x 
 
x 
 
 
 
x 
1D RSV + Nimenrix 
x 
 
 
x 
 
 
x 
1D RSV + Synflorix 
x 
 
 
 
x 
 
x 
1D RSV + Menveo 
x 
 
 
 
 
x 
x 
1D RSV + Placebo 
x 
 
 
 
 
 
x 
2D RSV + Bexsero 
 
x 
x 
 
 
 
 
2D RSV + Nimenrix 
 
x 
 
x 
 
 
 
2D RSV + Synflorix 
 
x 
 
 
x 
 
 
2D RSV + Menveo 
 
x 
 
 
 
x 
 
2D RSV + Placebo 
 
x 
 
 
 
 
 
Bexsero 
 
 
x 
 
 
 
x 
Nimenrix 
 
 
 
x 
 
 
x 
Synflorix 
 
 
 
 
x 
 
x 
Menveo 
 
 
 
 
 
x 
x 
Placebo 
 
 
 
 
 
 
x 
ChAd155-RSV: Chimpanzee Adenovirus Type 155 RSV vaccine; FB: Formulation buffer S9b; RSV ChAd: ChAd155-
RSV vaccine; 1D: 1 Dose (1.5x1010 vp/dose); 2D: 2 Dose (5x1010 vp/dose). 
• 
Controls: active comparator vaccines (Bexsero, or Nimenrix, or Synflorix, or Menveo, 
or Placebo (FB)*.  
* The choice of active comparator vaccine (Bexsero, Nimenrix, Synflorix, or Menveo) 
or Placebo is done at the country level. Refer to the ICF for the local choice of 
comparator/Placebo. 
• 
Vaccination schedules: 
− 
RSV investigational vaccine: In the 1 Dose (1D) groups, a single lower dose of 
1.5x1010 vp will be administered IM at Day 1 (Visit 1). Formulation buffer will 
be administered in the 1D groups at Day 31 (Visit 3). In the 2 Dose (2D) groups, 
two doses of 5x1010 vp will be administered IM according to a 0, 1-month 
schedule, (i.e., at Day 1 [Visit 1] and Day 31 [Visit  3]) (see Figure 1 and Table 
1). Dose 1 will be administered before the first RSV season and the second dose 
will be given one month after the first dose (RSV seasons will be determined for 
each country based on local epidemiological data and documented in the Study 
Procedures Manual [SPM]. The RSV season is defined as the period of the year 
when 70% of the RSV cases have occurred in previous years. For the 
calculation, where available, data from up to the ten previous years should be 
applied. If the data permit calculation of the actual date of the beginning of the 
season, rather than approximation to the nearest month, this is desirable.) 
− 
Comparator or Placebo: In countries where Bexsero or Nimenrix is used as a 
control, two doses will be administered IM with at least a 2-month interval 
between these primary doses. A booster dose will be administered IM in the 
second year of life at Visit 7, with an interval of at least 2 months between the 


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primary series and booster dose. The first Bexsero or Nimenrix dose will be 
administered at Day 1 (Visit 1) (in the groups receiving only Bexsero or 
Nimenrix, respectively). In the groups receiving only Bexsero or Nimenrix, the 
second dose will be at Day 61 (Visit 5). The first Bexsero or Nimenrix dose to be 
administered to the 1D and 2D RSV groups will be at Day 61 (Visit 5), 
following the 1 or 2 RSV vaccine doses, respectively. The second dose of 
Bexsero or Nimenrix in the 1D and 2D groups will be at Day 121 (Visit 6). 
Formulation buffer will be administered, when neither RSV vaccine nor 
comparator is scheduled, at the 5 vaccination visits (see  Figure 1 and Table 1).  
− 
In countries where Synflorix is used as a control, two doses will be administered 
IM with at least a 1 month interval between these primary doses. A booster dose 
will be administered IM in the second year of life at Visit 7. The first Synflorix 
dose will be administered at Day 31 (Visit 3) (in the group receiving only 
Synflorix). In the group receiving only Synflorix, the second dose will be at 
Day 61 (Visit 5). The first Synflorix dose to be administered to the 1D and 2D 
RSV groups will be at Day 61 (Visit 5), following the 1 or 2 RSV vaccine doses, 
respectively. The second dose of Synflorix in the 1D and 2D groups will be at 
Day 121 (Visit 6). Formulation buffer will be administered, when neither RSV 
vaccine nor comparator is scheduled, at the 5 vaccination visits (see Figure 1 
and Table 1).  
− 
In countries where Menveo is used as a control, two doses will be administered 
IM at least 3 months apart with the second dose in the second year of life at 
Visit 7. The first Menveo dose will be administered at Day 31 (Visit 3) (in the 
group receiving only Menveo). The first Menveo dose to be administered to the 
1D and 2D RSV groups will be at Day 61 (Visit 5), following the 1 or 2 RSV 
vaccine doses, respectively. Since the second Menveo dose has to be 
administered in the second year of life at Visit 7, no administration will be 
performed at Day 121 (Visit 6). Formulation buffer will be administered, when 
neither RSV vaccine or comparator is scheduled, at the 4 vaccination visits (see 
Figure 1 and Table 1).  
− 
In countries where Placebo is used as a control, one dose will be administered 
IM at Day 31 (Visit 3) in the 1D RSV + Placebo group and two IM doses will be 
administered IM according to a 0, 1-month schedule at Day 1 (Visit 1) and 
Day 31 (Visit 3) in the Placebo group (see Figure 1 and Table 1).  
• 
Treatment allocation: infants will be randomized using a centralized randomization 
system on internet (SBIR) before first vaccination and after assessment of eligibility 
(i.e., after screening conclusion) (refer to Section 6.2.2 of the protocol for details 
about randomization of treatment). The randomization algorithm will use a 
minimization procedure accounting for country as a minimization factor and the 
grouping comparator/placebo as a stratification factor.  
• 
Blinding: not applicable for Epoch 001 (Screening Visit), observer-blind in Epoch 
002 and single-blind in Epoch 003 and Epoch 004. Refer to Section 6.3 of the 
protocol for details of blinding procedure. 


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• 
Blinding of study epochs 
Study Epochs 
Blinding 
Epoch 001 
N/A 
Epoch 002 
observer-blind 
Epoch 003 
single-blind 
Epoch 004 
single-blind 
• 
Sampling schedule: 
− 
Blood samples for hematology/biochemistry will be taken from all infants at 
Screening (up to 30 days before first vaccination to Day -1). Blood samples for 
hematology/biochemistry may be taken from infants at any timepoints, if 
deemed necessary by the investigator. Refer to Table 12 of the protocol for the 
list of parameters to be tested. 
− 
Refer to Section 6.6.1.2.2 and Figure 2 of the protocol for information about the 
re-testing of samples in case of any Grade 1 abnormality with potential clinical 
relevance (according to investigators judgment) or any ≥ Grade 2 abnormality. 
− 
Blood samples for humoral immunogenicity will be taken from all subjects at 
Screening and on Day 31, Day 61, and at the visit occurring at the end of the 
first RSV transmission season. 
− 
Blood sample for assessment of mechanism of illness (potential ERD) will be 
taken from subjects hospitalized for LRTI (only for RSV-positive subjects using 
a locally available RSV test). 
− 
Nasal swab: there will be monthly nasal swab to detect asymptomatic RSV 
infections during the RSV season and if following active or a passive 
surveillance contacts, a subject present symptoms of RTI, a nasal swab will be 
collected (as well as a sample for local testing i.e., the type of sample to be 
determined locally [e.g., swab, etc.]) (Refer to the SPM). 
• 
Study visits: Other than the screening visit and assessment visits for active/passive 
surveillance, there will be 8 study visits except in countries where Menveo or 
Placebo is used as a control where there will be 7 study visits.  
− 
In countries where Menveo is used as a comparator, no administration will be 
performed at Day 121 and therefore in those countries there will be no Visit 6 
and it will be administered at the end of the first RSV season at Visit 7 (refer to 
Table 2 and 7 of the protocol). 
− 
In countries where Placebo is used as a control, no vaccine administration will 
be performed after Visit 3 and therefore in those countries there will be no Visit 
6. There will be a Visit 5 and Visit 7 for countries using Placebo and all other 
study procedures will occur at these visits except vaccination.  
− 
Visit 2 (Day 8), Visit 4 (Day 38), and Visit 8 (no blood sampling for immune 
response and no vaccine administration) may take place in the subject’s home or 
at the investigators clinical facility as appropriate to the circumstances in the 
judgment of the investigator.  


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o 
For authorized sites only, Visit 5 (Day 61) and Visit 7 (both with blood 
sampling) may also take place in the subject’s home or at the investigators 
clinical facility as appropriate to the circumstances in the judgment of the 
investigator.  
o 
Data collection: electronic Case Report Form ( eCRF). 
o 
Safety monitoring: internal safety review committee (iSRC) and IDMC 
(refer to Section 9.10 of the protocol). 
• 
Surveillance for RSV-RTI, difficulty in breathing, and wheezing episodes 
Surveillance period will be carried out from Visit 1 (after Dose 1) until the last study 
visit (end of the second RSV transmission season). In order to detect asymptomatic 
RSV-RTI, monthly nasal swabs for analysis at sponsor laboratory will be performed 
for all subjects during the RSV season. In order to timely detect RSV-RTI and to 
ensure cases are timely captured by the study sites, both active and passive 
surveillance will be conducted: 
− 
Passive surveillance: parent(s)/LAR(s) are instructed to contact the 
investigator/study staff as soon as the subject experiences new RTI symptoms 
(cough, runny nose or blocked nose) or worsening of RTI symptoms, or in case 
of difficulty in breathing or wheezing. 
− 
Active surveillance: parent(s)/LAR(s) of all the subjects will be contacted by 
the investigator/study staff on a regular basis (weekly during the RSV season 
and every month outside the RSV season) to identify any potential RSV-RTI 
and to remind the parent(s)/LAR(s) of the subjects to report any new occurrence 
of RTI symptoms (cough, runny nose or blocked nose), or in case of difficulty in 
breathing or wheezing as soon as possible. 
Refer to Section 9.2 of the protocol for more information about active and passive 
surveillance.  
• 
Surveillance for spontaneous or excessive bleeding - Subjects’ parent(s)/LAR(s) will 
be instructed to contact the investigator/study staff if their child presents symptoms 
of spontaneous bleeding or easy bruising or if their child develops a rash, within 30 
days after either vaccination (Visit 1 and Visit 3), in order to detect any 
thrombocytopenic petechiae or purpura. The investigator will, based on his/her 
medical judgment, measure the total blood count and appropriately investigate 
infants with clinical suspicion of low platelets.  
• 
Group description: - For the blinded report on safety/reactogenicity, the analyses 
will be presented as one group (RSV groups and Placebo group being pooled).  


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The following group names for the unblinded analysis will be used in the TFLs, to be in 
line with the T-domains:. 
Group 
order in 
tables 
Group label in 
tables 
Group definition for footnote 
Pooled Groups label 
in tables – 
UNBLINDED 
ANALYSIS  
Pooled definition 
for footnote - 
UNBLINDED 
ANALYSIS  
1 
RSVBEX1D 
RSV 1D + BEXERO 3D 
RSV 1D 
Pooled 1D RSV 
2 
RSVNIM1D 
RSV 1D +NIMENRIX 3D 
3 
RSVSYN1D 
RSV 1D +SYNFLORIX 3D 
4 
RSVMEN1D 
RSV 1D +MENVEO 2D 
5 
RSVPBO1D 
RSV 1D + PLACEBO 
6 
RSVBEX2D 
RSV 2D + BEXERO 3D 
RSV 2D 
Pooled 2D RSV 
7 
RSVNIM2D 
RSV 2D +NIMENRIX 3D 
8 
RSVSYN2D 
RSV 2D +SYNFLORIX 3D 
9 
RSVMEN2D 
RSV 2D +MENVEO 2D 
10 
RSVPBO2D 
RSV 2D + PLACEBO 
11 
BEXERO 
BEXERO 3D 
COMP_PLB 
Pooled comparator 
12 
NIMENRIX 
NIMENRIX 3D 
13 
SYNFLORIX 
SYNFLORIX 3D 
14 
MENVEO 
MENVEO 2D 
15 
PLACEBO 
PLACEBO 
3. 
OBJECTIVES/ENDPOINTS 
3.1. 
Objectives 
3.1.1. 
Primary Objective  
• 
To evaluate the safety and reactogenicity of the RSV investigational vaccine when 
administered IM as one (1.5x1010 vp) dose or as two (5x1010 vp) doses according to 
a 0, 1-month schedule, up to 60 days after Dose 1 (i.e., Day 61) in infants aged 6 and 
7 months. 
3.1.2. 
Secondary Objective 
• 
To evaluate the occurrence of RSV respiratory tract infections of any severity from 
Visit 1 (Day 1, after Dose 1) up to the end of the first RSV transmission season, in 
infants aged 6 and 7 months 
• 
To evaluate the safety of the RSV investigational vaccine when administered IM as 
one (1.5x1010 vp) dose or as two (5x1010 vp) doses according to a 0, 1-month 
schedule, from study start (Day 1) up to the end of the second RSV transmission 
season in infants aged 6 and 7 months 
• 
To evaluate the occurrence of RSV respiratory tract infections from Visit 1 (Day 1, 
after Dose 1) up to the end of the second RSV transmission season, in infants aged 6 
and 7 months. 


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• 
To evaluate the occurrence of very severe RSV-LRTI from Visit 1 (Day 1, after 
Dose 1) up to the end of the first RSV transmission season in RSV infected infants 
aged 6 and 7 months with a negative RSV exposure status (at screening based on in-
stream baseline serological testing. 
• 
To evaluate the humoral immunogenicity induced by the RSV investigational 
vaccine when administered IM as one (1.5x1010 vp) dose or as two (5x1010 vp) doses 
according to a 0, 1-month schedule, from study start (Day 1) up to the end of the first 
RSV transmission season, in infants aged 6 and 7 months. 
3.1.3. 
Tertiary objective 
• 
If deemed necessary, to further characterize the immune response of the RSV 
investigational vaccine when one (1.5x1010 vp) dose or two (5x1010 vp) doses are 
administered IM according to a 0, 1-month schedule to infants aged 6 and 7 months 
3.2. 
Endpoints 
3.2.1. 
Primary endpoints 
• 
Occurrence of adverse events (AEs) from first vaccination (Day 1) up to Day 61 
− Occurrence of each solicited local and general AE, during a 7-day follow-up 
period after each vaccination (i.e., the day of vaccination and 6 subsequent days) 
− Occurrence of any unsolicited AE, during a 30-day follow-up period after each 
vaccination (i.e., the day of vaccination and 29 subsequent days) 
− Occurrence of any serious adverse event (SAE) from Day 1 up to Day 61 
− Occurrence of episode of spontaneous or excessive bleeding (AE of special 
interest), during a 30-day follow-up period after each vaccination 
3.2.2. 
Secondary endpoints 
• 
Occurrence of RSV-RTI, RSV-LRTI, severe RSV-LRTI and very severe RSV-LRTI 
(according to standardized case definitions) as from first vaccination (Day 1) up to 
the end of the first RSV transmission seasons. 
• 
Occurrence of RSV-RTI, RSV-LRTI, severe RSV-LRTI and very severe RSV-LRTI 
(according to standardized case definitions) as from first vaccination (Day 1) up to 
the end of the second RSV transmission seasons. 
• 
Occurrence of SAEs from first vaccination (Day 1) up to the end of the second RSV 
transmission seasons. 
• 
Occurrence of RSV-LRTI (AE of special interest) as from first vaccination (Day 1) 
up to the end of the first RSV transmission season, and up to the end of the second 
RSV transmission seasons. 


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• 
Occurrence of very severe RSV-LRTI (according to standardized case definitions) 
among RSV infected infants with a negative RSV exposure status (at screening 
based on in-stream baseline serological testing) from first vaccination (Day 1) up to 
the end of the first RSV transmission seasons. 
• 
Humoral response to the investigational RSV vaccine, pre-vaccination (Screening), 
post-Dose 1 (Day 31) and post-Dose 2 (Day 61 and at the end of the first RSV 
transmission season): 
− 
Neutralizing antibody titers against RSV-A 
− 
RSV F antibody concentrations 
3.2.3. 
Tertiary endpoints 
• 
Humoral response to the investigational RSV vaccine, pre-vaccination (Screening), 
post-Dose 1 (Day 31) and post-Dose 2 (Day 61) 
− 
Palivizumab-competing antibody concentrations 
• 
Any further exploratory immunology to detect disease-related or vaccine-related 
immune responses, such as but not limited to 
− 
Anti-vector immunity: neutralization  
4. 
ANALYSIS SETS 
4.1. 
Definition 
4.1.1. 
Exposed Set 
The Exposed Set (ES) will include all subjects with at least one study vaccine 
administration documented. 
• 
A safety analysis based on the ES will include all vaccinated subjects. 
• 
An immunogenicity analysis will be conducted on the ES and will include all 
vaccinated subjects for whom immunogenicity data are available.  
The ES analysis will be performed per treatment actually administered at Dose 1 
4.1.2. 
Exposed Set of subjects with a negative RSV exposure status 
The Exposed Set of subjects with a negative RSV exposure status will include all 
vaccinated subjects assessed as RSV unexposed at screening based on in-stream baseline 
serological testing 
The safety analysis of incidence of RSV-LRTI will be conducted on the cohort of 
subjects with a negative RSV exposure status (at screening based on in-stream baseline 
serological testing) as well as on the entire ES. 


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4.1.3. 
Per-protocol Set for analysis of immunogenicity 
The per-protocol set (PPS) cohort for analysis of immunogenicity will be defined by 
timepoint (Day 31, Day 61 and End of the first RSV transmission season) and will consist 
of all subjects from the ES who complied with eligibility criteria, study procedures up to 
the end of the study and had immunogenicity results in the epoch as described below, 
More specifically, the PPS cohort for analysis of immunogenicity for specific timepoint 
(Day 31 [Visit 3], Day 61 [Visit 5] and at end of the first RSV transmission season [Visit 
7]) will include all evaluable subjects: 
• 
Who met all eligibility criteria (i.e., no protocol violation linked to the 
inclusion/exclusion criteria, including age). 
• 
Who received study vaccine as scheduled per protocol.  
• 
For whom the administration route and site of the vaccine was as according to 
protocol. 
• 
Who received the vaccine according to protocol procedures. 
• 
Who complied with the vaccination schedule, as specified Table 4 in of the SAP. 
• 
Who did not receive a concomitant medication/product/vaccine leading to exclusion 
from a PPS analysis, as described in Section 7.6.2 of the protocol, up to Day 31 
(Visit 3)/up to Day 61 (Visit 5) /at Visit 7 (end of the first RSV transmission season).  
• 
Who complied with the timings of the post vaccination blood sampling for immune 
response evaluation, up to Day 31 (Visit 3)/up to Day 61 (Visit 5) /at Visit 7 (end of 
the first RSV transmission season), as specified in Table 4 of the SAP.  
When presenting different time-points, the PPS for immunogenicity will be adapted for 
each time-point (Day 31, Day 61 and End of first RSV transmission season). 
Table 4 presents the intervals between study visits that determine subjects’ eligibility for 
inclusion in the PPS analysis. 
Table 4 
Maximum allowed interval between study visits for PPS 
Interval 
Allowed length of interval1 
Visit 1 (Day 1) → Visit 3 (Day 31) 
23 - 44 days 
Visit 1 (Day 1) → Visit 5 (Day 61) 
60 - 81 days 
Visit 3 (Day 31) → Visit 5 (Day 61) 
28 - 37 days 2 
Visit 5 (Day 61) → Visit 7 
(end of the first RSV transmission season) 
90 days to the defined end of transmission season or 
up to 4 weeks after 
1 Subjects will not be eligible for inclusion in the PP cohort for analysis of immunogenicity if they make the study visit 
outside this interval. 
2 The interval between Visit 1 and Visit 5 must be a minimum of 60 days to be in line with the active comparator 
vaccination schedules as per the respective approved labels. 


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4.2. 
Criteria for eliminating data from Analysis Sets 
Elimination codes are used to identify subjects to be eliminated from analysis. Detail is 
provided below for each set.  
4.2.1. 
Elimination from Exposed Set (ES) 
Code 1030 (Study vaccine not administered at all), code 900 (invalid informed consent) 
and code 800 (fraudulent data) will be used for identifying subjects eliminated from ES. 
4.2.2. 
Elimination from Exposed Set (ES) subjects with a negative RSV 
exposure status 
Code 1030 (Study vaccine not administered at all), code 900 (invalid informed consent) 
and code 800 (fraudulent data) will be used for identifying subjects eliminated from ES. 
Additionally, code 2020 (RSV- seropositive antibody status at baseline) will be used to 
identify all the subject with negative RSV exposure status.  
4.2.3. 
Elimination from Per-protocol analysis Set (PPS) 
4.2.3.1. 
Excluded subjects 
A subject will be excluded from the PPS analysis under the following conditions  
For codes 1040, 1070, 1080, 1090, 2040, 2060, 2070, 2080: subjects will be eliminated 
from a specific visit (at which the condition is met) onwards. 
For codes 2090, 2100, 2120: subjects will be eliminated at the specific visit at which the 
condition is met 
Code 
Condition under which the code is used 
Visit (timepoints) 
where the code is 
applicable 
Applicable for analysis 
set 
800 
Fraudulent data 
All 
All 
900 
Invalid informed consent  
All 
all 
1030 
Study vaccine not administered at all 
All 
Safety, immunology 
1040 
Administration of concomitant vaccine(s) forbidden in 
the protocol:- 
• 
Any investigational or non-registered product 
(drug or vaccine) other than the study vaccines 
used during the study period 
• 
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 dose of vaccine*, with the exception of: 
− 
Scheduled routine pediatric vaccines 
which may be administered  7 days 
before a dose and  7 days after a dose of 
study vaccines, with the exception of live 
viral vaccines which may be administered 
Visit 3,5, 7 
Immunogenicity 


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Code 
Condition under which the code is used 
Visit (timepoints) 
where the code is 
applicable 
Applicable for analysis 
set 
 14 days before a dose or  7 days after 
a dose. 
− 
Vaccines needed for urgent individual 
medical need (e.g., rabies prophylaxis 
1050 
Randomisation failure 
All 
Immunogenicity 
1060 
Randomisation code was broken 
All 
Immunogenicity 
1070 
Subjects got vaccinated with the correct vaccine but 
containing a lower volume 
All 
Immunogenicity 
1070 
Vaccination not according to protocol: 
• 
Wrong replacement or study vaccine 
administered (not compatible with the vaccine 
regimen associated to the treatment number) 
• 
Site or route of study vaccine administration 
wrong or unknown 
• 
Administration not according to protocol for 
reason specified by the investigator, other than 
side, site and route 
All 
Immunogenicity 
1080 
Vaccine temperature deviation (vaccine administered 
despite a Good Manufacturing Practices (GMP) no-go 
temperature deviation for RSV vaccines only) 
All  
Immunogenicity 
1090 
Expired vaccine administered (only applicable for RSV 
vaccine) 
All 
Immunogenicity 
2010 
Protocol violation (inclusion/exclusion criteria including 
age) 
All 
Immunogenicity 
2040 
Administration of any medication forbidden by the 
protocol: 
• 
Any investigational or non-registered product 
(drug) other than the study vaccines used during 
the study period 
• 
Long-acting immune-modifying drugs 
administered at any time during the study period 
• 
Immunosuppressants or other immune-
modifying drugs administered chronically (i.e., 
more than 14 days in total) during the study 
period 
• 
Immunoglobulins and/or any blood products 
administered during the study period 
Visit 3, 5, 7 
Immunogenicity 
2050 
Underlying medical condition forbidden by the protocol 
Visit 3, 5, 7 
Immunogenicity 
2060 
Intercurrent medical condition  
→ Intercurrent medical condition that has the 
capability of altering immune response, or alteration of 
initial immune status (suspected or confirmed 
immunosuppressive or immunodeficient condition) 
which may influence immune response 
Visit 3, 5, 7 
Immunogenicity 
2070 
Concomitant infection not related to the vaccine which 
may influence immune response 
Visit 3, 5, 7 
Immunogenicity 
2080 
Subjects did not comply with vaccination schedule:- 
Number of days between dose 1 and dose 2 is outside 
[23-44 days] 
Visit 3 
Immunogenicity 


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Code 
Condition under which the code is used 
Visit (timepoints) 
where the code is 
applicable 
Applicable for analysis 
set 
2090 
Subjects did not comply with blood sample schedule 
• 
Number of days between dose 1 and visit 3 
blood sample is outside [23-44 days]  
• 
Number of days between dose 1 and visit 5 
blood sample is outside [60-81 days] 
• 
Number of days between dose 2 and visit 5 
blood sample is outside [28-37 days] for RSV 2D 
group 
• 
Number of days between visit 5 blood sample 
and visit 7 blood sample is outside [92-148 days] 
Visit 3, 5, 7 
Immunogenicity 
2100 
Serological results not available post-vaccination:-  
No immunological result at visit x for all 2 tests - RSV 
A Neutralising antibody titer and RSVPreF3-specific 
IgG antibody concentration 
Visit 3, 5 and 7 
Immunogenicity 
2120 
Obvious incoherence or abnormality or error in data :-  
Incoherence between CRF and results, wrong sample 
labelling, Central/internal/external lab deviations; 
incorrect spinning/processing of sample including 
processing within the time required by protocol; 
temperature deviations from range defined in protocol 
and/or SPM - room temperature/refrigerator/freezer; 
an assessment was completed but was not completed 
according to protocol or SPM. 
Visit 3, 5, 7  
Immunogenicity 
5. 
STATISTICAL ANALYSES 
Note that standard data derivation rules and stat methods are described in “business rules 
document” and will not be repeated below. The study specific data derivation rules and 
stat methods will be described in section 9. 
5.1. 
Demography 
5.1.1. 
Analysis of demographics/baseline characteristics planned in the 
protocol 
The analysis of demographics will be performed on the ES and on the PPS cohort for 
immunogenicity for each RSV + comparator vaccine group and each active control 
comparator group and also for the pooled RSV vaccine and pooled comparator group. 
Demographic characteristics (age at vaccination in months, sex, country and race and 
vital signs), cohort description will be summarized by group using descriptive statistics: 
• 
Frequency tables will be generated for categorical variables such as race. 
• 
Mean, median, standard deviation and range will be provided for continuous data 
such as age. 
The distribution of subjects will be tabulated as a whole and per group. 


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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. 
5.1.2. 
Additional considerations 
• 
Summary of important protocol deviation leading to elimination will be presented. 
An individual listing will also be presented for this. 
• 
Consort tables for flow of subject from enrolment to randomization and 
randomization to exposed will also be presented. 
• 
The following table will be performed for web public disclosure  
− 
Percentage of Enrolled subjects by country will be tabulated by group, 
− 
Percentage of Enrolled subjects by age categories will be tabulated by group. 
5.2. 
Immunogenicity 
5.2.1. 
Analysis of immunogenicity planned in the protocol 
The primary analysis will be performed on the PPS for immunogenicity and, if in any 
group the percentage of vaccinated subjects with serological results excluded from the 
PPS for immunogenicity is more than 10%, a second analysis will be performed on the 
ES. The results from immunogenicity analysis will be reported by the pooled RSV 
vaccine group and the pooled comparator group 
For the final analysis, the Adapted PPS for immunogenicity analysis will be used which 
allows the summary of immunogenicity results by time point. In summary table on the 
Adapted PPS for immunogenicity, immunogenicity summary result at Day 31, Day 61 
and end of first RSV transmission season will be presented on PPS for immunogenicity at 
Day 31, Day 61 and end of first RSV transmission season, respectively. 
The infants are monitored for RSV infection starting from dose 1 and, therefore, 
immunogenicity analyses can be adjusted to exclude those infants with an infection prior 
to sampling. 


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5.2.1.1. 
Within groups assessment 
5.2.1.1.1. Analysis of secondary objectives 
For three pooled groups, at each timepoint that blood samples are collected for humoral 
immune response against the investigational RSV vaccine (neutralizing antibody titers 
against RSV-A, RSV F antibody concentrations). 
• 
Geometric mean titers/concentrations (GMTs/GMCs) will be tabulated with 95% CI 
and represented graphically. 
• 
Percentage of subjects above the sero-positivity threshold will be tabulated with 
exact 95% CI. 
• 
Antibody titers/concentrations will be displayed using reverse cumulative curves. 
• 
The distributions (< 128, 128-256, > 256-512, > 512-1024, > 1024-2048, > 2048-
4096, > 4096) of neutralizing antibody titers/concentrations will be tabulated. 
• 
Individual post-vaccination versus pre-vaccination results will be plotted using 
scatter plots. Results of the comparator group will be used as a reference. 
• 
Geometric mean of ratios of antibody titers/concentrations at each post-vaccination 
timepoint over pre-vaccination will be tabulated with 95% CI. 
• 
Distribution of the fold increase of the neutralizing antibody titers will be tabulated 
by pre-vaccination titer category. 
• 
The kinetics of individual antibody titers/antibody concentrations results will be 
plotted as a function of time for subjects with results available at all timepoints. 
An immunogenicity analysis will also be performed on the ES with a negative RSV 
exposure status (at screening based on in-stream baseline serological testing) for whom 
immunogenicity data are available.  
At study end, an additional analysis of immunogenicity will be performed on infants by 
baseline values (as per the cut-off used to define RSV naïve serostatus).  
5.2.1.1.2. Analysis of tertiary objective 
If available, any further exploratory immunology results (including, but not limited to 
anti-vector immunity and palivizumab-competing antibody concentrations) will be 
reported by timepoint for the two pooled RSV vaccine groups and the pooled comparator 
group using descriptive summary statistics.  
5.2.2. 
Additional considerations 
• 
Summary statistics for neutralizing antibody titers against RSV-A, RSV F antibody 
concentrations (Minimum, Mean, median, SD, 1st quartile, 3rd quartile, Maximum) 
will be presented. 
• 
Distribution of the fold increase of the neutralizing antibody titers will be tabulated 
by pre-vaccination titer category (percentage of subjects with a fold increase equal to 


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or above 1, 2, 2.5, 3, 4, 6, 8 10, 11 and 12 by pre-vaccination titre category: (< 128, 
128-256, > 256-512, > 512-1024, > 1024-2048, > 2048-4096,  > 4096, and by 
cumulative category: <128, ≥128, ≥256, ≥512, ≥1024, ≥2048, ≥4096.).The 
thresholds for presentation of titres in distribution table and for fold increase will be 
further adjusted at Day 61 analysis as needed. 
• 
For three pooled groups, at each timepoint that blood samples are collected for 
humoral immune response against the investigational RSV vaccine (neutralizing 
antibody titrs against RSV-A, RSV F antibody concentrations, following additional 
analysis will be performed on PPS by baseline values (sero-negative vs sero-positive 
for RSV as per cut-off defined for RSV naïve serostatus) at the end of study:-  
− 
Geometric mean titers/concentrations (GMTs/GMCs) will be tabulated with 
95% CI and represented graphically. 
− 
The distributions of neutralizing antibody titers/concentrations will be tabulated. 
− 
Geometric mean of ratios of antibody titers/concentrations at each post-
vaccination timepoint over pre-vaccination will be tabulated with 95% CI 
− 
Summary statistics for neutralizing antibody titers against RSV-A, RSV F 
antibody concentrations (Minimum, Mean, median, SD, 1st quartile, 3rd quartile, 
Maximum) will be presented. 
5.3. 
Analysis of safety and reactogenicity 
5.3.1. 
Analysis of safety and reactogenicity planned in the protocol 
5.3.1.1. 
Within groups assessment 
The safety will be descriptively summarized based on the ES. The analysis of local AEs, 
general AEs and fever will be reported for each RSV + comparator vaccine group and 
each active control comparator group and also for the pooled RSV vaccine and pooled 
comparator groups. For the analysis of SAEs and AE of specific interest, the analysis will 
be performed only on the pooled RSV and pooled comparator groups. 
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 vaccine dose and overall. The percentage of doses followed by at least one local AE 
(solicited and unsolicited), by at least one general AE (solicited and unsolicited) and by 
any AE during the 7-day or 30-day follow-up period will be tabulated, overall 
vaccination course, with exact 95% CI. The same computations will be done for Grade 3 
AEs, for any AEs considered related to vaccination for any Grade 3 AEs considered 
related to vaccination and AEs resulting in a medically attended visit.  
The percentage of subjects reporting each individual solicited local AE (any grade, Grade 
2, Grade 3, resulting in a medically attended visit) and solicited general AE (any grade, 
Grade 2, Grade 3, any related, Grade 2 related, Grade 3 related, resulting in medically 
attended visit) during the 7-day follow-up period (Day 1-7) will be tabulated for each 


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RSV + comparator vaccine group and each active control comparator group and also for 
the pooled RSV vaccine and pooled comparator groups after each vaccine dose and 
overall. Similarly, the percentage of doses followed by each individual solicited local and 
general AE and their sub-categories, will be tabulated, overall vaccination course, with 
exact 95% CI. 
For fever, the number and percentage of subjects reporting fever by half degree (°C) 
cumulative increments during the 7-day follow-up period (Day 1-7) will be tabulated for 
each RSV + comparator vaccine group and each active control comparator group and also 
for the pooled RSV vaccine and pooled comparator groups after each vaccine dose and 
overall. Similar tabulations will be performed for any fever with a causal relationship to 
vaccination, Grade 3 (> 40.0°C) causally related fever and for any fever resulting in a 
medically attended visit. In addition, the prevalence of any and Grade 3 fever will be 
presented graphically over time after vaccination. 
For clinical safety laboratory parameters, a listing of laboratory value outside the normal 
range for the unscheduled visits will be provided as per the toxicity scale referred in the 
protocol. Laboratory values will be classified according to toxicity criteria (Table 7) of 
the SAP. 
Laboratory values that are outside the normal range will also be flagged in the data 
listings, along with corresponding normal ranges and assessment of clinical significance 
The percentage of subjects with unsolicited AEs within 30 days (Day 1-30) after each 
vaccine dose (overall doses) with its exact 95% CI will be tabulated RSV + comparator 
vaccine group and each active control comparator group and also for the pooled RSV 
vaccine and pooled comparator groups and by 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 AEs 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 subject with episode of spontaneous or excessive bleeding (AE of 
specific interest), during a 30-day follow-up period after each vaccination will be 
tabulated according to associated Preferred Term code mentioned in Section 9.4 of the 
SAP.  
The percentage of subjects with RSV-LRTI (AE of specific interest) from Dose 1 up to 
end of the first RSV transmission season and from Dose 1 up to end of second RSV 
season will be tabulated according to associated Preferred Term code presented in the 
Section 9.4 of the SAP.  
The percentage of subjects with SAE within 30 days (Day 1-30) after each vaccine dose 
with its exact 95% CI will be tabulated and by MedDRA preferred term. Similar tables 
will be generated for SAEs from Dose 1 to end of first RSV season and from Dose 1 to 
end of the second RSV season. 


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SAEs reported throughout the study and AE of special interest will be described in detail. 
The percentage of subjects using concomitant medication (any medication, any 
antipyretic and any antipyretic taken prophylactically, respectively) during the 7-day 
follow-up period (Day 1-7) and during the 30-day follow-up period (Day 1-30) will be 
summarized by the pooled RSV vaccine and pooled comparator groups after each vaccine 
dose and overall.  
5.3.1.2. 
Between groups assessment 
Exploratory comparisons between the pooled RSV vaccine group and the pooled 
comparator group will be done in terms of the percentage of subjects, overall doses, 
reporting any Grade 2/3 AE during the 7-day follow-up period (Day 1-7) after 
vaccination, and/ or any fever >39.0°C during the 7-day follow-up period (Day 1-7) after 
vaccination, and/ or any vaccine-related SAE during the 7-day follow-up period (Day 1-
7) after vaccination. 
The standardized asymptotic 95% CI for the difference between the pooled RSV group 
and (minus) the pooled comparator group will be computed. 
The standardized asymptotic 95% CI for the following differences will be computed:  
• 
RSV1D minus COMP_PLB 
• 
RSV2D minus COMP_PLB 
5.3.2. 
Additional considerations 
Descriptive summary of the number of days with solicited local/general adverse event 
during the 7 day (Days 1-7) post-vaccination period will be presented.  
Percentage of subjects reporting fever (any and grade 3) and other solicited general 
adverse events (any grade, grade 2,3 and grade 3) during the 7-day (Days 1-7) post-
vaccination period by maximum intensity will be presented in figure. 
Percentage of subjects reporting solicited local adverse events (any grade, grade 2,3 and 
grade 3) during the 7-day (Days 1-7) post-vaccination period by maximum intensity will 
be presented in figure.  


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5.3.2.1. 
Combined Solicited and Unsolicited Adverse Events 
A summary of subjects with all combined solicited (regardless of their duration) and 
unsolicited adverse events will be provided. Solicited adverse events will be coded by 
MedDRA as per the following codes 
Solicited symptom 
Lower level term 
name 
Lower level term code 
Corresponding Primary Term 
code 
Pain 
Pain 
10033371 
10033371 
Redness 
Erythema 
10015150 
10015150 
Swelling 
Swelling 
10042674 
10042674 
Drowsiness 
Drowsiness 
10013649 
10013649 
Fever 
Fever 
10016558 
10016558 
Irritability/Fussiness 
Irritability 
10022998 
10022998 
Loss of appetite  
Appetite lost  
10003028 
10003028 
For clintrial.gov and EudraCT posting purposes, a summary of combined solicited and 
unsolicited non-serious adverse events will be produced by System Organ Class and 
preferred terms and according to occurrence of each event. 
5.3.2.2. 
Exclusion of implausible solicited Adverse Event 
Some local and systemic adverse events will be directly measured by the subject and will 
not be subject to a reconciliation process, even if they are biologically implausible. 
Therefore, these implausible measurements will be removed from the analysis but 
included in listings. Implausible measurements are summarized in the table below: 
Table 5 
Implausible Solicited Adverse Events 
Parameter 
Implausible measurements 
Body temperature 
≤ 33°C or ≥ 42°C 
Swelling 
For subjects < 6 years: ≥ 250 mm 
Measurements < 0 mm 
5.3.2.3. 
Solicited Adverse Events 
All analyses will be based on the ‘as treated’ analysis set. Solicited adverse events will be 
reported daily during the 7-day (from Day 1 to Day 7) follow up period after each 
vaccination, using structured diaries.  
In order to summarize the data, the maximum intensity of local injection site 
redness/swelling (in mm) and fever (in °C) will be categorized as follows: 
Grading 
Redness/swelling 
Fever 
0: 
None 
< 38.0°C (100.4°F) 
1: 
<5 mm 
≥ 38.0°C (100.4°F) -  39.0°C (102.2°F) 
2: 
> 5 -  20 mm 
> 39.0°C (102.2°F) -  40.0°C (104.0°F) 
3: 
> 20 mm 
> 40.0°C (104.0°F) 


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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. Body temperature will also be summarized by 0.5°C increments as follows: 
≥38.0, >38.5, >39.0, >39.5, >40.0 °C.  
For each of the time points or time intervals presented in the summaries, only subjects 
with at least one plausible observation (i.e., any non-missing values but excluding “Not 
done/unknown” and implausible values) for the solicited adverse events in the interval of 
interest will be considered. Subjects without plausible data (i.e. missing values or 
reported as “Not done/unknown” and implausible values) will be removed from the 
denominator to prevent a downward bias (towards zero). 
5.3.2.4. 
Unsolicited Adverse Events 
All the unsolicited adverse events occurring during the study, judged either as related, or 
not related to vaccination by the investigator, will be recorded. All the unsolicited 
adverse events/AE of specific interest (Spontaneous or excessive bleeding) occurring 
during the 30-day (Day 1 to Day 30) follow up period after each vaccination, and all 
serious adverse events/AE of specific interest (RSV LRTI) occurring from Dose 1 up to 
study end will be recorded according to the protocol-specified reporting rules. The 
original verbatim terms used by investigators to identify adverse events in the CRFs will 
be mapped to preferred terms using the MedDRA dictionary. The unsolicited adverse 
events will then be grouped by MedDRA preferred terms into frequency tables according 
to system organ class. Adverse events judged by the investigator as at least possibly 
related to study vaccine will be summarized by vaccine group, according to system organ 
class and preferred term within system organ class. When an unsolicited adverse event 
occurs more than once for a subject, the maximal severity and strongest relationship to 
the vaccine group will be counted. 
Only vaccine-emergent adverse events will be analyzed, i.e., excluding those after a 
subject has given informed consent but before vaccination. The selection of unsolicited 
adverse events and the assignment to time intervals will be done by day of onset and not 
by days ongoing/persisting. 
The analysis of unsolicited adverse events during the 30-day post vaccination period 
includes the following categories: 
• 
Any unsolicited adverse event. 
• 
Possibly related unsolicited adverse events. 
• 
Grade 3 unsolicited adverse events 
• 
Grade 3 related unsolicited adverse events.  
• 
Serious adverse events (SAEs) 
• 
Possibly related SAEs. 
• 
Medically attended adverse events 
• 
AE of specific interest (spontaneous or excessive bleeding) 
SAE and AE of specific interest (RSV-LRTI) has to be reported from Day 1 up to Day 
61, from Day 1 to end of 1st RSV season and from Day 1 to end of 2nd RSV season. 


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5.4. 
Analysis of RTI and LRTI 
5.4.1. 
Analysis of RTI and LRTI planned in protocol 
The primary analysis will be performed on the ES of subjects with a negative RSV 
exposure status (at screening based on in-stream baseline serological testing) in the 
pooled single dose RSV vaccine group, the pooled two dose RSV vaccine group, and the 
pooled comparator group separately for first and second RSV seasons and overall. A 
similar analysis will be performed on the entire ES. As primary analysis, the assessment 
of RSV infection will be performed using the quantitative RT-PCR according to 
standardized case definitions (see Table 6 of the SAP) based on the available WHO case 
definitions.  
The number of RSV infections within each group and the maximum disease severity of 
the event will be tabulated.  The rate (with 95% CI) of RSV-RTI and RSV-LRTI and 
infections progressing to hospitalization will be evaluated for each of the three pooled 
groups.  
The rate of very severe RSV-LRTI among RSV infected infants with a negative RSV 
exposure status (at screening based on in-stream baseline serological testing) from first 
vaccination (Day 1) up to the end of the first RSV transmission season will be estimated 
as well as 95% one-sided lower CI.  
The proportion and the relative risk of subjects with at least one RSV-associated RTI 
(with 95% CI) between each of two pooled RSV vaccine groups and the pooled control 
group will be calculated for both the cohort of subjects with a negative RSV exposure 
status (at screening based on in-stream baseline serological testing) on the ES and on the 
entire ES. The same descriptive analysis will be performed for subjects with at least one 
RSV-associated LRTI and those with at least one RSV-associated severe LRTI.  
Descriptive analyses (mean, median, min, max) of viral load assessed by the quantitative 
RT-PCR (RSV-A/B) of all cases as listed in Table 6 of the SAP will be tabulated by case 
category. This analysis will also be done on the three pooled groups.  
The incidence rate of all cases as listed in Table 6 of the SAP (with 95% CI) will be 
calculated by the three pooled groups. The same descriptive analysis will be performed 
for all cause LRTI and all cause severe LRTI. These will also be presented for each viral 
etiology identified by the multiplex PCR.  
The incidence rate of asymptomatic RSV infections (with 95% CI) detected by the 
quantitative PCR (RSV-A/B), will be tabulated by the three pooled groups. Descriptive 
analyses (mean, median, min, max) of viral load assessed by the quantitative RT-PCR 
(RSV-A/B) of those asymptomatic RSV infections will also be done on the three pooled 
groups.  
The RVP (Multiplex PCR) on specimens from all RSV-A/B positive and confirmed LRTI 
cases, according to case definition presented in Table 6 (Figure 3 of the protocol for the 
decision tree ), will be tabulated as a qualitative assessment profiling the potential co-
infections occurring in these subjects. 


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5.4.2. 
Additional consideration 
In addition to above planned analysis for RTI and LRTI, following additional analysis is 
planned: -  
• 
Descriptive analysis on maximum viral load per subject based on qRT-PCR 
confirmed RSV infection of maximum severity will be performed. 
• 
Listing will be presented for all cases of RSV infection at Day 731 with the details of 
gender, age at episode, country, site, day of event (i.e days since first visit), 
classification according to maximum severity of episode as RSV RTI/RSV LRTI/ 
RSV severe LRTI and RSV very severe LRTI, RSV hospitalization ‘Yes/No’, SpO2 
value, respiratory rate, result of RSV qRT-PCR and RVP result will be presented. 
• 
Listings will be generated at Day 731 for all hospitalized cases with gender, age at 
episode, classification according to maximum severity of episode as (RSV RTI/RSV 
LRTI/ RSV severe LRTI and RSV very severe LRTI), RVP result, total number of 
calendar days on which the child was hospitalized, days requiring 
monitoring/nursing observation, days requiring nasogastric or intravenous fluids, 
days requiring supplemental oxygen, days requiring respiratory support excluding 
mechanical ventilation, days requiring mechanical ventilation and days requiring 
pediatric intensive care unit management.  
6. 
ANALYSIS INTERPRETATION 
For the occurrence of very severe RSV-LRTI among RSV infected infants with a 
negative RSV exposure status (at screening based on in-stream baseline serological 
testing) from first vaccination (Day 1) up to the end of the first RSV transmission season, 
if the upper boundary of the 95% one-sided lower CI of the rate is under 80%, it indicates 
that the very severe RSV-LRTI rate is less than that of the historic RSV-FI trials [Kim, 
1969].   
Comparative analyses will be exploratory and should be interpreted with caution 
considering that there is no adjustment for multiplicity and that group sizes are small for 
these comparisons. 
7. 
CONDUCT OF ANALYSES 
7.1. 
Sequence of analyses 
The statistical analyses will be performed in 3 steps: 
• 
An analysis will be performed when all data up to Day 61 are available. Additional 
safety data available at the time of this analysis will be described. At this point, the 
statistician will be unblinded (i.e., individual subject treatment assignments will be 
available) and the study will be conducted in a single blind manner, with patients 
remaining blinded up to the last study visit (end of the second RSV transmission 
season). Summary results may unblind some specific subjects, but no individual 
listings will be provided and the investigator will not have access to the treatment 


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allocation up to the last study visit (end of the second RSV transmission season), 
except in case of emergency unblinding (see Section 9.8 of the protocol) 
• 
An analysis will be performed when all data up to Visit 7 (end of the first RSV 
transmission season, i.e., data that are as clean as possible) are available. No 
individual listings will be provided. 
• 
The final analysis will be performed when all data up to study conclusion (end of the 
second RSV transmission season) are available. An integrated clinical study report 
containing all data will be written and made available to the investigators at that 
time. 
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. 
Description 
Disclosure Purpose 
(CTRS=public posting, SR=study report, internal) 
Day 61 analysis 
Internal, web disclosure 
End of RSV season 1 
Internal 
End of RSV season 2 
Web disclosure, Study report 
7.2. 
Statistical considerations for interim analyses 
No interim analyses are planned 
8. 
CHANGES FROM PLANNED ANALYSES 
Following are few changes from planned analysis:-  
• 
In the protocol, we have PPS up to Day 61 which included Day 31 as well. To have 
better clarity with respect to PPS for Day 31, the text has been re-worded for the 
definition of PPS population. PPS has also been defined for Day 31 timepoint along 
with PPS at Day 61 and end of 1st RSV transmission season. Also, as the timepoint 
‘End of 1st RSV transmission season is not exactly Day 365, so the Day 365 has been 
removed and only kept as PPS at end of 1st RSV transmission season. The criteria of 
eliminating subject from the PPS of respective timepoint is accordingly reworded.  
• 
In the protocol amendment 3, it is mentioned under Analysis of Immunogenicity 
section that ‘In summary table on the Adapted PPS for immunogenicity, PPS for 
immunogenicity at Day 61 will be used for Pre, Day 31 and Day 61 immunogenicity 
summary and PPS for immunogenicity at Day 365 for Day 365 immunogenicity 
summary.’ As we have added the PPS for Day 31 in the SAP, accordingly the 
summary table presentation has been modified as ‘In summary table on the Adapted 
PPS for immunogenicity, immunogenicity summary result at Day 31, Day 61 and 
end of first RSV transmission season) will be based on PPS of Day 31, Day 61 and 
end of first RSV transmission season, respectively’. 
• 
Table to present percentage of responders in terms of neutralizing antibody titers 
with 95% CI has been removed as there is no definition of response available.  


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9. 
NON-STANDARD DATA DERIVATION RULES AND 
STATISTICAL METHODS 
The following sections describe additional derivation rules and statistical methods which 
are not presented in section 10.1 (Business rules for standard data derivations and 
statistical methods). 
9.1. 
Immunogenicity 
• 
Assay cut-off for the humoral immunity will be per the following table 
Component 
Method 
Unit 
Cut-off 
Respiratory Syncytial Virus A Ab  
NEUTRALIZATION  
ED60  
18 
Respiratory Syncytial Virus F protein Ab.IgG 
(Anti-RSV PreF antibody)  
ELISA  
EU/ml  
10 
Respiratory Syncytial Virus F protein Ab.IgG 
(Palivizumab competing Ab)  
ELISA  
µg/ml  
9.6 
• 
For RSV neutralizing assay, the LLOQ and ULOQ is set at 18ED60 and 21654 
ED60. For analysis, the cut-off is set at the lower limit of quantification. For results 
below the cut-off, an arbitrary value of half of the cut-off will be considered for 
calculation of GMC and fold increase. The result above the ULOQ is set at ULOQ 
for analysis.    
• 
For anti-RSV PreF antibody and RSV PCA, the cut-off is set at the level of 
detection. For results below the cut-off (LOD), an arbitrary value of half of the cut-
off will be considered for calculation of GMC and fold increase. 
9.2. 
RTI and LRTI  
During the analysis of the study, all cases identified during the surveillance of RSV-RTI 
will be definitively classified as either RTI, LRTI, severe LRTI or very severe LRTI 
according to the standardized case definitions (Table 6 in the SAP) based on the available 
World Health Organization (WHO) case definitions (Table 6 in the protocol) 
Table 6 
Case definitions for data analysis 
Case 
At sea level up to 2500 meters elevation 
Above 2500 
meters elevation 
RSV-RTI 
Runny nose OR blocked nose OR cough 
AND  
Confirmed RSV infection 4 
Same 
RSV-LRTI 
History of cough OR difficulty breathing 1 
AND 
SpO2 < 95% 2, OR RR increase 3 
AND 
Confirmed RSV infection 4 
Same but with 
SpO2 <92% 
severe RSV-
LRTI 
Meeting the case definition of RSV-LRTI  
AND 
SpO2 < 93% 2, OR lower chest wall in-drawing 
Same but with 
SpO2 <90% 
very severe 
RSV-LRTI 
Meeting the case definition of RSV-LRTI  
AND  
SpO2 < 90% 2, OR inability to feed, OR failure to respond / unconscious 
Same but with 
SpO2 <88% 


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Case 
At sea level up to 2500 meters elevation 
Above 2500 
meters elevation 
RSV 
hospitalization 
Confirmed RSV infection 5 
AND 
Hospitalized for acute medical condition 6 
Same 
All-cause LRTI 
History of cough OR difficulty breathing 1  
AND  
SpO2 < 95% 2, OR RR increase 3 
Same but with 
SpO2 <92% 
LRTI = lower respiratory tract infections; RR = respiratory rate; RTI = respiratory tract infections; SpO2 = blood oxygen 
saturation. 
1 Based on history reported by parents.  
2 The lowest value during the course of illness will be used. 
3 RR increase defined as: 50/minute (2 to 11 months of age) ;  40/minute (12 months of age or above) ; 
 The highest value during the course of the illness will be used. 
4 RSV infection confirmed on nasal swab positive for RSV A or B by quantitative Reverse Transcription Polymerase 
Chain Reaction (qRT-PCR). 
5 RSV sampling and testing is based on medical judgment of medical practitioner or driven by algorithm. 
6 Hospitalization is defined as a medical decision that the infant requires admission for observation or treatment. 
• 
For the analysis of RTI episode, a new RTI episode will be defined as any 
occurrence of cough, runny nose, blocked nose, wheezing or difficulty breathing 
with an interval of at least 7 symptom free days since the last episode of RTI that 
was diagnosed. 
• 
For molecular biology (qRT-PCR test), the following cut-off will be applied: - 
System 
Component 
Method 
Unit 
Cut-off 
Nasal swab 
RSV-A RNA 
Quantitative real-time PCR (qRT-PCR) 
Copies/ml 
1.12 X 103 
Nasal swab 
RSV-B RNA 
Quantitative real-time PCR (qRT-PCR) 
Copies/ml 
1.47 x 103 
9.3. 
Hematology and Biochemistry parameters 
The grading of the hematology and biochemistry lab result will be done as per the 
toxicity grading scales provided in the Table 7 below (Table 28 of the protocol). 
Table 7 
Toxicity grading scales for hematology and biochemistry 
parameters applicable for this study 
Component 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hemoglobin (g/dL) 
9.0 to < 10.5 
8.0 to < 9.0 
7.0 to < 8.0 
< 7.0 
Leukocytes (cell/mm3) 
2500 to < 3500 
1500 to < 2500 
1000 to < 1500 
< 1000 
Absolute neutrophil count 
(cell/mm³) 
1000 to < 1300 
750 to < 1000 
500 to < 750 
< 500 
Absolute lymphocyte count 
(cell/mm³) 
600 to < 650 
500 to < 600 
350 to < 500 
< 350 
Platelets (cell//mm3) 
75000 to < 150000 50000 to < 75000 
25000 to < 50000 
< 25000 
Alanine Aminotransferase 
(increase by factor) 
1.1 to < 2.0 xULN 
2.0 to < 3.0 xULN 
3.00 to ≤ 8.0 xULN 
> 8.0 xULN 
Aspartate Aminotransferase 
(increase by factor) 
1.1 to < 2.0 xULN 
2.0 to < 3.0 xULN 
3.00 to ≤ 8.0 xULN 
> 8.0 xULN 
Creatinine (mg/dL) 
0.6 to < 0.9 
0.9 to < 1.2 
1.2 to ≤ 1.5 
> 1.5 
ULN: upper limit of normal. 


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9.4. 
Coding for the AE of specific interest 
Any of the below listed preferred term reported as an Expedited Adverse Event must be 
immediately escalated to the CRDL or Central Safety Physician to assess or confirm the 
need for an urgent IDMC review. 
The list of preferred terms and associated PT codes is given below: 
HAEMATOMA 
Preferred term 
PT code 
abdominal wall haematoma 
10067383 
administration site haematoma 
10075100 
adrenal haematoma 
10059194 
aortic intramural haematoma 
10067975 
application site haematoma 
10068317 
arterial intramural haematoma 
10074971 
auricular haematoma 
10003797 
basal ganglia haematoma 
10077031 
brain stem haematoma 
10073230 
breast haematoma 
10064753 
broad ligament haematoma 
10006375 
bursal haematoma 
10077818 
catheter site haematoma 
10055662 
cephalhaematoma 
10008014 
cerebellar haematoma 
10061038 
cerebral haematoma 
10053942 
cervix haematoma uterine 
10050020 
chest wall haematoma 
10076597 
colonic haematoma 
10009996 
deep dissecting haematoma 
10074718 
extradural haematoma 
10015769 
eyelid haematoma 
10064976 
haematoma 
10018852 
haematoma evacuation 
10060733 
haematoma infection 
10051564 
hepatic haematoma 
10019676 
incision site haematoma 
10059241 
infusion site haematoma 
10065463 
injection site haematoma 
10022066 
instillation site haematoma 
10073609 
intestinal haematoma 
10069829 
intra-abdominal haematoma 
10056457 
intracerebral haematoma evacuation 
10062025 


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Preferred term 
PT code 
intracranial haematoma 
10059491 
intraocular haematoma 
10071934 
laryngeal haematoma 
10070885 
lip haematoma 
10066304 
mediastinal haematoma 
10049941 
medical device site haematoma 
10075577 
mesenteric haematoma 
10071557 
nasal septum haematoma 
10075027 
oesophageal intramural haematoma 
10077486 
oral mucosa haematoma 
10074779 
ovarian haematoma 
10033263 
paranasal sinus haematoma 
10069702 
pelvic haematoma 
10054974 
penile haematoma 
10070656 
perineal haematoma 
10034520 
periorbital haematoma 
10034544 
periosteal haematoma 
10077341 
perirenal haematoma 
10049450 
peritoneal haematoma 
10058095 
pharyngeal haematoma 
10068121 
post procedural haematoma 
10063188 
pulmonary haematoma 
10054991 
renal haematoma 
10038459 
retroperitoneal haematoma 
10058360 
scrotal haematoma 
10039749 
spinal cord haematoma 
10076051 
spinal epidural haematoma 
10050162 
spinal subdural haematoma 
10050164 
splenic haematoma 
10041646 
spontaneous haematoma 
10065304 
subarachnoid haematoma 
10076701 
subcutaneous haematoma 
10042345 
subdural haematoma 
10042361 
subgaleal haematoma 
10069510 
subretinal haematoma 
10071935 
tongue haematoma 
10043959 
uterine haematoma 
10063875 
vaccination site haematoma 
10069472 
vaginal haematoma 
10046909 
vitreous haematoma 
10071936 
vulval haematoma 
10047756 


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HAEMORRHAGE 
Preferred term 
PT code 
abdominal wall haemorrhage 
10067788 
acute haemorrhagic conjunctivitis 
10067817 
administration site haemorrhage 
10075101 
adrenal haemorrhage 
10001361 
anal haemorrhage 
10049555 
anastomotic haemorrhage 
10056346 
angina bullosa haemorrhagica 
10064223 
application site haemorrhage 
10072694 
arterial haemorrhage 
10060964 
basal ganglia haemorrhage 
10067057 
bone marrow haemorrhage 
10073581 
brain stem haemorrhage 
10006145 
brain stem microhaemorrhage 
10071205 
breast haemorrhage 
10006254 
bronchial haemorrhage 
10065739 
catheter site haemorrhage 
10051099 
central nervous system haemorrhage 
10072043 
cerebellar haemorrhage 
10008030 
cerebellar microhaemorrhage 
10071206 
cerebral haemorrhage 
10008111 
cerebral microhaemorrhage 
10067277 
cervix haemorrhage uterine 
10050022 
ciliary body haemorrhage 
10057417 
conjunctival haemorrhage 
10010719 
diverticulitis intestinal haemorrhagic 
10013541 
diverticulum intestinal haemorrhagic 
10013560 
duodenitis haemorrhagic 
10013865 
ear haemorrhage 
10014009 
encephalitis haemorrhagic 
10014589 
gastric haemorrhage 
10017788 
gastroduodenal haemorrhage 
10053768 
gastrointestinal haemorrhage 
10017955 
genital haemorrhage 
10061178 
haemarthrosis 
10018829 
haematemesis 
10018830 
haematochezia 
10018836 
haematotympanum 
10063013 
Haematuria 
10018867 
haemorrhage 
10055798 
haemorrhage coronary artery 
10055803 


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Preferred term 
PT code 
haemorrhage intracranial 
10018985 
haemorrhage subcutaneous 
10018999 
haemorrhage subepidermal 
10019001 
haemorrhage urinary tract 
10055847 
haemorrhagic anaemia 
10052293 
haemorrhagic diathesis 
10062713 
haemorrhagic disorder 
10019009 
haemorrhagic infarction 
10019013 
haemorrhagic ovarian cyst 
10060781 
haemorrhagic pneumonia 
10077933 
haemorrhagic thyroid cyst 
10072256 
haemorrhagic urticaria 
10059499 
injection site haemorrhage 
10022067 
internal haemorrhage 
10075192 
intestinal haemorrhage 
10059175 
intra-abdominal haemorrhage 
10061249 
intraventricular haemorrhage 
10022840 
iris haemorrhage 
10057418 
joint microhaemorrhage 
10077666 
lacrimal haemorrhage 
10069930 
large intestinal haemorrhage 
10052534 
laryngeal haemorrhage 
10065740 
lip haemorrhage 
10049297 
lower gastrointestinal haemorrhage 
10050953 
lymph node haemorrhage 
10074270 
mediastinal haemorrhage 
10056343 
mesenteric haemorrhage 
10060717 
mouth haemorrhage 
10028024 
mucocutaneous haemorrhage 
10076048 
mucosal haemorrhage 
10061298 
muscle haemorrhage 
10028309 
myocardial haemorrhage 
10048849 
naevus haemorrhage 
10062955 
ocular retrobulbar haemorrhage 
10057571 
oesophageal haemorrhage 
10030172 
optic disc haemorrhage 
10030919 
optic nerve sheath haemorrhage 
10030941 
ovarian haemorrhage 
10065741 
pancreatic haemorrhage 
10033625 
papillary muscle haemorrhage 
10059164 
parathyroid haemorrhage 
10059051 


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Preferred term 
PT code 
parotid gland haemorrhage 
10051166 
pelvic haemorrhage 
10063678 
penile haemorrhage 
10034305 
pericardial haemorrhage 
10034476 
periorbital haemorrhage 
10071697 
peritoneal haemorrhage 
10034666 
Petechiae 
10034754 
pharyngeal haemorrhage 
10034827 
pituitary haemorrhage 
10049760 
post procedural haemorrhage 
10051077 
procedural haemorrhage 
10071229 
prostatic haemorrhage 
10036960 
pulmonary alveolar haemorrhage 
10037313 
pulmonary haemorrhage 
10037394 
putamen haemorrhage 
10058940 
rectal haemorrhage 
10038063 
renal haemorrhage 
10038460 
respiratory tract haemorrhage 
10038727 
retinal haemorrhage 
10038867 
retroperitoneal haemorrhage 
10038980 
scleral haemorrhage 
10050508 
skin haemorrhage 
10064265 
small intestinal haemorrhage 
10052535 
soft tissue haemorrhage 
10051297 
spermatic cord haemorrhage 
10065742 
spinal cord haemorrhage 
10048992 
spinal epidural haemorrhage 
10049236 
spinal subarachnoid haemorrhage 
10073564 
spinal subdural haemorrhage 
10073563 
splenic haemorrhage 
10041647 
spontaneous haemorrhage 
10074557 
subarachnoid haemorrhage 
10042316 
subdural haemorrhage 
10042364 
testicular haemorrhage 
10051877 
thalamus haemorrhage 
10058939 
thoracic haemorrhage 
10062744 
thyroid haemorrhage 
10064224 
tongue haemorrhage 
10049870 
tracheal haemorrhage 
10062543 
upper gastrointestinal haemorrhage 
10046274 
ureteric haemorrhage 
10065743 


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Preferred term 
PT code 
urethral haemorrhage 
10049710 
urinary bladder haemorrhage 
10046528 
urogenital haemorrhage 
10050058 
uterine haemorrhage 
10046788 
vaccination site haemorrhage 
10069475 
vaginal haemorrhage 
10046910 
venous haemorrhage 
10065441 
vitreous haemorrhage 
10047655 
vulval haemorrhage 
10063816 
THROMBOCYTOPENIA 
Preferred term 
PT code 
bleeding time abnormal 
10049227 
bleeding time prolonged 
10005140 
coagulation test abnormal 
10063557 
platelet count abnormal 
10035526 
platelet count decreased 
10035528 
platelet disorder 
10035532 
platelet dysfunction 
10073391 
Thrombocytopenia 
10043554 
thrombocytopenic purpura 
10043561 
LOWER RESPIRATORY TRACT INFECTION 
Preferred term 
PT code 
atypical pneumonia 
10003757 
Bronchitis 
10006451 
bronchitis viral 
10053160 
haemorrhagic pneumonia 
10077933 
lower respiratory tract infection 
10024968 
lower respiratory tract infection viral 
10065188 
lung infection 
10061229 
Pneumonia 
10035664 
pneumonia respiratory syncytial viral 
10035732 
pulmonary sepsis 
10051739 
respiratory syncytial virus bronchiolitis 
10038718 
respiratory syncytial virus bronchitis 
10069811 
respiratory tract infection 
10062352 
respiratory tract infection viral 
10062106 


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10. 
ANNEXES  
As the SAP and TFL TOC has been developed using the old template and process, we 
will not have TFL as annex to this SAP. All the template applicable to the study has been 
added in the SAP in Section 13. 
10.1. 
Business rules for standard data derivations and statistical 
methods 
10.1.1. 
Attributing events to vaccine doses 
The dose relative to an event is the most recent study dose given to a subject prior to the 
start of a given event. For example, if the start date of an adverse event is between Dose 1 
and Dose 2, the relative dose will be Dose 1. 
If an event starts on the same day as a study dose, the relative dose will be derived from 
the additional information provided in the CRF using the contents of the flag indicating if 
the event occurred before or after vaccination. If ‘after vaccination’ is selected, the 
relative dose for the event will be the one administered on the start day of the event. If 
‘before vaccination’ is selected, the relative dose for the event will be the dose prior to 
this one. 
10.1.2. 
Handling of missing data 
10.1.2.1. 
Dates 
When partially completed dates (i.e. with missing day or month) are used in calculations, 
the following standard rules will be applied: 
• 
A missing day will be replaced by 15 
• 
A missing day and month will be replaced by June 30th. 
The following exceptions apply: 
• 
Adverse event start dates with missing day: 
− 
If the event starts in the same month as at least one of the study doses, the 
contents of AE.AESTRTPT (the flag indicating if the event occurred before or 
after vaccination) will be used to complete the date. If ‘after vaccination’ is 
selected, the imputed start date will match the first (or only) study dose given 
during that month. If ‘before vaccination’ is selected, the imputed date will be 
one day before the first (or only) study dose given during that month. 
• 
Adverse event start dates with missing day and month: 
− 
If the event starts in the same year as at least one of the study doses, the contents 
of AE.AESTRTPT (the flag indicating if the event occurred before or after 
vaccination) will be used to complete the date. If ‘after vaccination’ is selected, 
the imputed start date will match the first (or only) study dose given during that 


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


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The following table shows how subjects contribute to each category for a specific 
solicited symptom over the Day X to Day Y post-vaccination period: 
Solicited symptom 
category 
Subjects included in the calculation of the numerator 
Any 
All subjects with at least one occurrence of the symptom at grade 1, grade 2, or 
grade 3 between Day X and Day Y or with the symptom marked as present and at 
least one missing daily recording between Day X and Day Y 
At least grade 1 
All subjects with at least one occurrence of the symptom at grade 1, grade 2, or 
grade 3 between Day X and Day Y 
At least grade 2 
All subjects with at least one occurrence of the symptom at grade 2 or grade 3 
between Day X and Day Y 
At least grade 3 
All subjects with at least one occurrence of the symptom at grade 3 between Day X 
and Day Y 
10.1.2.4. 
Unsolicited adverse events 
Missing severity, relationship with study vaccine, and outcome of unsolicited adverse 
events will not be replaced and will appear as ‘UNKNOWN’ in all statistical output. 
10.1.3. 
Data derivation 
10.1.3.1. 
Age at vaccination in days 
When age at vaccination is to be displayed in days, it will be calculated as: 
Age = date of vaccination minus date of birth 
10.1.3.2. 
Age at vaccination in months 
When age at vaccination is to be displayed in months, it will be calculated as the number 
of complete calendar months between the date of birth (DOB) and the date of 
vaccination. For example: 
DOB = 10JUN2017, Date of vaccination = 09JUL2018 -> Age = 12 months 
DOB = 10JUN2017, Date of vaccination = 10JUL2018 -> Age = 13 months 
10.1.3.3. 
Age at vaccination in years 
When age at vaccination is to be displayed in years, it will be calculated as the number of 
complete calendar years between the date of birth and the date of vaccination. For 
example: 
DOB = 10SEP1983, Date of vaccination = 09SEP2018 -> Age = 34 years 
DOB = 10SEP1983, Date of vaccination = 10SEP2018 -> Age = 35 years 


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10.1.3.4. 
Weight 
Weight will be presented in kilograms. Weights reported in pounds will be converted as 
follows: 
Weight in kilograms = Weight in pounds / 2.2 
10.1.3.5. 
Height 
Height will be presented in centimeters. Heights reported in feet and inches will be 
converted as follows: 
Height in centimeters = Height in inches x 2.54 
10.1.3.6. 
Body mass index (BMI) 
BMI will be calculated as follows: 
BMI = (Weight in kilograms) / (Height in meters)2 
10.1.3.7. 
Temperature 
Temperatures will be presented in degrees Celsius (°C). Temperatures reported in degrees 
Fahrenheit (°F) will be converted as follows: 
Temperature (Celsius) = ((Temperature (Fahrenheit) - 32) x 5)/9 
10.1.3.8. 
Numerical serology results 
Numerical serology results will be derived from the content of IS.ISORRES in the SDTM 
dataset. For assays with a specific cut-off, the following derivation rules apply: 
IS.ISORRES 
Derived value 
“value” and value is >= cut-off 
value 
“value” and value is < cut-off 
cut-off/2 
“value” and value is >ULOQ (applicable 
for RSV neutralizing assay) 
ULOQ 
“value” and value is <LLOQ (applicable 
for RSV neutralizing assay) 
LLOQ/2 
value” and value is >=LLOQ and <ULOQ 
(applicable for RSV neutralizing assay) 
value 
All other cases 
missing 


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10.1.3.9. 
Geometric mean titers (GMTs) and concentrations (GMCs) 
Geometric Mean Titer (GMT) or Concentration (GMC) calculations are performed by 
taking the inverse logarithm of the mean of the log titer or concentration transformations. 
Antibody titers or concentrations below the cut-off of the assay will be given an arbitrary 
value of half the cut-off of the assay for the purpose of GMT/GMC calculation. The cut-
off value is defined by the laboratory before the analysis and is described in the protocol. 
10.1.3.10. Onset day 
The onset day for an event (e.g. AE, medication, vaccination) is the number of days 
between the last study vaccination and the start date of the event. This is 1 for an event 
occurring on the same day as a vaccination (and reported as starting after vaccination). 
10.1.3.11. Duration of events 
The duration of an event with a start and end date will be the number of days between the 
start and end dates plus one day, i.e. an event that starts on 03MAR2018 and ends on 
12MAR2018 has a duration of 10 days. 
The duration of solicited events will be calculated as the sum of the individual days with 
the symptom reported at grade 1 or higher. 
10.1.3.12. Counting rules for combining solicited and unsolicited adverse events 
For output combining solicited and unsolicited adverse events, all serious adverse events 
will be considered general events since the administration site flag is not included in the 
expedited adverse event CRF pages. 
Multiple events with the same preferred term which start on the same day are counted as 
only one occurrence. 
10.1.3.13. Counting rules for occurrences of solicited adverse events 
When the occurrences of solicited adverse events are summarized, each event recorded as 
having occurred during a specific period will be counted as only one occurrence 
regardless of the number of days on which it occurs. Also, in the case of co-administered 
study vaccines, an injection site reaction recorded for a subject following multiple 
vaccines will be counted as only one occurrence. 


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10.1.3.14. Display of decimals 
10.1.3.15. Percentages 
Percentages and their corresponding confidence limits will be displayed with: 
• 
no decimals when there are fewer than 50 subjects in each tabulated group 
• 
one decimal when there are at least 50 subjects in at least one tabulated group 
− 
Exceptions will be made for percentages that are not 0% or 100% but appear as 
0% or 100% due to rounding. For these specific cases the number of decimals 
will be increased until the displayed value is no longer 0% or 100%. Examples 
are given in the following table. 
n/N Displayed percentage 
10/45 22% 
1/45 2% 
10/55 18.2% 
1/55 1.8% 
1/300 0.3% 
1/3000 0.03% 
1/30000 0.003% 
299/300 99.7% 
2999/3000 99.97% 
29999/30000 99.997% 
− 
The display of additional decimals for values close to 0% or 100% will be 
applied only to point estimates and not confidence limits, which can be rounded 
and displayed as 0% or 100%. 
− 
Values of exactly 0% or 100% will be presented with no decimals regardless of 
the number of subjects per tabulated group. 
10.1.3.16. Differences in percentages 
Differences in percentages and their corresponding confidence limits will be displayed 
with one more decimal than the maximum number used to display the individual 
percentages, for example the difference between two percentages displayed with one 
decimal will be displayed with two decimals. 
10.1.3.17. Demographic/baseline characteristics statistics 
The mean, median, and standard deviation for continuous baseline characteristics (height, 
weight, body mass index (BMI), pre-vaccination body temperature) will be presented 
with one decimal. 
The minimum and maximum values and quartile values (if required) will be presented 
with the same number of decimals as the observed values.  


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The maxima and minima of transformed height variables will be displayed with no 
decimals. 
The maxima and minima of transformed weight variables will be displayed with no 
decimals with the exception of values are below 10kg where one decimal will be 
displayed. 
The maximum and minima of transformed body temperatures will be displayed with one 
decimal. 
10.1.3.18. Serological summary statistics 
The number of decimals used when displaying geometric mean titers (GMT) or 
concentrations (GMC) and their confidence limits is shown in the following table: 
GMT or GMC value 
Number of decimals to display 
<0.1 
3 
>=0.1 and <10 
2 
>=10 and <1000 
1 
>=1000 
0 
When multiple categories of GMT or GMC values are present in the same table, the 
number of decimals displayed should match that of the smallest category (i.e. the one 
with the higher number of decimals). For example, if GMT or GMC values of <0.1 
appear in the same table as values of >=0.1 and <10, 3 decimals should be displayed for 
both. 
GMT or GMC ratios and their confidence limits will be displayed with 2 decimals 
regardless of the actual values. 
10.1.3.19. Statistical methodology 
10.1.3.20. Exact confidence intervals around proportions 
The exact confidence intervals around within-group proportions are derived using the 
method of Clopper and Pearson [Clopper, 1934]. 
10.1.3.21. Standardized asymptotic confidence intervals around differences in 
proportions 
The standardized asymptotic confidence intervals around differences in proportions are 
derived using the method of Mietinnen and Nurminen [Miettinen, 1985]. 


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10.2. 
TFL and/or TFL ToC 
The TFL ToC can be found in eTMF folder section 11.1.1. As the process of TFL came 
when the SAP was already developed using previous process, no separate TFL has been 
prepared. The mock template are present in the SAP in Section 13 and tables to be 
generated for synopsis, in-text, post-text and posting has been flagged in the TFL ToC for 
different timepoints when the analysis is planned.   


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11. 
REFERENCES 
Clopper CJ, Pearson E. The Use of Confidence or Fiducial Limits Illustrated in the case 
of the Binomial. Biometrika. 1934;26:404-13. 
Miettinen, O. S. and Nurminen, M. Comparative analysis of two rates. Statistics in 
Medicine, 1985;4,213-226. 
Kim HW, Canchola JG, Brandt CD, et al. Respiratory syncytial virus disease in infants 
despite prior administration of antigenic inactivated vaccine. Am J Epidemiol. 1969; 
89(4): 422-34 


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12. 
LIST OF LISTINGS FOR THE FINAL ANALYSIS 
The following listings will be generated using the macros developed by DSCS 
Appendix Table I.B – Demography 
Appendix Table IBii - Vital signs 
Appendix Table I.Cii - Reason for visit not done 
Appendix Table I.D - General medical history - Physical examination 
Appendix Table I.Eii – Screening conclusion 
Appendix Table I.I - Reason for not administration of vaccine 
Appendix Table II.Ai - Solicited local adverse events 
Appendix Table II.B - Solicited general adverse events 
Appendix Table II.Ci - Unsolicited adverse events within (30) days post-vaccination 
Appendix Table II.Cii - Unsolicited adverse events after (30) days post-vaccination 
Appendix Table II.Di - Concomitant medications 
Appendix Table II.Dii - Concomitant vaccinations 
Appendix Table IV.A – Haematology and Biochemistry 
Appendix Table V.A - RTI Assessment, Surveillance / Asymptomatic visit and 
Worsening data 
Randomisation list 


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13. 
MOCK TABLES 
Template 1 
Number of subjects by country and center - <RSV 1D, RSV 2D, 
Comparator/Placebo> groups (Exposed Set) 
 
<Each group> 
N=XXXX 
<Each group> 
N=XXXX 
Total 
N=XXXX 
Country 
Center-Investigator Name 
n 
% 
n 
% 
n 
% 
<each country> 
<each center-investigator name > 
XXX 
XX.X 
XXX 
XX.X 
XXX XX.X 
All 
XXX 
XX.X 
XXX 
XX.X 
XXX XX.X 
Short group label = long group label 
N = total number of subjects 
n = number of subjects in a given center or country 
% = n/N x 100 
Center = GSK Biologicals assigned center number 
Template 2 
Summary of study completion with reasons for withdrawal <RSV 1D, 
RSV 2D, Comparator/Placebo> <groups> < pooled RSV 1D, RSV 2D, 
Comparator/Placebo groups> (Exposed Set) 
 
<Each Group> 
N=XXXX 
<Total> 
N=XXXX 
 n 
% 
n 
% 
Completed the study 
   xxx 
xx.x 
   xxx 
xx.x 
Withdrawn from the study 
   xxx 
     xx.x    xxx 
      xx.x 
Primary reason for withdrawal 
 Adverse Event Requiring Expedited Reporting 
   xxx 
xx.x 
   xxx 
xx.x 
 Unsolicited Non-Serious Adverse Event 
 Solicited Adverse Event 
   xxx 
   xxx 
xx.x 
xx.x 
   xxx 
   xxx 
xx.x 
xx.x 
 Protocol Deviation 
   xxx 
xx.x 
   xxx 
xx.x 
 Withdrawal By Subject 
   xxx 
xx.x 
   xxx 
xx.x 
 Sponsor Study Termination  
   xxx 
xx.x 
   xxx 
xx.x 
 Lost To Follow-up 
   xxx 
xx.x 
   xxx 
xx.x 
 Migrated / Moved From The Study Area 
   xxx 
xx.x 
   xxx 
xx.x 
 Other 
   xxx 
xx.x 
   xxx 
xx.x 
Short group label = long group label 
Completed = number of subjects who completed last study visit 
Withdrawn = number of subjects who did not come for the last study visit 


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Template 3 
Summary of visit attendance/phone contact completion <RSV 1D, 
RSV 2D, Comparator/Placebo> groups (Exposed Set) 
 
<Group 1> 
N=XXXX 
<Group 2> 
N=XXXX 
Total 
N=XXXX 
 n 
% 
n 
% 
n 
% 
Visit 1 (Day 1) 
 
 
 
 
 
 
 Attended 
   xxx 
xx.x 
   xxx 
xx.x 
   xxx 
xx.x 
 Did not attend yet 
   xxx 
xx.x 
   xxx 
xx.x 
   xxx 
xx.x 
 Withdrawal at visit or earlier 
   xxx 
xx.x 
   xxx 
xx.x 
   xxx 
xx.x 
 Did not attend 
   xxx 
xx.x 
   xxx 
xx.x 
   xxx 
xx.x 
 
 
 
 
 
 
Visit X (Day Y) 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
Phone contact X (Day Y) 
 
 
 
 
 
 
 Completed 
   xxx 
xx.x 
   xxx 
xx.x 
   xxx 
xx.x 
 Did not complete yet 
   xxx 
xx.x 
   xxx 
xx.x 
   xxx 
xx.x 
 Withdrawal at visit or earlier 
   xxx 
xx.x 
   xxx 
xx.x 
   xxx 
xx.x 
 Did not complete 
   xxx 
xx.x 
   xxx 
xx.x 
   xxx 
xx.x 
 
 
 
 
 
 
Phone contact X (Day Y) 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
Visit X (Day Y) 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Last study contact (Day Y)  
 
 
 
 
 
 
 Completed 
   xxx 
xx.x 
   xxx 
xx.x 
   xxx 
xx.x 
 Did not complete yet 
   xxx 
xx.x 
   xxx 
xx.x 
   xxx 
xx.x 
 Withdrawal at visit or earlier 
   xxx 
xx.x 
   xxx 
xx.x 
   xxx 
xx.x 
 Did not complete 
   xxx 
xx.x 
   xxx 
xx.x 
   xxx 
xx.x 
Short group label = long group label 
N = Number of subjects in each group or in total 
n/% = number / percentage of subjects in a given category 


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27-MAR-2019 
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Template 4 
Summary of important protocol deviations leading to elimination 
from any analyses <RSV 1D, RSV 2D, Comparator/Placebo> 
<groups>< -pooled RSV 1D, RSV 2D, Comparator/Placebo groups> 
Category 
 Sub-category 
                <Each group> 
                  N=XXXX 
    occ              n                 % 
            Total 
            N=XXXX 
occ            n               % 
At least one important protocol 
deviation 
<Category 1> 
 <Sub-category 1> 
 <Sub-category 2> 
  
<Category 2> 
  
      xxx              xxx 
 
      xxx              xxx 
      xxx              xxx 
      xxx              xxx 
 
      xxx              xxx 
          xx.x 
          xx.x 
          xx.x 
          xx.x 
          xx.x 
 
  xxx              xxx        xx.x       
 
   xxx              xxx        xx.x     
   xxx              xxx        xx.x     
   xxx              xxx        xx.x     
 
 
   xxx              xxx        xx.x     
 
 
 
Short group label = long group label 
N = Total number of subjects 
Occ = number of occurrences = number of important protocol deviations 
n/% = number / percentage of subjects with important protocol deviations 
Template 5 
Summary of subject disposition from enrolled set to randomized set 
(Exposed Set) 
              
                                                              Total 
                                                             N=XXX 
                                                             n       % 
Withdrawals prior to randomization 
   <Withdrawal reason 1> 
   <Withdrawal reason 2> 
    
Number of subjects included in 
randomized set 
 
                                                                        xxx     xx.x 
                                                                       xxx     xx.x 
                                                                       xxx     xx.x 
                                                                       xxx     xx.x 
                                                                       xxx     xx.x 
 
 
 
Short group label = long group label 
N = Number of subjects 
n = number of subjects enrolled by center 
% = n / Number of subjects with available results x 100 


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204894 (RSV-PED-011) 
Statistical Analysis Plan Final 
27-MAR-2019 
Page 59 of 97 
Template 6 
Summary of subject disposition from randomized set to exposed set 
              
<Group 1> 
   N=XXX 
   N       % 
<Group 2> 
  N=XXX 
  N     % 
Total 
N=XXX 
N        % 
Withdrawals 
   <Withdrawal reason 1> 
   <Withdrawal reason 2> 
   
Eliminations 
   <Elimination reason 1 
(code)>   
   <Elimination reason 2 
(code)> 
    
Number of subjects included 
in Exposed Set 
 
 xxx      xx.x 
xxx      xx.x 
xxx      xx.x 
xxx      xx.x 
xxx      xx.x 
xxx      xx.x 
xxx      xx.x 
xxx      xx.x 
xxx      xx.x 
xxx      xx.x 
xxx      xx.x 
xxx      xx.x 
xxx      xx.x 
xxx      xx.x 
xxx      xx.x 
xxx      xx.x 
xxx      xx.x 
xxx      xx.x 
xxx      xx.x 
xxx      xx.x 
xxx      xx.x 
Short group label = long group label 
N = Number of subjects 
n = number of subjects enrolled by center 
% = n / Number of subjects with available results x 100 
Template 7 
Summary of subject disposition from Exposed Set to Per Protocol 
Set at <Day 31/Day 61/end of first RSV season> <RSV 1D, RSV 2D, 
Comparator/Placebo> groups (Exposed set) 
 
              
<Group 1> 
   N=XXX 
   n       % 
<Group 2> 
  N=XXX 
  n     % 
Total 
N=XXX 
n        % 
Withdrawals 
   <Withdrawal reason 1> 
   <Withdrawal reason 2> 
   
Eliminations 
   <Elimination reason 1 
(code)>   
   <Elimination reason 2 
(code)> 
    
Number of subjects included 
in Per Protocol Set at <Day 
31/Day 61/End of first RSV 
season> 
 
 xxx      xx.x 
xxx      xx.x 
xxx      xx.x 
 
 
xxx      xx.x 
xxx      xx.x 
xxx      xx.x 
 
 
xxx      xx.x 
xxx      xx.x 
xxx      xx.x 
xxx      xx.x 
xxx      xx.x 
xxx      xx.x 
xxx      xx.x 
xxx      xx.x 
xxx      xx.x 
xxx      xx.x 
xxx      xx.x 
xxx      xx.x 
xxx      xx.x 
xxx      xx.x 
xxx      xx.x 
Short group label = long group label 
N = Number of subjects 
n = number of subjects enrolled by center 
% = n / Number of subjects with available results x 100 


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204894 (RSV-PED-011) 
Statistical Analysis Plan Final 
27-MAR-2019 
Page 60 of 97 
Template 8 
Summary of subject disposition from Exposed Set to End of study 
<RSV 1D, RSV 2D, Comparator/Placebo> groups (Exposed set) 
Short group label = long group label 
N = Number of subjects 
n = number of subjects enrolled by center 
% = n / Number of subjects with available results x 100 
      <Group 1> 
         N=XXX 
      n          % 
  <Group 2> 
     N=XXX 
   n           % 
    Total 
  N=XXX 
 N        % 
Eliminations 
   <Elimination reason 1 
(code)> 
   <Elimination reason 2 
(code)> 
    
Withdrawals 
   <Withdrawal reason 1> 
   < Withdrawal reason 2> 
    
Number of subjects who 
completed the study 
   Completed with 1 dose 
   Completed with X doses  
 
 
 
xxx      xx.x 
xxx      xx.x 
xxx      xx.x 
xxx      xx.x 
xxx      xx.x 
xxx      xx.x 
xxx      xx.x 
xxx      xx.x 
xxx      xx.x 
 
 
 
xxx      xx.x 
xxx      xx.x 
xxx      xx.x 
xxx      xx.x 
xxx      xx.x 
xxx      xx.x 
      
xxx      xx.x 
xxx      xx.x 
xxx      xx.x 
 
  
xxx      xx.x 
xxx      xx.x 
xxx      xx.x 
xxx      xx.x 
xxx      xx.x 
xxx      xx.x 
      
xxx      xx.x 
xxx      xx.x 
xxx      xx.x 
 
  


CONFIDENTIAL 
204894 (RSV-PED-011) 
Statistical Analysis Plan Final 
27-MAR-2019 
Page 61 of 97 
Template 9 
Deviations from protocol for age and intervals between study visits 
<RSV 1D, RSV 2D, Comparator/Placebo> groups (Exposed Set) 
Type of interval    Interval range 
            <Group 1> 
     Value                % 
        <Group 2 
Value               % 
Age (years) at first 
vaccine 
administration        
Number of days 
between 
vaccination <x> 
and vaccination 
<y> 
Number of days 
between 
vaccination <x> 
and visit <y> 
Number of days 
between 
vaccination <x> 
and blood 
sampling <y> 
From <x> to <y> 
years 
From <x> to <y> 
days     
From <x> to <y> 
days  
From <x> to <y> 
days  
N 
n 
Below 
<x> 
Above 
<y> 
               xxx 
               xxx              
xx.x 
               xxx              
xx.x  
               xxx              
xx.x 
                          
 
         xxx 
         xxx           xx.x 
         xxx           xx.x 
         xxx           xx.x 
             
 
 
 
Short group label = long group label 
N = total number of subjects with available results 
n/% = number / percentage of subjects with results outside of the interval 
range = minimum-maximum for age and intervals 
Template 10 Minimum and maximum visit dates <RSV 1D, RSV 2D, 
Comparator/Placebo> groups (Exposed Set) 
 
<each group> 
<each group> 
Overall 
Visit Description 
Parameter 
Date 
Date 
Date 
< each informed consent> 
Minimum 
DDMMYYYY 
DDMMYYYY 
DDMMYYYY 
Maximum 
DDMMYYYY 
DDMMYYYY 
DDMMYYYY 
[Randomization] 
Minimum 
DDMMYYYY 
DDMMYYYY 
DDMMYYYY 
Maximum 
DDMMYYYY 
DDMMYYYY 
DDMMYYYY 
<each visit> 
Minimum 
DDMMYYYY 
DDMMYYYY 
DDMMYYYY 
Maximum 
DDMMYYYY 
DDMMYYYY 
DDMMYYYY 
Short group label = long group label 


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204894 (RSV-PED-011) 
Statistical Analysis Plan Final 
27-MAR-2019 
Page 62 of 97 
Template 11 Summary of demographic characteristics - <RSV 1D, RSV 2D, 
Comparator/Placebo> <groups>< -pooled RSV 1D, RSV 2D, 
Comparator/Placebo groups> (Exposed Set, PPS for 
immunogenicity at <Day 31/Day 61/end of first RSV season>) 
 
<Group 1> 
N =  
<Group 2> 
N =  
<Group 3> 
N =  
Total 
N = 
 
Value or n 
% 
Value or n % Value or n % Value or n % 
Age (months) at first vaccination 
 
 
 
 
 
 
 
 
n 
 
 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
 
 
Standard Deviation 
 
 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
 
 
Minimum 
 
 
 
 
 
 
 
 
Maximum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sex 
 
 
 
 
 
 
 
 
Female 
 
 
 
 
 
 
 
 
Male 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Geographic Ancestry 
 
 
 
 
 
 
 
 
African Heritage / African American 
 
 
 
 
 
 
 
 
American Indian or Alaskan Native 
 
 
 
 
 
 
 
 
Asian - Central/South Asian Heritage 
 
 
 
 
 
 
 
 
Asian - East Asian Heritage 
 
 
 
 
 
 
 
 
Asian - Japanese Heritage 
 
 
 
 
 
 
 
 
Asian - South East Asian Heritage 
 
 
 
 
 
 
 
 
Native Hawaiian or Other Pacific Islander 
 
 
 
 
 
 
 
 
White - Arabic / North African Heritage 
 
 
 
 
 
 
 
 
White - Caucasian / European Heritage 
 
 
 
 
 
 
 
 
Other 
 
 
 
 
 
 
 
 
<each group>: 
N = total number of subjects 
n/% = number / percentage of subjects in a given category 
Value = value of the considered parameter 
SD = standard deviation 


CONFIDENTIAL 
204894 (RSV-PED-011) 
Statistical Analysis Plan Final 
27-MAR-2019 
Page 63 of 97 
Template 12 Summary of vital signs characteristics - <RSV 1D, RSV 2D, 
Comparator/Placebo> <groups>< pooled RSV 1D, RSV 2D, 
Comparator/Placebo groups> (Exposed set, PPS for immunogenicity 
at <Day 31/Day 61/end of first RSV season>) 
 
<each group> 
N =  
Total 
N =  
Visit 
Characteristics 
Parameters 
Value 
Value 
<Each visit> 
Height (Cm) 
N with data 
 
 
 
 
Mean 
 
 
SD 
 
 
Median 
 
 
 
 
Minimum 
 
 
Maximum 
 
Weight (Kg) 
N with data 
 
 
Mean 
 
 
 
 
SD 
 
 
Median 
 
 
Minimum 
 
 
Maximum 
 
Heart rate (Beats per minute) 
N with data 
 
 
Mean 
 
 
SD 
 
 
Median 
 
 
Minimum 
 
 
Maximum 
 
Respiratory rate (Breadth per minute) N with data 
 
 
Mean 
 
 
SD 
 
 
 
 
Median 
 
 
Minimum 
 
 
Maximum 
 
Temperature/(Axillary) (°C) 
N with data 
 
 
Mean 
 
 
SD 
 
 
Median 
 
 
Minimum 
 
 
Maximum 
<each group>: 
N = total number of subjects 
N with data = number of subjects with documentation of the corresponding data  
Value = value of the considered parameter 
SD = standard deviation 


CONFIDENTIAL 
204894 (RSV-PED-011) 
Statistical Analysis Plan Final 
27-MAR-2019 
Page 64 of 97 
Template 13 Number of enrolled subjects by age category <RSV 1D, RSV 2D, 
Comparator/Placebo> groups 
 
 
<each group> 
N = 
Total 
N = 
Characteristics 
Categories 
n 
n 
Age category 
1=Infants and toddlers (28 days-23 month) 
 
 
 
Missing 
 
 
<each group>: 
N = Number of enrolled subjects 
n= number of enrolled subjects included in each group or in total for a given age category or for all age categories 
Missing = age at dose 1 unknown 
Template 14 Compliance in completing solicited adverse events information 
<RSV 1D, RSV 2D, Comparator/Placebo> groups (Exposed Set) 
                <Group 1> 
    N                n                 
Compliance  
                                                (%) 
                    <Group 2> 
   N             n          
Compliance  
                                      (%) 
<Vaccination at visit 
1> 
<Vaccination at visit 
X>   
Per vaccination 
General solicited adverse 
events 
Local solicited adverse events 
General solicited adverse 
events 
Local solicited adverse events 
General solicited adverse 
events 
Local solicited adverse events 
      xxx              xxx 
      xxx              xxx 
      xxx              xxx 
      xxx              xxx 
      
       xxx              
xxx 
      xxx              xxx 
          xx.x 
          xx.x 
          xx.x 
          xx.x 
          xx.x       
          xx.x 
   xxx              xxx          xx.x    
   xxx              xxx          xx.x    
 
   xxx              xxx          xx.x    
   xxx              xxx          xx.x   
   xxx              xxx          xx.x 
   xxx              xxx          xx.x    
Short group label = long group label 
N=Number of administered vaccination 
n = number of vaccination with Adverse Event Screen returned 
 Compliance (%) = (n / N) X 100 


CONFIDENTIAL 
204894 (RSV-PED-011) 
Statistical Analysis Plan Final 
27-MAR-2019 
Page 65 of 97 
Template 15 Summary of <grade 3> adverse events (solicited and unsolicited) 
<with causal relationship to vaccination, with medically attend visit> 
within <7, 30> days following first and second vaccination and 
overall <RSV 1D, RSV 2D, Comparator/Placebo> <groups>< pooled 
RSV 1D, RSV 2D, Comparator/Placebo groups> (Exposed Set) 
Short group label = long group label 
For each vaccination: 
  N = number of subjects with the corresponding administered vaccination  
  n/% = number/percentage of subjects presenting at least one type of adverse event following the corresponding dose 
For per vaccination: 
  N = number of administered vaccination 
  n/% = number/percentage of vaccination followed by at least one type of adverse event 
For per subject: 
  N = number of subjects with at least one administered vaccination 
  n/% = number/percentage of subjects presenting at least one type of adverse event  
95% CI = Exact 95% confidence interval; LL = lower limit, UL = upper limit 
 
 
<Each Group > 
 
95% CI 
  
 
n 
% 
LL 
UL 
<Vaccination at visit 1> 
N 
xxx 
 
 
 
 Any adverse event 
xxx 
xx.x 
xx.x 
xx.x 
 Local adverse event 
 General adverse event 
xxx 
xxx 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
 
 
<Vaccination at visit X> 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Per subject 
 
 
 
 
Per vaccination 
 
 
 
 


CONFIDENTIAL 
204894 (RSV-PED-011) 
Statistical Analysis Plan Final 
27-MAR-2019 
Page 66 of 97 
Template 16 Percentage of subjects with solicited local adverse events by 
maximum intensity within the 7-day (Days 1-7) following first and 
second vaccination and overall - <RSV 1D, RSV 2D, 
Comparator/Placebo> <groups> < pooled RSV 1D, RSV 2D, 
Comparator/Placebo groups>(Exposed Set) 
Adverse event: Pain 
Adverse event: Swelling/Redness 
<each group>: 
For each vaccination: 
 N = number of subjects with the corresponding documented vaccination 
 n/% = number/percentage of subjects reporting the type of adverse event at least once following the corresponding 
vaccination  
For Per vaccination: 
 N = number of documented vaccination 
 n/% = number/percentage of vaccination followed by at least one type of adverse event 
For Per subject: 
 N = number of subjects with at least one documented vaccination 
 
 
<Group 1> 
<Group 2>  
 
 
95% CI 
 
95% CI 
  
 
n 
% 
LL 
UL 
n 
% 
LL 
UL 
<Vaccination at visit 1> N 
xxx 
 
 
 
xxx 
 
 
 
Any 
xxx 
xx.x 
xx.x 
xx.x 
xxx 
xx.x 
xx.x 
xx.x 
Grade 2 
xxx 
xx.x 
xx.x 
xx.x 
xxx 
xx.x 
xx.x 
xx.x 
Grade 3 
xxx 
xx.x 
xx.x 
xx.x 
xxx 
xx.x 
xx.x 
xx.x 
Medically attended visits 
 
 
 
 
 
 
 
 
<Vaccination at visit 3> 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Per subject 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Per vaccination 
 
 
 
 
 
 
 
 
 
 
<Group 1> 
<Group 2>  
 
 
95% CI 
 
95% CI 
  
 
n 
% 
LL 
UL 
n 
% 
LL 
UL 
<Vaccination at visit 1> N 
xxx 
 
 
 
xxx 
 
 
 
Any 
xxx 
xx.x 
xx.x 
xx.x 
xxx 
xx.x 
xx.x 
xx.x 
≥5 - ≤ 20 
xxx 
xx.x 
xx.x 
xx.x 
xxx 
xx.x 
xx.x 
xx.x 
>20 
xxx 
xx.x 
xx.x 
xx.x 
xxx 
xx.x 
xx.x 
xx.x 
Medically attended visits 
 
 
 
 
 
 
 
 
<Vaccination at visit 3> 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Per subject 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Per vaccination 
 
 
 
 
 
 
 
 


CONFIDENTIAL 
204894 (RSV-PED-011) 
Statistical Analysis Plan Final 
27-MAR-2019 
Page 67 of 97 
 n/% = number/percentage of subjects reporting the type of adverse event at least once  
95%CI= Exact 95% confidence interval; LL = lower limit, UL = upper limit 
The maximum intensity of local injection site redness/swelling was coded as follows: 
1: > 0.1 mm to < 5 mm 
2: ≥ 5 mm to ≤ 20 mm 
3: > 20 mm 
Please note – The N may vary for each symptom depending on how many subjects has filled in diary card for particular 
symptom. 
Template 17 Duration in days of solicited <general, local> adverse events within 
7 days following first and second vaccination and overall <RSV 1D, 
RSV 2D, Comparator/Placebo> groups (Exposed Set) 
              
  Symptom 
            <Group 1> 
                Value  
     <Group 2> 
          Value  
<Vaccination at 
visit 1> 
<Vaccination at 
visit X> 
Per vaccination 
<Symptom 1> 
 n 
 Mean 
 Minimum 
 Q1 
 Median 
 Q3 
 Maximum 
<Symptom 2>  
                             
                            xxx 
                            xxx.x 
                            xxx 
                            xxx.x 
                            xxx.x 
                            xxx.x 
                            xxx 
 
          
          xxx 
          xxx.x 
          xxx 
          xxx.x 
          xxx.x 
          xxx.x 
          xxx  
 
Short group label = long group label 
n = number of doses with the adverse event 
Q1 = 25th percentile 
Q3 = 75th percentile 


CONFIDENTIAL 
204894 (RSV-PED-011) 
Statistical Analysis Plan Final 
27-MAR-2019 
Page 68 of 97 
Template 18 Percentage of subjects with solicited general adverse events by 
maximum intensity within the 7-day (Days 1-7) following first and 
second vaccination and overall - <RSV 1D, RSV 2D, 
Comparator/Placebo> <groups> < pooled RSV 1D, RSV 2D, 
Comparator/Placebo groups >(Exposed Set) 
Adverse event: Irritability/Fussiness or Drowsiness or Loss of appetite 
Adverse event: Temperature (C) 
 
 
<Group 1> 
<Group 2>  
 
 
95% CI 
 
95% CI 
  
 
n 
% 
LL 
UL 
n 
% 
LL 
UL 
 
 
 
 
 
 
 
 
<Vaccination at visit 1> N 
xxx 
 
 
 
xxx 
 
 
 
Any 
xxx 
xx.x 
xx.x 
xx.x 
xxx 
xx.x 
xx.x 
xx.x 
Grade 2 
xxx 
xx.x 
xx.x 
xx.x 
xxx 
xx.x 
xx.x 
xx.x 
Grade 3 
xxx 
xx.x 
xx.x 
xx.x 
xxx 
xx.x 
xx.x 
xx.x 
Any related 
 
 
 
 
 
 
 
 
Grade 2 related 
 
 
 
 
 
 
 
 
Grade 3 related 
 
 
 
 
 
 
 
 
Medically attended visits 
 
 
 
 
 
 
 
 
<Vaccination at visit 3> 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Per subject 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Per vaccination 
 
 
 
 
 
 
 
 
 
 
<Group 1> 
<Group 2>  
 
 
95% CI 
 
95% CI 
  
 
n 
% 
LL 
UL 
n 
% 
LL 
UL 
 
 
 
 
 
 
 
 
<Vaccination at visit 1> N 
xxx 
 
 
 
xxx 
 
 
 
Any 
xxx 
xx.x 
xx.x 
xx.x 
xxx 
xx.x 
xx.x 
xx.x 
≥38.0  
xxx 
xx.x 
xx.x 
xx.x 
xxx 
xx.x 
xx.x 
xx.x 
≥38.5 
xxx 
xx.x 
xx.x 
xx.x 
xxx 
xx.x 
xx.x 
xx.x 
≥39.0 
 
 
 
 
 
 
 
 
≥39.5 
 
 
 
 
 
 
 
 
>40.0 
 
 
 
 
 
 
 
 
Related 
 
 
 
 
 
 
 
 
>39.0 - ≤40.0 Related 
 
 
 
 
 
 
 
 
>40.0 Related 
 
 
 
 
 
 
 
 
Medically attended visits 
 
 
 
 
 
 
 
 
<Vaccination at visit 3> 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Per subject 
 
 
 
 
 
 
 
 
Per vaccination 
 
 
 
 
 
 
 
 


CONFIDENTIAL 
204894 (RSV-PED-011) 
Statistical Analysis Plan Final 
27-MAR-2019 
Page 69 of 97 
<each group>: 
For each vaccination: 
 N = number of subjects with the corresponding documented vaccination 
 n/% = number/percentage of subjects reporting the type of adverse event at least once following the corresponding 
vaccination  
For Per vaccination: 
 N = number of documented vaccination 
 n/% = number/percentage of vaccination followed by at least one type of adverse event 
For Per subject: 
 N = number of subjects with at least one documented vaccination 
 n/% = number/percentage of subjects reporting the type of adverse event at least once  
95%CI= Exact 95% confidence interval; LL = lower limit, UL = upper limit 
Please note – The N may vary for each adverse event depending on how many subjects has filled in diary card for 
particular symptom. 
Template 19 Percentage of subjects reporting solicited local adverse events (any 
grade /grade 2,3/ grade 3) within 7-days following first and second 
vaccination by maximum intensity for pooled RSV 1D, RSV 2D, 
Comparator/Placebo groups (Exposed Set) 
 
<each group> 
Please note – this graph will be presented on pooled group only  


CONFIDENTIAL 
204894 (RSV-PED-011) 
Statistical Analysis Plan Final 
27-MAR-2019 
Page 70 of 97 
Template 20 Percentage of subjects reporting fever (any and grade 3) and other 
solicited general adverse events (any grade /grade 2,3/ grade 3) 
within 7-days following first and second vaccination by maximum 
intensity for pooled RSV 1D, RSV 2D and Comparator/Placebo 
groups (Exposed Set) 
 
<each group> 
Please note the figure is only template 
Please note – this graph will be presented on pooled group only  


CONFIDENTIAL 
204894 (RSV-PED-011) 
Statistical Analysis Plan Final 
27-MAR-2019 
Page 71 of 97 
Template 21 Summary of subjects with at least one <Ø/grade 3/ related/ grade 3 
related/serious/ medically attended> unsolicited adverse event 
<episode of spontaneous or excessive bleeding> classified by 
MedDRA Primary System Organ Class and Preferred Term <with 
onset within 30 days of first and second vaccination><from 
vaccination dose 1 up to Day 61> <pooled> <RSV 1D, RSV 2D, 
Comparator/Placebo> groups (Exposed Set) 
Short group label = long group label 
Any adverse event = at least one adverse event experienced (regardless of the MedDRA Preferred Term) 
N = number of subjects with at least one administered vaccination 
n* = number of events reported  
n/% = number/percentage of subjects reporting the adverse event at least once 
95% CI = exact 95% confidence interval; LL = Lower Limit, UL = Upper Limit 
 
<Group 1> 
N=XXXX 
<Group 2>  
N=XXXX 
Primary System Organ Class (CODE) 
95% CI 
 
95% CI 
  Preferred Term (CODE) 
n 
% 
LL 
UL 
N 
% 
LL 
UL 
 
 
 
 
 
 
 
 
Any <Ø, grade 3, related, grade3 related> 
unsolicited adverse event 
xxx 
xx.x 
xx.x 
xx.x 
Xxx 
xx.x 
xx.x 
xx.x 
 
 
 
 
 
 
 
 
<SOC 1 (code)> 
xxx 
xx.x 
xx.x 
xx.x 
Xxx 
xx.x 
xx.x 
xx.x 
 <Preferred Term 1 (code)> 
xxx 
xx.x 
xx.x 
xx.x 
Xxx 
xx.x 
xx.x 
xx.x 
 <Preferred Term 2 (code)> 
xxx 
xx.x 
xx.x 
xx.x 
Xxx 
xx.x 
xx.x 
xx.x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
<SOC 2 (code)> 
xxx 
xx.x 
xx.x 
xx.x 
xxx 
xx.x 
xx.x 
xx.x 
 <Preferred Term 1 (code)> 
xxx 
xx.x 
xx.x 
xx.x 
xxx 
xx.x 
xx.x 
xx.x 
 <Preferred Term 2 (code)> 
xxx 
xx.x 
xx.x 
xx.x 
xxx 
xx.x 
xx.x 
xx.x 
 
 
 
 
 
 
 
 


CONFIDENTIAL 
204894 (RSV-PED-011) 
Statistical Analysis Plan Final 
27-MAR-2019 
Page 72 of 97 
Template 22 Summary of subjects with at least one <episode of RSV-LRTI (AE of 
specific interest)/serious adverse event> classified by MedDRA 
Primary System Organ Class and Preferred Term <from vaccination 
dose 1 up to end of <first/second> RSV season for pooled RSV 1D, 
RSV 2D and Comparator/Placebo groups (Exposed Set) 
Short group label = long group label 
Any adverse event = at least one adverse event experienced (regardless of the MedDRA Preferred Term) 
N = number of subjects with at least one administered vaccination 
n* = number of events reported  
n/% = number/percentage of subjects reporting the adverse event at least once 
95% CI = exact 95% confidence interval; LL = Lower Limit, UL = Upper Limit 
 
<Group 1> 
N=XXXX 
<Group 2>  
N=XXXX 
Primary System Organ Class (CODE) 
95% CI 
 
95% CI 
  Preferred Term (CODE) 
n 
% 
LL 
UL 
N 
% 
LL 
UL 
 
 
 
 
 
 
 
 
Any <Ø, grade 3, related, grade3 related> 
unsolicited adverse event 
xxx 
xx.x 
xx.x 
xx.x 
Xxx 
xx.x 
xx.x 
xx.x 
 
 
 
 
 
 
 
 
<SOC 1 (code)> 
xxx 
xx.x 
xx.x 
xx.x 
Xxx 
xx.x 
xx.x 
xx.x 
 <Preferred Term 1 (code)> 
xxx 
xx.x 
xx.x 
xx.x 
Xxx 
xx.x 
xx.x 
xx.x 
 <Preferred Term 2 (code)> 
xxx 
xx.x 
xx.x 
xx.x 
Xxx 
xx.x 
xx.x 
xx.x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
<SOC 2 (code)> 
xxx 
xx.x 
xx.x 
xx.x 
xxx 
xx.x 
xx.x 
xx.x 
 <Preferred Term 1 (code)> 
xxx 
xx.x 
xx.x 
xx.x 
xxx 
xx.x 
xx.x 
xx.x 
 <Preferred Term 2 (code)> 
xxx 
xx.x 
xx.x 
xx.x 
xxx 
xx.x 
xx.x 
xx.x 
 
 
 
 
 
 
 
 


CONFIDENTIAL 
204894 (RSV-PED-011) 
Statistical Analysis Plan Final 
27-MAR-2019 
Page 73 of 97 
Template 23 Listing of SAE from vaccination dose 1 up to <Day 61/end of first 
RSV season/study end> (Exposed Set) 
Group     Subject 
number 
Gender 
Country 
Race 
Age at 
onset  
(Year) 
Verbatim                   Preferred Term 
 
 
 
 
 
 
 
  
xxxxx 
xxxxx 
xxxxx 
 xxxxxxx        xxxxxx 
xx 
xxxxx                          xxxxx 
  
 
Group     Subject 
number 
Primary System 
Organ Class 
Medical 
visit type Vaccin
ation 
Day of 
onset 
Duration Intensity Causality Outco
me 
 
 
 
 
 
 
  
 
       
xxxxx 
xxxxx 
xxxxx 
 xxxxxxx 
xxxxxx xx 
xx 
xxxx 
x
x
x
 xxxxx   
Group     Subject 
number 
Seriousness 
criteria  
Potential 
AESI 
(prefered 
term) 
 
 
 
 
 
 
  
 
       
xxxxx 
xxxxx 
xxxxx 
 xxxxxxx 
xxxxxx xx 
xx 
xxxx 
x
x
x
 
 xxxxx   
Template 24 Listing of AEs related to LRTI and association to RSV infection from 
vaccination dose 1 up to <Day 61/end of first RSV season/study 
end> (Exposed Set) 
Gro
up 
Su
b. 
No
. 
Age 
at 
onset 
(mon
th) 
Verba
tim 
Prefer
red 
term 
ME
D 
typ
e 
Previ
ous 
Dose 
Day 
of 
ons
et 
Sta
rt 
dat
e 
En
d 
da
te 
Durati
on 
Intens
ity 
Causa
lity 
Outco
me 
Loc
al 
RS
V 
test 
res
ult 
Date 
of 
sam
ple 
for 
local 
testi
ng 
Cent
ral 
test 
RSV 
A 
Cent
ral 
test 
RSV 
B 
Date 
of 
sam
ple 
for 
centr
al 
testi
ng 
AE
SI 
 
 
 
 
 
 
 
 
 
 
 
<each group>: 
AESI: AEs of Special Interest - LRTI identified by the Investigator 
*AEs related to LRTI will be identified based on the list of preferred terms described in in section 9.4–Annex 2  


CONFIDENTIAL 
204894 (RSV-PED-011) 
Statistical Analysis Plan Final 
27-MAR-2019 
Page 74 of 97 
Template 25 Listing of AEs related to spontaneous or excessive bleeding 
together with hemoglobin and platelet count results with 30 days of 
first and second vaccination (Exposed Set) 
Gr
ou
p 
Sub. 
No. 
Age 
at 
ons
et 
(mo
nth) 
Verb
atim 
Preferre
d term* 
Prev
ious 
Dos
e 
Da
y 
of 
on
set 
Dura
tion 
Inte
nsit
y 
Start 
date 
End 
date 
A
E
SI 
Dat
e of 
sa
mpl
e 
Labor
atory 
param
eter 
Ra
w 
res
ult 
U
ni
t 
xx 
xx 
 
xx 
xx 
xx 
xx 
 
 
xx 
xx 
 
xx 
Hemo
globin 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Platel
et 
count 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xx 
Hemo
globin 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Platel
et 
count 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
<each group>: 
*AEs related to spontaneous or excessive bleeding will be identified based on the list of preferred terms described in 
section 9.4 –Annex 
AESI: AEs of Special Interest – Spontaneous or excessive bleeding identified by the Investigator 
Template 26 Listing of adverse events, SAEs and solicited symptoms leading to 
study or treatment discontinuation from vaccination dose 1 up to 
<Day 61/end of first RSV season/end of second RSV 
season>(Exposed Set) 
Type of discontinuation: <study/treatment> 
Group  Subject 
number 
Gender Country Race AE 
Description 
SAE (Y/N)   Causality  Outcome 
Vaccination 
and visit 
xxxxx xxxxx 
xxxxx 
xxxxxxx    xxxxxx xxxxxx 
x 
xxxxx     xxxxx            Vaccination: x at visit 
x 
 
Template 27 Listing of unscheduled safety visit from vaccination dose 1 up to 
<Day 61/end of first RSV season/study end> (Exposed Set) 
Group Sub.No. Gen
der 
Cou
ntry 
Race Age at 
unschedul
ed visit 
(Month) 
Date of 
previous 
safety 
BS 
Date of 
unscheduled 
safety BS 
Result of 
previous 
safety 
BS out of 
lab range 
Grade of 
abnormality 
per protocol – 
previous 
safety BS 
Result of 
biochemistry/
hematology at 
unscheduled 
visit 
Outcome of 
unschedule
d safety 
visit 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
<each group>: 
Please note that only unscheduled safety visits with abnormal safety parameters will be presented.  


CONFIDENTIAL 
204894 (RSV-PED-011) 
Statistical Analysis Plan Final 
27-MAR-2019 
Page 75 of 97 
Template 28 Summary of subjects taking a concomitant medication within <7/30> 
days following each vaccination and overall <RSV 1D, RSV 2D, 
Comparator/Placebo> <groups>< for pooled RSV 1D, RSV 2D and 
Comparator/Placebo groups> (Exposed Set) 
Short group label = long group label 
For each vaccination: 
N = number of subjects with the corresponding administered vaccination 
n/% = number/percentage of subjects who took the specified type of concomitant medication at least once during the 
considered period 
For per vaccination: 
  N = number of administered vaccination 
  n/% = number/percentage of vaccines after which the specified type of concomitant medication was taken at least 
once during the considered period 
For per subject: 
  N = number of subjects with at least one administered vaccination 
  n/% = number/percentage of subjects who took the specified type of concomitant medication at least once during the 
considered period 
95% CI = Exact 95% confidence interval; LL = lower limit, UL = upper limit 
 
 
<Group 1> 
<Group 2>  
 
95% CI 
 
95% CI 
  
 
n 
% 
LL 
UL 
n 
% 
LL 
UL 
<Vaccination at visit 1> N 
xxx 
 
 
 
xxx 
 
 
 
Any 
Any antipyretic 
Any prophylactic  
antipyretic  
xxx 
xxx 
xxx 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xxx 
xxx 
xxx 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
<Vaccination at visit X> 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Per subject 
 
 
 
 
 
 
 
 
Per vaccination 
  
 
 
 
 
 
 
 
 


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204894 (RSV-PED-011) 
Statistical Analysis Plan Final 
27-MAR-2019 
Page 76 of 97 
Template 29 Summary of occurrences and subjects with at least one solicited 
and unsolicited adverse event classified by MedDRA Primary 
System Organ Class and Preferred Term with onset within 30 days 
of first and second vaccination – SAE excluded <RSV 1D, RSV 2D, 
Comparator/Placebo> groups (Exposed Set) 
Short group label = long group label 
Any adverse event = at least one adverse event experienced (regardless of the MedDRA Preferred Term) 
N = number of subjects with at least one administered vaccination 
n* = number of events reported  
n/% = number/percentage of subjects reporting the adverse event at least once 
95% CI = exact 95% confidence interval; LL = Lower Limit, UL = Upper Limit 
Primary System Organ Class (CODE) 
<Group 1> 
N=XXXX 
<Group 2>  
N=XXXX 
  Preferred Term (CODE) 
occ 
n 
% 
occ 
n 
% 
 
 
 
 
 
 
Any solicited and unsolicited adverse event  
xxx 
xxx 
xx.x 
xxx 
xxx 
xx.x 
 
 
 
 
 
 
<SOC 1 (code)> 
xxx 
xxx 
xx.x 
xxx 
xxx 
xx.x 
 <Preferred Term 1 (code)> 
xxx 
xxx 
xx.x 
xxx 
xxx 
xx.x 
 <Preferred Term 2 (code)> 
xxx 
xxx 
xx.x 
xxx 
xxx 
xx.x 
 
 
 
 
 
 
 
 
 
 
 
 
<SOC 2 (code)> 
xxx 
xxx 
xx.x 
xxx 
xxx 
xx.x 
 <Preferred Term 1 (code)> 
xxx 
xxx 
xx.x 
xxx 
xxx 
xx.x 
 <Preferred Term 2 (code)> 
xxx 
xxx 
xx.x 
xxx 
xxx 
xx.x 


CONFIDENTIAL 
204894 (RSV-PED-011) 
Statistical Analysis Plan Final 
27-MAR-2019 
Page 77 of 97 
Template 30 Number (%) of subjects with serious adverse events <from Day 1 up 
to <Day 61/end of second RSV season>, including number of events 
reported for pooled RSV 1D, RSV 2D and Comparator/Placebo> 
groups (Exposed Set) 
 
<Each group> 
N=XXXX 
<Each group> 
N=XXXX 
Type of Event 
Primary System 
Organ Class (CODE) 
Preferred Term 
(CODE) 
n* 
n 
% 
n* 
n 
% 
SAE 
 
At least one symptom xxx 
xxx 
xx.x 
xxx 
xxx 
xx.x 
<each SOC (SOC 
code)> 
<each PT (PT code)> 
xxx 
xxx 
xx.x 
xxx 
xxx 
xx.x 
 
 
xxx 
xxx 
xx.x 
xxx 
xxx 
xx.x 
Related SAE 
 
At least one symptom xxx 
xxx 
xx.x 
xxx 
xxx 
xx.x 
<each SOC (SOC 
code)> 
<each PT (PT code)> 
xxx 
xxx 
xx.x 
xxx 
xxx 
xx.x 
 
 
xxx 
xxx 
xx.x 
xxx 
xxx 
xx.x 
Fatal SAE 
 
At least one symptom xxx 
xxx 
xx.x 
xxx 
xxx 
xx.x 
<each SOC (SOC 
code)> 
<each PT (PT code)> 
xxx 
xxx 
xx.x 
xxx 
xxx 
xx.x 
 
 
xxx 
xxx 
xx.x 
xxx 
xxx 
xx.x 
Related Fatal 
SAE 
 
At least one symptom xxx 
xxx 
xx.x 
xxx 
xxx 
xx.x 
<each SOC (SOC 
code)> 
<each PT (PT code)> 
xxx 
xxx 
xx.x 
xxx 
xxx 
xx.x 
 
 
xxx 
xxx 
xx.x 
xxx 
xxx 
xx.x 
Short group label = long group label 
N = number of subjects with administered vaccination 
n/% = number/percentage of subjects reporting the adverse event at least once 
n* = Number of adverse events reported 
Related = assessed by the investigator as related 
Template 31 Number and percentage of subjects with <anti-RSV A antibody titre, 
anti-RSV F concentration> equal to or above <cut-off ><unit>  and 
gm<t,c> for pooled RSV 1D, RSV 2D and Comparator/Placebo> 
groups (<Adapted>PPS of immunogenicity at <Day X, end of 1st RSV 
season>) 
Antibody         Time point          Cut-
off 
 
 
<Group 1> 
 
  <Group 2>  
 
 
                          95% CI 
 
 
   95% CI 
 
N 
n value
LL UL 
N 
n value LL 
UL 
<Antibody 1>  <Time point 1> <Cut-
off 1> 
%>=<cut-off 1> 
<unit> 
xxx xxx xx.x xx.x xx.x 
xxx 
xxx
xx.x 
xx.x  xx.x 
 
 
 
 
 
 
 
 
 
 
GM<T,C> 
xxx
 
xx.x xx.x xx.x 
xxx 
 
xx.x 
xx.x   
xx.x 
Short group label = long group label  
GMT/C = geometric mean antibody titer/concentration 
N = Number of subjects with available results  
n/% = number/percentage of subjects with titer/concentration equal to or above specified value 
95% CI = 95% confidence interval; LL = lower limit, UL = upper limit 
PRE= Pre-vaccination  
D31 = Post-vaccination at Day 31 
D61 = Post-vaccination at Day 61 
RSV1S = End of 1st RSV transmission season 


CONFIDENTIAL 
204894 (RSV-PED-011) 
Statistical Analysis Plan Final 
27-MAR-2019 
Page 78 of 97 
Template 32 Distribution of <RSV-A neutralising antibody titre, RSV-F antibody 
concentration> for pooled RSV 1D, RSV 2D and 
Comparator/Placebo> groups (<Adapted>PPS for immunogenicity 
<at Day X, end of 1st RSV season>) 
Antibody         Time point             Cut-off 
 <Group 1> 
 
  <Group 2>  
 
 
           95% CI 
 
 
   95% CI 
 
N 
n 
value 
LL 
UL 
N 
n 
value LL 
UL 
<Antibody 1>  <Time point 1>  <cut-off 1  xxx 
xxx 
xx.x 
xx.x xx.x 
xxx 
xxx 
xx.x 
xx.x  xx.x 
>=cut-off 2  xxx 
xxx 
xx.x 
xx.x xx.x 
xxx 
xxx 
xx.x 
xx.x  xx.x 
                                                >=cut-off 3 xxx 
xxx 
xx.x 
xx.x xx.x 
xxx 
xxx 
xx.x 
xx.x  xx.x 
                      <Time point 2>  <cut-off 1  xxx 
xxx 
xx.x 
xx.x xx.x 
xxx 
xxx 
xx.x 
xx.x  xx.x 
             
>=cut-off 2  xxx 
xxx 
xx.x 
xx.x xx.x 
xxx 
xxx 
xx.x 
xx.x  xx.x 
                       
>=cut-off 3  xxx 
xxx 
xx.x 
xx.x xx.x 
xxx 
xxx 
xx.x 
xx.x  xx.x 
Short group label = long group label  
N = number of subjects with available results 
n/% = number/percentage of subjects with <titer, concentration> within the specified criterion 
<95>% CI = <95>% confidence interval; LL = Lower Limit, UL = Upper Limit 
PRE= Pre-vaccination  
D31 = Post-vaccination at Day 31 
D61 = Post-vaccination at Day 61 
RSV1S = End of 1st RSV transmission season 


CONFIDENTIAL 
204894 (RSV-PED-011) 
Statistical Analysis Plan Final 
27-MAR-2019 
Page 79 of 97 
Template 33 Vaccine response for anti-RSV-A neutralising antibody titre at each 
post-vaccination timepoint for pooled RSV 1D, RSV 2D and 
Comparator/Placebo> groups (PPS for analysis of immunogenicity 
at <Day X, End of 1st RSV season>) 
 
Antibody         Time point     Pre-vaccination  
Category                                     <Group 1>                                  <Group 2> 
 
  
 
 
                     
95% CI 
 
 
95% CI 
 
N 
n 
value LL 
UL 
N 
n 
value LL 
UL 
<Antibody 1> <Time point 
1> 
<128  
xxx xxx 
xx.x 
xx.x 
xx.x 
xxx 
xxx 
xx.x 
xx.x 
xx.x 
≥128 - ≤256 
 
xxx 
 
xxx 
 
xx.x 
 
xx.x 
 
xx.x 
 
xxx 
 
xxx 
 
xx.x 
 
xx.x 
 
xx.x 
>256-≤1024 
≥1024 
Total response 
 
xxx 
 
 
xxx 
 
xxx 
 
xxx 
 
xx.x 
 
 
xx.x 
 
xx.x 
 
 
xx.x 
 
xx.x 
 
 
xx.x 
 
xxx 
 
 
xxx 
 
xxx 
 
 
xxx 
 
xx.x 
 
 
xx.x 
 
xx.x 
 
 
xx.x 
 
xx.x 
 
 
xx.x 
Short group label = long group label  
Total = all subjects with pre-and post- vaccination result available 
Vaccine response defined as : 
  For subjects with pre-vaccination titer <128: antibody titer at post-vaccination>= 4 fold the pre-vaccination antibody 
titer 
  For subjects with pre-vaccination titer in ≥128 - ≤256: antibody titer at post-vaccination >= 3 fold the pre-vaccination 
antibody titer 
  For subjects with pre-vaccination titer in >256-≤1024: antibody titer at post-vaccination>= 2.5 fold the pre-vaccination 
antibody titer 
  For subjects with pre-vaccination titer >1024: antibody titer at post-vaccination >= 1 fold the pre-vaccination antibody 
titer 
N = number of subjects with both pre- and post-vaccination results available 
n/% = number/percentage of responders 
95% CI = exact 95% confidence interval, LL = Lower Limit, UL = Upper Limit 
PRE= Pre-vaccination  
<D31 = Post-vaccination at Day 31> 
<D61 = Post-vaccination at Day 61> 
<RSV1S = End of 1st RSV transmission season> 


CONFIDENTIAL 
204894 (RSV-PED-011) 
Statistical Analysis Plan Final 
27-MAR-2019 
Page 80 of 97 
Template 34 Number and percentage of subjects with <anti-RSV A antibody titre, 
anti-RSV F concentration> equal to or above <cut-off ><unit> and 
GMR for pooled RSV 1D, RSV 2D and Comparator/Placebo> groups 
(PPS of immunogenicity at <Day X, End of 1st RSV season>) 
Antibody         Time point          
Cut-off 
 
 
   <Group 1> 
 
           <Group 2>  
 
 
                       95% CI 
 
 
   95% CI 
 
N 
n value LL UL 
N 
n 
value 
LL      UL 
 
 
 
 
 
 
 
 
 
 
<Antibody 1>  <Time point 1> 
<Cut-off 1> 
%>=<cut-off 1> <unit> xxx xxx xx.x xx.x xx.x xxx xxx
xx.x 
xx.x       xx.x 
GMC/T 
xxx  
xx.x xx.x xx.x xxx 
 
xx.x 
xx.x       xx.x 
Visit comparison / 
baseline 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
GMR 
xxx  
xx.x xx.x xx.x xxx 
 
xx.x 
xx.x       xx.x 
Short group label = long group label  
GMT = geometric mean antibody titer 
N = Number of subjects with available results at the two considered time points  
95% CI = 95% confidence interval; LL = Lower Limit, UL = Upper Limit 
PRE= Pre-vaccination  
D31 = Post-vaccination at Day 31 
D61 = Post-vaccination at Day 61 
RSV1S = End of 1st RSV transmission season 


CONFIDENTIAL 
204894 (RSV-PED-011) 
Statistical Analysis Plan Final 
27-MAR-2019 
Page 81 of 97 
Template 35 Distribution of fold of anti-RSV-A neutralising antibody titer by 
<cumulative> pre-vaccination titer category for pooled RSV 1D, RSV 
2D and Comparator/Placebo> groups (PPS for analysis of 
immunogenicity at <Day X, end of first RSV season>) 
Antibody         Time point          
Fold 
Pre-vaccination 
status 
 
<Group 1> 
 
              <Group 2>  
 
 
                  95% CI 
 
         95% CI 
 
N 
n Value LL UL 
N 
n Value LL      UL 
 
 
 
 
 
 
 
 
 
 
<Antibody 1>  <Time point 1> <1 <128  
xxx xxx xx.x xx.x xx.x xxx xxx xx.x xx.x       xx.x 
≥128-≤256 
xxx xxx xx.x xx.x xx.x xxx xxx xx.x xx.x       xx.x 
>256-≤512 
xxx xxx xx.x xx.x xx.x xxx xxx xx.x xx.x       xx.x 
>1024-≤2048 
xxx xxx xx.x xx.x xx.x xxx xxx xx.x xx.x       xx.x 
>2048-≤4096 
 
xxx 
Xxx  xx.x    xx.x xx.x     xxx xxx  xx.x   xx.x       xx.x 
>4096 
 
xxx 
Xxx  xx.x    xx.x xx.x     xxx xxx  xx.x   xx.x       xx.x 
Total 
  
xxx 
xxx   xx.x   xx.x xx.x      xxx xxx xx.x xx.x       xx.x 
                                               ≥1 <128 <unit> 
xxx xxx xx.x xx.x xx.x xxx xxx xx.x xx.x       xx.x 
                                               ≥2 <128 <unit> 
xxx xxx xx.x xx.x xx.x xxx xxx xx.x xx.x       xx.x 
 
 
 
 
 
 
 
 
 
Short group label = long group label  
N = number of subjects with pre and corresponding post-vaccination results available 
n/% = number/percentage of subjects with titre fold change meeting the specified criterion 
PRE= Pre-vaccination  
D31 = Post-vaccination at Day 31 
D61 = Post-vaccination at Day 61 
RSV1S = End of 1st RSV transmission season 


CONFIDENTIAL 
204894 (RSV-PED-011) 
Statistical Analysis Plan Final 
27-MAR-2019 
Page 82 of 97 
Template 36 Descriptive statistics of <anti-RSV A neutralizing antibody titre, anti-
RSV F antibody concentration>at pre-vaccination, Day <31, 61,> 
<and end of 1st RSV transmission season> for pooled RSV 1D, RSV 
2D and Comparator/Placebo> groups (<Adapted> PPS for 
immunogenicity) 
 
Each Group 
N=XXXX 
Visit  
Characteristics 
Value 
PRE 
N with data  
 
 
Mean 
 
 
SD 
 
 
Q1 
 
 
Median  
 
 
Q3 
 
 
95% CI 
(xx.x ; xx.x) 
PI(D8) 
… 
 
PI(D31) 
… 
 
PI(D61) 
… 
 
PI(D91) 
… 
 
  Short group label = long group label  
  N = total number of subjects 
  N with data = number of subjects with available results  
  Value = value of the considered parameter 
  SD = standard deviation 
 Q1 and Q3 = 1st and 3rd quantiles 
 LL, UL = Exact 95% Lower and Upper confidence limits 
PRE= Pre-vaccination  
D31 = Post-vaccination at Day 31 
D61 = Post-vaccination at Day 61 
RSV1S = End of 1st RSV transmission season 


CONFIDENTIAL 
204894 (RSV-PED-011) 
Statistical Analysis Plan Final 
27-MAR-2019 
Page 83 of 97 
Template 37 Reverse cumulative distribution curves for anti-RSV-A neutralising 
antibody titres in each group at baseline and <Day 31, Day 61, End 
of first RSV season> for pooled RSV 1D, RSV 2D and 
Comparator/Placebo> group <PPS for analysis of immunogenicity at 
<Day X, End of 1st RSV season> 
 
Short group label = long group label  
Template 38 Individual results of anti-RSV-A neutralising antibody titre at Day 
<61/end of first RSV season> versus pre-vaccination in <each 
pooled <RSV 1D, RSV 2D> group> and Comparator/placebo group> 
(PPS for analysis of immunogenicity at <Day X>) 
 
Short group label = long group label  
Note: This graph is provided as an example. The same graph will be generated for each assay and each timepoint 
separately (Days 61, end of first RSV season) 


CONFIDENTIAL 
204894 (RSV-PED-011) 
Statistical Analysis Plan Final 
27-MAR-2019 
Page 84 of 97 
Template 39 Number and percentage of subjects with at least one RSV infection, 
RSV-RTI, RSV-LRTI, RSV-severe LRTI, RSV-very severe LRTI, All-
cause LRTI and RSV hospitalization (based on WHO case definition) 
from vaccination dose 1 up to end of <first, second> RSV season for 
pooled RSV 1D, RSV 2D and Comparator/Placebo group (<Exposed 
Set, Exposed Set with a negative RSV exposure status>)   
 
<each group> 
N =  
Total  
 N =  
 
 
95% CI 
 
95% CI 
Categories 
n 
% 
LL 
UL 
n % LL 
UL 
No infection 
 
 
 
 
 
 
 
 
RSV-infection symptomatic or asymptomatic* 
 
 
 
 
 
 
 
 
RSV-RTI 
 
 
 
 
 
 
 
 
RSV-LRTI 
 
 
 
 
 
 
 
 
RSV-severe LRTI 
 
 
 
 
 
 
 
 
RSV-very severe LRTI 
 
 
 
 
 
 
 
 
All-cause LRTI 
 
 
 
 
 
 
 
 
RSV hospitalization** 
 
 
 
 
 
 
 
 
Short group label = long group label  
* Association to RSV based on central testing only for asymptomatic visit (no local test available) 
** Confirmed RSV infection and hospitalized for acute medical condition 
N = number of subjects with at least one administered dose 
n/%= number/percentage of subjects reporting at least once the symptom 
95%CI= Exact 95% confidence interval; LL = lower limit, UL = upper limit 
Template 40 Proportion of subjects with at least one RSV hospitalization over the 
number of subjects with at least one RSV infection (symptomatic or 
asymptomatic*) from vaccination dose 1 up to end of <first, second> 
RSV season for pooled RSV 1D, RSV 2D and Comparator/Placebo 
group <Exposed Set, Exposed Set with negative RSV baseline 
status> 
 
<each group> 
N= 
 
 
95 % CI 
Symptom 
n 
% 
LL 
UL 
RSV hospitalization** 
 
 
 
 
Short group label = long group label  
* Association to RSV based on central testing only for asymptomatic visit (no local test available) 
** Confirmed RSV infection and hospitalized for acute medical condition 
N= number of subjects with at least one RSV infection (symptomatic or asymptomatic) 
n/%= number/percentage of subjects reporting at least one RSV hospitalization 
95%CI= Exact 95% confidence interval; LL = lower limit, UL = upper limit 


CONFIDENTIAL 
204894 (RSV-PED-011) 
Statistical Analysis Plan Final 
27-MAR-2019 
Page 85 of 97 
Template 41 Number and percentage of subjects reporting the RSV infection of 
different severity (based on WHO case definition) by number of 
events experienced between vaccination dose 1 up to end of <first, 
second> RSV season for pooled RSV 1D, RSV 2D and 
Comparator/Placebo group <Exposed Set, Exposed Set with 
negative RSV baseline status> 
 
<Each group> 
N=xx 
 
95% CI 
Characteristics 
Categories 
n 
% 
LL 
UL 
RSV infection-symptomatic or asymptomatic* 
0 
 
 
 
 
 
1 
 
 
 
 
 
2 
 
 
 
 
RSV-RTI 
0 
 
 
 
 
 
1 
 
 
 
 
RSV-LRTI 
0 
 
 
 
 
 
1 
 
 
 
 
 
2 
 
 
 
 
RSV-Severe LRTI 
0 
 
 
 
 
 
1 
 
 
 
 
RSV-very severe LRTI 
0 
 
 
 
 
 
1 
 
 
 
 
All cause LRTI 
0 
 
 
 
 
 
1 
 
 
 
 
 
2 
 
 
 
 
 
3 
 
 
 
 
RSV hospitalization$ 
0 
 
 
 
 
 
1 
 
 
 
 
 
2 
 
 
 
 
 
3 
 
 
 
 
Short group label = long group label  
  N = number of subjects in each group 
  n = number of subjects in a given category 
  % =100*n/N 
  LL, UL for percentage = Exact 95% Lower and Upper confidence limits 
  Please note – Single episode can be considered in multiple category depending on the symptom experienced 
* Association to RSV based on central testing only for asymptomatic visit (no local test available) 
  $Confirmed RSV infection and hospitalized for acute medical condition 


CONFIDENTIAL 
204894 (RSV-PED-011) 
Statistical Analysis Plan Final 
27-MAR-2019 
Page 86 of 97 
Template 42 Number and percentage of RSV infections and associated disease 
severity (based on WHO case definition) and relative risk from  
vaccination dose 1 up to end of <first, second> RSV season for 
pooled RSV 1D, RSV 2D and Comparator/Placebo group <Exposed 
Set, Exposed Set with negative RSV baseline status> 
 
<Each 
Group> 
N =  
Relative risk  
(RSV1D vs 
Comparator/Placebo) 
Relative risk  
(RSV2D vs 
Comparator/Placebo) 
 
 
95% CI 
 
95% CI 
 
95% CI 
Categories 
n % LL UL Values 
LL 
UL 
Values LL 
UL 
RSV asymptomatic (Excluding RSV-RTI, 
LRTI, RSV-severe LRTI or RSV-very severe 
LRTI) 
  
 
 
 
 
 
RSV RTI (Excluding LRTI, RSV-severe or 
very severe LRTI) 
  
 
 
 
 
 
RSV LRTI (Excluding RSV-severe or very 
severe LRTI) 
  
 
 
 
 
 
RSV-severe LRTI (Excluding RSV-very 
severe LRTI) 
  
 
 
 
 
 
RSV-very severe LRTI 
  
 
 
 
 
 
  Short group label = long group label  
 * Association to RSV based on central testing only for asymptomatic visit (no local test available) 
  N = number of RSV positive samples in each group 
  n** = number of cases in each category 
  n/%= number/percentage of cases in each category 
  95%CI= Exact 95% confidence interval; LL = lower limit, UL = upper limit 
  Please note – Single episode is considered in single category of highest severity based on the symptom experienced 
Template 43 Number and percentage of RSV infections (based on WHO case 
definition) requiring hospitalization between vaccination dose 1 up 
to end of <first, second> RSV season for pooled RSV 1D, RSV 2D 
and Comparator/Placebo group <Exposed Set, Exposed Set with 
negative RSV baseline status> 
 
Group 
N = 
Total  
 N =  
 
 
 
95% CI 
 
 
95% CI 
Categories 
n** n % LL UL 
n** 
N % LL UL 
RSV RTI*(Excluding LRTI, severe or very severe LRTI) 
 
  
 
 
 
 
 
 
 
RSV LRTI (Excluding severe or very severe LRTI) 
 
  
 
 
 
 
 
 
 
RSV-severe LRTI (Excluding very severe LRTI) 
 
  
 
 
 
 
 
 
 
RSV-very severe LRTI 
 
  
 
 
 
 
 
 
 
    Short group label = long group label  
  N = number of RSV infections in each group 
  n** = number of cases in each category 
  n/%= number/percentage of subjects reporting at least once the case 
  95%CI= Exact 95% confidence interval; LL = lower limit, UL = upper limit 


CONFIDENTIAL 
204894 (RSV-PED-011) 
Statistical Analysis Plan Final 
27-MAR-2019 
Page 87 of 97 
Template 44 Descriptive statistics of viral load calculated on all qRT-PCR 
confirmed RSV infection episodes with varying disease severity 
(based on WHO case definition) from vaccination dose 1 up to end 
of <first, second> RSV season for pooled RSV 1D, RSV 2D and 
Comparator/Placebo group <Exposed Set, Exposed Set with 
negative RSV baseline status> 
 
Group 
N= 
Symptoms 
Parameters 
Value 
LL 
UL 
RSV asymptomatic* (Excluding RSV-RTI, RSV-LRTI, RSV-severe 
LRTI or RSV-very severe LRTI) 
n 
 
 
 
 
GM 
 
 
 
 
95% CI 
 
 
 
 
SD 
 
 
 
 
Q1 
 
 
 
 
Median  
 
 
 
 
Q3 
 
 
 
 
Min/Max 
 
 
 
RSV RTI (Excluding RSV-LRTI, RSV-severe LRTI or RSV-very 
severe LRTI) 
 
 
 
RSV LRTI (Excluding RSV-severe or RSV-very severe LRTI) 
 
 
 
RSV-severe LRTI (Excluding RSV-very severe LRTI) 
 
 
 
RSV-very severe LRTI 
 
 
 
RSV hospitalization$ 
 
 
 
    Short group label = long group label  
  N = number of RSV infections episodes in each group 
  n= Number of events in each category 
 SD=Standard Deviation 
 Q1 and Q3 = 1st and 3rd quantiles 
 Min/Max = Minimum/Maximum 
 GM = Geometric mean  
  LL, UL for GM = Exact 95% Lower and Upper confidence limits 
 Total RSV viral load computed as RSV A Viral load + RSV B Viral load 
* Association to RSV based on central testing only for asymptomatic visit (no local test available) 
  $Confirmed RSV infection and hospitalized for acute medical condition 
Please note: each episode for a subject is considered to be independent. We may have multiple swab for one episode. 
We have considered the swab with maximum viral load from one episode for the table 
Please note – Except for RSV hospitalization, single episode is considered in single category of highest severity based 
on the symptom experienced 
Please check:- To check for cases where asymptomatic swab has been taken but the 
subject hasve symptoms of RTI or LRTI. In this case, asymptomatic is also 
considered as RSV RTI/LRTI and maximum viral load of all the episode should be 
considered. 


CONFIDENTIAL 
204894 (RSV-PED-011) 
Statistical Analysis Plan Final 
27-MAR-2019 
Page 88 of 97 
Template 45 Descriptive statistics of maximum viral load per subjects based on 
qRT-PCR confirmed episode with varying disease severity (based on 
WHO case definition) form vaccination dose 1 up to end of <first, 
second> RSV season for pooled RSV 1D, RSV 2D and 
Comparator/Placebo group <Exposed Set, Exposed Set with 
negative RSV baseline status> 
 
Each Group 
N= 
 
 
95% CI 
Symptoms 
Parameters 
Value 
LL 
UL 
RSV asymptomatic* (Excluding RSV-RTI, RSV-LRTI, RSV-severe 
LRTI or RSV-very severe LRTI) 
n 
 
 
 
 
GM 
 
 
 
 
95% CI 
 
 
 
 
SD 
 
 
 
 
Q1 
 
 
 
 
Median  
 
 
 
 
Q3 
 
 
 
 
Min/Max 
 
 
 
RSV RTI (Excluding RSV-LRTI, RSV-severe or RSV-very severe 
LRTI) 
… 
 
 
 
RSV LRTI (Excluding RSV-severe or RSV-very severe LRTI) 
… 
 
 
 
RSV-severe LRTI (Excluding RSV-very severe LRTI) 
… 
 
 
 
RSV-very severe LRTI 
… 
 
 
 
RSV hospitalization$ 
… 
 
 
 
    Short group label = long group label  
  N = number of RSV positive subjects in each group 
  n= Number of subjects in each category 
 SD=Standard Deviation 
 Q1 and Q3 = 1st and 3rd quantiles 
 Min/Max = Minimum/Maximum 
 GM = Geometric mean  
  LL, UL for GM = Exact 95% Lower and Upper confidence limits 
 Total RSV viral load computed as RSV A Viral load + RSV B Viral load 
 Please note: Except of RSV hospitalization, the subject has been considered only once in one of the category based 
on the maximum severity of event experienced  
* Association to RSV based on central testing only for asymptomatic visit (no local test available) 
  $Confirmed RSV infection and hospitalized for acute medical condition 


CONFIDENTIAL 
204894 (RSV-PED-011) 
Statistical Analysis Plan Final 
27-MAR-2019 
Page 89 of 97 
Template 46 Frequency of multiple respiratory pathogen for qRT-PCR confirmed 
RSV-RTI episodes from vaccination dose 1 up to end of <first, 
second> RSV season for pooled RSV 1D, RSV 2D and 
Comparator/Placebo groups <Exposed Set, Exposed Set with 
negative RSV baseline status> 
 
Group 
N = 
Total  
 N =  
 
 
95% CI 
 
95% CI 
Categories 
n 
% 
LL 
UL 
n 
% 
LL 
UL 
Influenza Virus A/California/7/2009(H1N1) 
 
 
 
 
 
 
 
 
Adenovirus 
 
 
 
 
 
 
 
 
Human Coronavirus OC43 
 
 
 
 
 
 
 
 
Human Coronavirus 229E 
 
 
 
 
 
 
 
 
Human Coronavirus NL63 
 
 
 
 
 
 
 
 
Human Coronavirus HKU1 
 
 
 
 
 
 
 
 
Enterovirus + Rhinovirus 
 
 
 
 
 
 
 
 
Influenza Virus A 
 
 
 
 
 
 
 
 
Influenza Virus B 
 
 
 
 
 
 
 
 
Influenza Virus A (H1N1) 
 
 
 
 
 
 
 
 
Influenza Virus A (H3N2) 
 
 
 
 
 
 
 
 
Human bocavirus 
 
 
 
 
 
 
 
 
Human metapneumovirus 
 
 
 
 
 
 
 
 
Parainfluenza virus 1 
 
 
 
 
 
 
 
 
Parainfluenza virus 2 
 
 
 
 
 
 
 
 
Parainfluenza virus 3 
 
 
 
 
 
 
 
 
Parainfluenza virus 4 
 
 
 
 
 
 
 
 
   Short group label = long group label  
  N = number of qRT-PCR confirmed RSV-RTI infection episodes in each group 
  n = number of episodes in a given category 
  % =100*n/N 
  LL, UL for percentage = Exact 95% Lower and Upper confidence limits 


CONFIDENTIAL 
204894 (RSV-PED-011) 
Statistical Analysis Plan Final 
27-MAR-2019 
Page 90 of 97 
Template 47 Frequency of multiple respiratory pathogen for confirmed LRTI 
episodes from vaccination dose 1 up to end of <first, second> RSV 
season for pooled RSV 1D, RSV 2D and Comparator/Placebo groups 
<Exposed Set, Exposed Set with negative RSV baseline status> 
 
Group 
N = 
Total  
 N =  
 
 
95% CI 
 
95% CI 
Categories 
n 
% 
LL 
UL n 
% 
LL 
UL 
Respiratory syncytial virus 
 
 
 
 
 
 
 
 
Influenza Virus A/California/7/2009(H1N1) 
 
 
 
 
 
 
 
 
Adenovirus 
 
 
 
 
 
 
 
 
Human Coronavirus OC43 
 
 
 
 
 
 
 
 
Human Coronavirus 229E 
 
 
 
 
 
 
 
 
Human Coronavirus NL63 
 
 
 
 
 
 
 
 
Human Coronavirus HKU1 
 
 
 
 
 
 
 
 
Enterovirus + Rhinovirus 
 
 
 
 
 
 
 
 
Influenza Virus A 
 
 
 
 
 
 
 
 
Influenza Virus B 
 
 
 
 
 
 
 
 
Influenza Virus A (H1N1) 
 
 
 
 
 
 
 
 
Influenza Virus A (H3N2) 
 
 
 
 
 
 
 
 
Human bocavirus 
 
 
 
 
 
 
 
 
Human metapneumovirus 
 
 
 
 
 
 
 
 
Parainfluenza virus 1 
 
 
 
 
 
 
 
 
Parainfluenza virus 2 
 
 
 
 
 
 
 
 
Parainfluenza virus 3 
 
 
 
 
 
 
 
 
Parainfluenza virus 4 
 
 
 
 
 
 
 
 
    Short group label = long group label  
  N = number of confirmed LRTI infection episodes in each group 
  n = number of episodes in a given category 
  % =100*n/N 
  LL, UL for percentage = Exact 95% Lower and Upper confidence limits 
Template 48 Listing of RSV-RTI cases identified according to WHO case 
definitions from vaccination dose 1 up to end of second RSV season 
<Exposed Set, Exposed Set with negative RSV baseline status> 
Gro
up 
Su
b. 
No
. 
Sex Age at 
episo
de(mo
nth) 
Count
ry 
Si
te 
Surveill
ance 
type 
Epis
ode 
nb 
Do
se  
Do
se 
nb. 
On
set 
day 
Sp
O2 
Respir
atory 
rate 
Cen
tral 
test 
RSV 
A 
Cen
tral 
test 
RSV 
B 
RSV
-RTI 
RSV
-
LRT
I 
Sev
ere 
RSV
-
LRT
I 
RSV
-
very 
sev
ere 
LRT
I 
Hospita
lization 
RVP 
resul
t 
 
 
 
 
 
 
Yes/
No 
Yes/
No 
Yes/
No 
Yes/
No 
Yes/No 
Short group label = long group label  


CONFIDENTIAL 
204894 (RSV-PED-011) 
Statistical Analysis Plan Final 
27-MAR-2019 
Page 91 of 97 
Template 49 Listing of RSV-RTI requiring hospitalization and type of inpatient 
facility required from vaccination dose 1 up to end of second RSV 
season <Exposed Set, Exposed Set with negative RSV baseline 
status> 
Gro
up 
Sub 
No. 
Sex Age at 
episode
(month) 
Coun
try 
Classific
ation of 
episode 
per 
WHO* 
Total 
days 
hospitali
zed 
No. of 
days of 
monitor
ing or 
nursing 
No. of 
days of 
nasoga
stric or 
intraven
ous 
fluids 
given  
No. of 
days 
oxygen 
administ
ered 
No. of 
days 
respirat
ory 
support 
given  
No. of 
days 
mechan
ical 
ventilati
on 
given 
No. of 
days 
child 
kept in 
paediat
rics 
intensiv
e care 
unit  
RVP 
resu
lt 
Patho
gen 
identif
ied in 
RVP 
 
 
Yes/
No 
    Short group label = long group label  
*subject will be classified per maximum severity experienced 
Template 50 Number and percentage of subjects with highest associated severity 
of RSV infection (based on WHO case definition) from vaccination 
dose 1 up to <first, second> RSV season for pooled RSV 1D, RSV 2D 
and Comparator/Placebo groups <Exposed Set, Exposed Set with 
negative RSV baseline status> 
 
Group 
N = 
Total  
 N =  
 
 
 
95% CI 
 
 
95% CI 
Categories 
n** n % LL UL n** 
n % LL UL 
No Infection 
 
  
 
 
 
  
 
 
RSV asymptomatic (Excluding RSV-RTI, RSV-LRTI, RSV-severe LRTI 
or RSV-very severe LRTI) 
 
  
 
 
 
  
 
 
RSV RTI (Excluding RSV-LRTI, RSV-severe or very severe LRTI) 
 
  
 
 
 
  
 
 
RSV LRTI (Excluding RSV-severe or very severe LRTI) 
 
  
 
 
 
  
 
 
RSV-severe LRTI (Excluding RSV-very severe LRTI) 
 
  
 
 
 
  
 
 
RSV-very severe LRTI 
 
  
 
 
 
  
 
 
Short group label = long group label  
N = number of subjects in each group 
  n** = number of cases in each category 
  n/%= number/percentage of subjects reporting at least once the case 
  95%CI= Exact 95% confidence interval; LL = lower limit, UL = upper limit 
Please note – Single episode can be considered in single category depending on the highest severity symptom 
experienced 


CONFIDENTIAL 
204894 (RSV-PED-011) 
Statistical Analysis Plan Final 
27-MAR-2019 
Page 92 of 97 
Template 51 Number and percentage of subjects reporting the RSV infection of 
maximum severity (based on WHO case definition) by number of 
events experienced between vaccination dose 1 up to end of <first, 
second> RSV season for pooled RSV 1D, RSV 2D and 
Comparator/Placebo groups <Exposed Set, Exposed Set with 
negative RSV baseline status > 
 
Total 
 
 
95% CI 
Characteristics 
Categories N 
n 
% 
LL 
UL 
RSV asymptomatic (Excluding RSV-RTI, RSV-LRTI, RSV-
severe LRTI or RSV-very severe LRTI) 
0 
 
 
 
 
 
 
1 
 
 
 
 
 
 
2 
 
 
 
 
 
RSV-RTI  (Excluding RSV-LRTI, RSV severe or very severe 
LRTI) 
0 
 
 
 
 
 
 
1 
 
 
 
 
 
RSV-LRTI (Excluding RSV severe or very severe LRTI) 
0 
 
 
 
 
 
 
1 
 
 
 
 
 
RSV-Severe LRTI Excluding RSV very severe LRTI) 
0 
 
 
 
 
 
 
1 
 
 
 
 
 
RSV-very severe LRTI 
0 
 
 
 
 
 
 
1 
 
 
 
 
 
   Short group label = long group label  
  N = number of subjects in each group 
  n = number of subjects in a given category 
  % =100*n/N 
  LL, UL for percentage = Exact 95% Lower and Upper confidence limits 
 Please note – Single episode will be considered in single category depending on the maximum severity experienced 


CONFIDENTIAL 
204894 (RSV-PED-011) 
Statistical Analysis Plan Final 
27-MAR-2019 
Page 93 of 97 
Template 52 Number and percentage of subjects with <anti-RSV A antibody titre, 
anti-RSV F concentration> equal to or above <cut-off ><unit>  and 
gm<t,c> for pooled RSV 1D, RSV 2D and Comparator/Placebo> 
groups – by RSV baseline status (<Adapted>PPS of immunogenicity 
at <Day X, end of 1st RSV season>) 
 
 
<Each group> 
Antibody         Time point          Cut-
off 
                                  <RSV+ve> 
                  <RSV-ve> 
 
 
                          95% CI 
 
 
   95% CI 
 
N 
n value
LL UL 
N 
n value LL 
UL 
 
 
 
 
 
 
 
 
 
 
<Antibody 1>  <Time point 1> <Cut-
off 1> 
%>=<cut-off 1> 
<unit> 
xxx xxx xx.x xx.x xx.x 
xxx 
xxx
xx.x 
xx.x  xx.x 
 
 
 
 
 
 
 
 
 
 
GM<T,C> 
xxx
 
xx.x xx.x xx.x 
xxx 
 
xx.x 
xx.x   
xx.x 
Short group label = long group label  
GMT/C = geometric mean antibody titer/concentration 
N = Number of subjects with available results  
n/% = number/percentage of subjects with titer/concentration equal to or above specified value 
95% CI = 95% confidence interval; LL = lower limit, UL = upper limit 
PRE= Pre-vaccination  
D31 = Post-vaccination at Day 31 
D61 = Post-vaccination at Day 61 
RSV1S = End of 1st RSV transmission season 
RSV+ve = Subjects are RSV positive at baseline 
RSV-ve = Subject are RSV negative at baseline 


CONFIDENTIAL 
204894 (RSV-PED-011) 
Statistical Analysis Plan Final 
27-MAR-2019 
Page 94 of 97 
Template 53 Distribution of <RSV-A neutralising antibody titre, RSV-F antibody 
concentration> for pooled RSV 1D, RSV 2D and 
Comparator/Placebo> groups – by RSV baseline 
status(<Adapted>PPS for immunogenicity <at Day X, end of 1st RSV 
season>) 
 
<Each group> 
Antibody         Time point             Cut-off 
 <RSV+ve> 
 
  <RSV-ve>  
 
 
           95% CI 
 
 
   95% CI 
 
N 
n 
value 
LL 
UL 
N 
n 
value LL 
UL 
<Antibody 1>  <Time point 1>  <cut-off 1  xxx 
xxx 
xx.x 
xx.x xx.x 
xxx 
xxx 
xx.x 
xx.x  xx.x 
>=cut-off 2  xxx 
xxx 
xx.x 
xx.x xx.x 
xxx 
xxx 
xx.x 
xx.x  xx.x 
                                                >=cut-off 3 xxx 
xxx 
xx.x 
xx.x xx.x 
xxx 
xxx 
xx.x 
xx.x  xx.x 
                      <Time point 2>  <cut-off 1  xxx 
xxx 
xx.x 
xx.x xx.x 
xxx 
xxx 
xx.x 
xx.x  xx.x 
             
>=cut-off 2  xxx 
xxx 
xx.x 
xx.x xx.x 
xxx 
xxx 
xx.x 
xx.x  xx.x 
                       
>=cut-off 3  xxx 
xxx 
xx.x 
xx.x xx.x 
xxx 
xxx 
xx.x 
xx.x  xx.x 
 
 
 
 
 
Short group label = long group label  
N = number of subjects with available results 
n/% = number/percentage of subjects with <titer, concentration> within the specified criterion 
<95>% CI = <95>% confidence interval; LL = Lower Limit, UL = Upper Limit 
PRE= Pre-vaccination  
D31 = Post-vaccination at Day 31 
D61 = Post-vaccination at Day 61 
RSV1S = End of 1st RSV transmission season 
RSV+ve = Subjects are RSV positive at baseline 
RSV-ve = Subject are RSV negative at baseline 


CONFIDENTIAL 
204894 (RSV-PED-011) 
Statistical Analysis Plan Final 
27-MAR-2019 
Page 95 of 97 
Template 54 Number and percentage of subjects with <anti-RSV A antibody titre, 
anti-RSV F concentration> equal to or above <cut-off ><unit> and 
GMR for pooled RSV 1D, RSV 2D and Comparator/Placebo> groups 
– by RSV baseline status (PPS of immunogenicity at <Day X, End of 
1st RSV season>) 
                                    <Each group> 
Antibody         Time point          
Cut-off 
 
 
   <RSV+ve> 
 
           <RSV-ve>  
 
 
                       95% CI 
 
 
   95% CI 
 
N 
n value LL UL 
N 
n 
value 
LL      UL 
 
 
 
 
 
 
 
 
 
 
<Antibody 1>  <Time point 1> 
<Cut-off 1> 
%>=<cut-off 1> <unit> xxx xxx xx.x xx.x xx.x xxx xxx
xx.x 
xx.x       xx.x 
GMC/T 
xxx  
xx.x xx.x xx.x xxx 
 
xx.x 
xx.x       xx.x 
 
 
 
 
 
 
 
 
 
Visit comparison / 
baseline 
 
 
 
 
 
 
 
 
 
 
GMR 
xxx  
xx.x xx.x xx.x xxx 
 
xx.x 
xx.x       xx.x 
Short group label = long group label  
GMT = geometric mean antibody titer 
N = Number of subjects with available results at the two considered time points  
95% CI = 95% confidence interval; LL = Lower Limit, UL = Upper Limit 
PRE= Pre-vaccination  
D31 = Post-vaccination at Day 31 
D61 = Post-vaccination at Day 61 
RSV1S = End of 1st RSV transmission season 
RSV+ve = Subjects are RSV positive at baseline 
RSV-ve = Subject are RSV negative at baseline 


CONFIDENTIAL 
204894 (RSV-PED-011) 
Statistical Analysis Plan Final 
27-MAR-2019 
Page 96 of 97 
Template 55 Descriptive statistics of <anti-RSV A neutralizing antibody titre, anti-
RSV F antibody concentration>at pre-vaccination, Day <31, 61,> 
<and end of 1st RSV transmission season> for pooled RSV 1D, RSV 
2D and Comparator/Placebo> groups – by RSV baseline status 
(<Adapted> PPS for immunogenicity) 
 
Each Group 
N=XXXX 
 
RSV+ve 
N=XXXX 
RSV-ve 
N=XXXX 
Visit  
Characteristics 
Value 
Value 
PRE 
N with data  
 
 
Mean 
 
 
SD 
 
 
Q1 
 
 
Median  
 
 
Q3 
 
 
95% CI 
(xx.x ; xx.x) 
(xx.x ; xx.x) 
D31 
… 
 
D61 
… 
 
RSV1S 
… 
 
  Short group label = long group label  
  N = total number of subjects 
  N with data = number of subjects with available results  
  Value = value of the considered parameter 
  SD = standard deviation 
  Q1 and Q3 = 1st and 3rd quantiles 
  LL, UL = Exact 95% Lower and Upper confidence limits 
  PRE= Pre-vaccination  
  D31 = Post-vaccination at Day 31 
  D61 = Post-vaccination at Day 61 
  RSV1S = End of 1st RSV transmission season 
  RSV+ve = Subjects are RSV positive at baseline 
  RSV-ve = Subject are RSV negative at baseline 
Template 56 Summary of subjects by unsolicited adverse event category with 
onset within 30 days of first and second vaccination (Exposed Set) 
Any adverse event = at least one adverse event experienced (regardless of the MedDRA Preferred Term) 
N = number of subjects with at least one administered vaccination 
n/% = number/percentage of subjects reporting the adverse event at least once 
95% CI = exact 95% confidence interval; LL = Lower Limit, UL = Upper Limit 
 
<Group 1> 
N=XXXX 
<Group 2>  
N=XXXX 
 
95% CI 
 
95% CI 
 
n 
% 
LL 
UL 
n 
% 
LL 
UL 
 
 
 
 
 
 
 
At least one unsolicited adverse event 
At least one related unsolicited adverse event 
xxx 
xxx 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xxx 
xxx 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
At least one grade 3 unsolicited adverse event 
xxx 
xx.x 
xx.x 
xx.x xxx 
xx.x 
xx.x 
xx.x 
At least one grade 3 related unsolicited adverse 
event 
xxx 
xx.x 
xx.x 
xx.x xxx 
xx.x 
xx.x 
xx.x 
At least one medically attended unsolicited adverse 
event 
xxx 
xx.x 
xx.x 
xx.x xxx 
xx.x 
xx.x 
xx.x 


CONFIDENTIAL 
204894 (RSV-PED-011) 
Statistical Analysis Plan Final 
27-MAR-2019 
Page 97 of 97 
Template 57 Number and percentage of subjects with at least one RSV-RTI 
progressing to RSV-LRTI, RSV-severe LRTI, RSV-very severe LRTI 
and RSV hospitalization from vaccination dose 1 up to end of <first, 
second> RSV season for pooled RSV 1D, RSV 2D and 
Comparator/Placebo groups <ES, Exposed Set with negative RSV 
exposure status> 
 
<each group> 
N =  
Total  
 N =  
 
 
90% CI 
 
90% CI 
Categories 
n 
% 
LL 
UL 
n 
% 
LL 
UL 
RSV-LRTI 
 
 
 
 
 
 
 
 
RSV-severe LRTI 
 
 
 
 
 
 
 
 
RSV-very severe LRTI 
 
 
 
 
 
 
 
 
RSV hospitalization* 
 
 
 
 
 
 
 
 
<Blinded = Blinded group> 
<RSV 1D = Pooled 1D RSV> 
<RSV 2D = Pooled 2D RSV> 
<COMP_PLB = Pooled comparator or placebo> 
* Confirmed RSV infection and hospitalized for acute medical condition 
N = number of subjects with at least one RSV-RTI infection 
n/%= number/percentage of subjects reporting at least once the symptom 
90%CI= Exact 90% confidence interval; LL = lower limit, UL = upper limit 
Please note – Single episode is considered in single category of highest severity based on the symptom experienced