A Prospective, Epidemiological Study to Assess the Disease Burden of RSV Associated, Suspected LRTIs From 0 to 2 Years and Population Attributable Risk Percent of RSV LRTI on the Development of Recurrent Wheeze and Asthma From 0 to 6 Years
Phase: NA
Conditions: Respiratory Syncytial Virus
Sponsor: GlaxoSmithKline

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eTrack study number and 
Abbreviated Title 
Study Protocol 
Sponsor: 
GlaxoSmithKline Biologicals 
Rue de l’Institut 89, 
1330 Rixensart, Belgium 
200150 (EPI-RSV-005 BOD) 
Date of protocol 
Final Version 1: 27 June 2013 
Date of Amendment 
Amendment 1 Final: 27 November 2013 
Amendment 2 Final: 06 July 2016 
Amendment 3 Final: 15 December 2017 
Title 
A prospective, epidemiological study to assess the 
disease burden of RSV associated, suspected LRTIs 
from 0 to 2 years and population attributable risk 
percent of RSV LRTI on the development of recurrent 
wheeze and asthma from 0 to 6 years 
Detailed Title 
A prospective, epidemiological, interventional, multi- 
country based, cohort study to assess the disease 
burden of respiratory syncytial virus (RSV) associated, 
suspected lower respiratory tract infections (LRTIs) in 
newborns, from birth up to 2 years of age and 
population attributable risk percent of RSV LRTI on 
the development of wheeze and asthma from birth up to 
6 years of age. 
 
Co-ordinating author 
, Scientific Writer 
Contributing authors 
• 
, RSV Epidemiologist 
(Amended 15-DEC-2017) 
•
Lead 
Clinical Research & Development 
• 
, Clinical and Epidemiology 
Project Lead 
• 
, Senior Manager, Epidemiology, 
Discovery and Early Development 
• 
, Senior Epidemiology Lead, 
• 
, Project Delivery Lead 
• 
, Project Delivery Lead 
• 
, Project Delivery Lead 
• 
, Study Delivery Lead 
• 
, Study Delivery Lead 
• 
, Study Delivery Manager 

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eTrack study number and 
Abbreviated Title 
200150 (EPI-RSV-005 BOD) 
Date of protocol 
Final Version 1: 27 June 2013 
Date of Amendment 
Amendment 2 Final: 06 July 2016 
Amendment 3 Final: 15 December 2017 
Detailed Title 
A prospective, epidemiological, interventional, multi- 
country based, cohort study to assess the disease 
burden of respiratory syncytial virus (RSV) associated, 
suspected lower respiratory tract infections (LRTIs) in 
newborns, from birth up to 2 years of age and 
population attributable risk percent of RSV LRTI on 
the development of wheeze and asthma from birth up to 
6 years of age. 
 
Contributing authors 
(Amended 15-DEC-2017) 
• 
, Study Delivery Manager, 
Harrison Clinical Research Benelux n.v. a 
SynteractHCR, Inc Company for GlaxoSmithKline 
Biologicals 
• 
, Study Delivery Manager, 
Novellas Healthcare for GlaxoSmithKline 
Biologicals 
• 
, Clinical Safety representative 
• 
, Lead EPI Statistician 
• 
, Study statistician 
• 
, Project Statistician 
• 
, Oversight Data Manager 
• 
, Study Data Manager, TCS for 
GSK Biologicals 
• 
, Study Data Manager, TCS for GSK 
Biologicals 
• 
, Project Data Manager 
• 
, Project Data Manager 
• 
, Study Data Manager 
• 
, Clinical Read-Out Team Leader 
• 
, Global Vaccines Clinical 
Laboratory, Laboratory Study Manager, Business 
and Decision Life Sciences for GlaxoSmithKline 
Biologicals 
• 
, Vaccine Supply Co- 
ordinator 
• 
, Clinical Laboratory Sciences 
Study Manager 

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eTrack study number and 
Abbreviated Title 
200150 (EPI-RSV-005 BOD) 
Date of protocol 
Final Version 1: 27 June 2013 
Date of Amendment 
Amendment 2 Final: 06 July 2016 
Amendment 3 Final: 15 December 2017 
Detailed Title 
A prospective, epidemiological, interventional, multi- 
country based, cohort study to assess the disease 
burden of respiratory syncytial virus (RSV) associated, 
suspected lower respiratory tract infections (LRTIs) in 
newborns, from birth up to 2 years of age and 
population attributable risk percent of RSV LRTI on 
the development of wheeze and asthma from birth up to 
6 years of age. 
 
Contributing authors 
(Amended 15-DEC-2017) 
• 
, Clinical Laboratory Sciences 
Study Manager 
• 
, Senior Manager, Biometrics 
• 
, Director, Epidemiology 
• 
, Director, Clinical Research and 
Translational Science 
GSK Biologicals’ protocol template for observational studies and interventional studies 
without administration of medicinal products as described in a research protocol based on 
the Protocol Document Standard version 14.0 
Copyright 2013-2017 of the GlaxoSmithKline group of companies. All rights reserved. Unauthorized 
copying or use of this information is prohibited. 

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Protocol Amendment 3 Sponsor Signatory Approval 
 
eTrack study number and 
Abbreviated Title 
200150 (EPI-RSV-005 BOD) 
 
Date of Amendment 
Amendment 3 Final: 15 December 2017 
 
Detailed Title 
A prospective, epidemiological, interventional, multi- 
country based, cohort study to assess the disease 
burden of respiratory syncytial virus (RSV) 
associated, suspected lower respiratory tract 
infections (LRTIs) in newborns, from birth up to 2 
years of age and population attributable risk percent 
of RSV LRTI on the development of wheeze and 
asthma from birth up to 6 years of age. 
 
Sponsor signatory (Amended 
15-DEC-2017) 
Amanda Leach 
Clinical and Epidemiology R&D Project Leader 
RSV Program, GSK Biologicals 
 
 
Signature 
 
 
 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
For internal use only 
 
 
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Protocol Amendment 3 Rationale 
 
 
 
Amendment 3 
Amendment number: 
Rationale/background for changes: 
The protocol has been amended to reflect the following changes and provide the 
following clarifications / corrections. 
The Bisgaard and Jackson asthma case definitions were adapted so as to integrate 
asthma treatment advances while preserving the case definitions’ core intent. 
The International Study of Asthma and Allergies in Childhood (ISAAC) asthma case 
definitions, which facilitate a wider range of international results comparisons, were 
added. 
Throughout the document, text has been consolidated and clarified for consistency with 
these changes and to better facilitate uniform, harmonized implementation of the 
protocol. Beginning with Section 2.0, text pertaining to the primary study has been 
shaded in grey to differentiate it from text pertaining to the extension study. Some 
details regarding (a) recruitment into the primary study and (b) primary study visits and 
procedures have been moved from the body of the document to newly created 
Appendices. 
Text that has been added or moved appears in boldface italics. A detailed summary of 
changes (including deletions) appears in Appendix G. 

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Protocol Amendment 3 Investigator Agreement 
 
I agree: 
 
• 
To conduct the study in compliance with this protocol, any mutually agreed future 
protocol amendments or protocol administrative changes, with the terms of the study 
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) or other 
applicable guidelines and all applicable regulatory requirements. 
• 
To ensure that all persons assisting me with the study are adequately informed about 
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 samples (including serum samples) are retained onsite or 
elsewhere without the approval of GSK Biologicals and the express written informed 
consent of the subject’s parent(s)/legally acceptable representative(s) (LARs). 
• 
To perform no other biological assays on the 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, 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 
200150 (EPI-RSV-005 BOD) 
 
Date of Amendment 
Amendment 3 Final: 15 December 2017 
 
Detailed Title 
A prospective, epidemiological, interventional, multi- 
country based, cohort study to assess the disease 
burden of respiratory syncytial virus (RSV) associated, 
suspected lower respiratory tract infections (LRTIs) in 
newborns, from birth up to 2 years of age and 
population attributable risk percent of RSV LRTI on 
the development of wheeze and asthma from birth up 
to 6 years of age. 
 
Investigator name 
 
 
 
Signature 
 
 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
For internal use only 
 
 
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Sponsor Information 
 
Sponsor 
 
GlaxoSmithKline Biologicals 
Rue de l’Institut 89, 
1330 Rixensart, Belgium 
Sponsor Medical Expert for the Study 
Refer to the local study contact information document. 
 
Sponsor Study Monitor 
Refer to the local study contact information document. 
 
Study Contact for Reporting of a Serious Adverse Event (SAE) 
GSK Biologicals Central Back-up Study Contact for Reporting SAEs: refer to 
protocol Section 7.3.2. 

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SYNOPSIS 
Detailed Title 
A prospective, epidemiological, interventional, multi-country 
based, cohort study to assess the disease burden of respiratory 
syncytial virus (RSV) associated, suspected lower respiratory 
tract infections (LRTIs) in newborns, from birth up to 2 years of 
age and population attributable risk percent of RSV LRTI on the 
development of wheeze and asthma from birth up to 6 years of 
age. 
Rationale for the 
study (Amended 15- 
DEC-2017) 
This study aims to assess the incidence and associated 
healthcare utilization of RSV-associated, suspected LRTI 
in a general population of infants from birth up to 2 years 
of age, and also to assess the accuracy of a newly 
developed LRTI case definition and severity scale, 
compared to two existing scales developed by the World 
Health Organization (WHO) [Modjarrad, 2016] and 
Nokes, 2008. 
 
This study will also assess the extent to which RSV LRTI 
in early life (up to 2 years of age) accounts for the total 
burden of wheeze and asthma up to the sixth birthday, 
and test the performance of 3 asthma case definitions – 
those of Bisgaard, Jackson and International Study of 
Asthma and Allergies in Childhood (ISAAC). 
 
The LRTI case definition and severity scale to be used in this 
study has been developed as a consensus model derived from 
existing definitions in the literature, and existing guidelines by 
GlaxoSmithKline (GSK) clinical staff, taking into account the 
advice of a panel of international RSV experts. 
 
Considering asthma case definitions, this study anticipates that 
one (Bisgaard) will be more specific and another (Jackson) 
more sensitive. Although it is likely that the third symptom- 
based case definition (ISAAC) will be the most sensitive and 
least specific of all three definitions, its incorporation will 
facilitate wider international results comparisons. 
 
If, in future, a maternal and/or pediatric RSV vaccine is 
introduced, results of this study may be used to evaluate post- 
vaccination incidence reduction (in RSV LRTI and/or wheeze 
and asthma) and the vaccine’s potential public health impact. 

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Objectives for the 
Primary study 
(Amended 15-DEC- 
2017) 
Co-Primary 
In a cohort of infants followed-up from birth up to 2 years of 
age: 
• 
To determine the total health burden* of RSV-associated 
RTI with a suspicion of involvement of the lower 
respiratory tract. 
 
*Health burden refers to burden of the disease imposed on the 
study population in terms of incidence of the disease and 
associated healthcare utilization in any healthcare setting. 
 
• 
To assess the performance of the LRTI case definition and 
severity scale for RSV associated cases. 
Secondary 
In a cohort of infants followed-up from birth up to 2 years of 
age: 
• 
To determine the total health burden of non-RSV-associated 
RTI with a suspicion of involvement of the lower 
respiratory tract. 
• 
To evaluate the association between RSV-associated LRTI, 
RSV-associated severe LRTI and RSV neutralizing 
antibodies in the baseline cord blood samples collected from 
subjects, at birth. 
• 
To determine the prevalence of RSV infection, at 2, 4, 6, 12, 
18 and 24 months in a randomly selected sub-cohort of 
subjects by assessing antibodies in serum. 
• 
To assess the between calendar year variability in the 
incidence rates of RSV-associated LRTI. 
Tertiary 
In a cohort of infants followed-up from birth up to 2 years of 
age: 
• 
To explore the association of co-infections with the 
incidence of RSV-associated LRTI and/or severe LRTI (as 
determined by the LRTI case definition and severity scale) 
using xTAG™ respiratory viral panel (RVP) fast assay. 
• 
To explore the association of RSV and other respiratory 
viruses with the incidence of LRTI and/or severe LRTI (as 
determined by the LRTI case definition and severity scale) 
using xTAG™ RVP Fast assay. 

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Objectives for the 
extension study 
(Amended 15-DEC- 
2017) 
• 
To explore the association of RSV viral load with the 
incidence of RSV-associated RTI, LRTI and/or severe LRTI 
(as determined by the LRTI case definition and severity 
scale). 
• 
To explore the impact of changes to the symptoms and 
threshold levels of symptoms in the LRTI case definition 
and severity scale. 
• 
To assess the impact of potential RSV risk factors (e.g. 
complications at birth, family history of respiratory disease, 
living environment and household composition, breast 
feeding, passive smoking, day care attendance) on the 
incidence and severity of RSV-associated LRTI. 
• 
To explore the impact of variations in cord-blood sample 
collection variables on the stability of test results. 
• 
To assess the natural decay of maternal antibody levels 
using a single follow-up blood sample collected from a 
randomly selected sub-cohort of subjects at 2, 4, 6, 12, 18 
and 24 months. 
Primary: None 
Secondary: 
In a cohort of infants followed-up from birth up to 6 years of 
age: 
• 
To determine the population attributable risk of recurrent 
wheeze and asthma from birth to sixth birthday associated 
with RSV clinical LRTI in the first two years of life. 
• 
To determine the population attributable risk percent of 
recurrent wheeze and asthma from birth to sixth birthday 
associated with RSV clinical LRTI in the first two years of 
life. 
Tertiary 
 
In a cohort of infants followed-up from birth up to 6 years of 
age: 
• 
To explore the association of RSV clinical LRTI in the first 
two years of life with other potential risk factors for wheeze 
and asthma. 
• 
To explore the performance of asthma case definitions. 

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Study design 
 
(Amended 15-DEC- 
2017) 
• 
Type of design: Prospective, epidemiological, 
interventional, multi-country, cohort study. 
• 
Study population: A cohort of approximately 2400 infants 
will be included in the study at birth and followed-up to 2 
years of age. A maximum of 2400 children will be included 
in the extension and followed to 6 years of age. 
• 
Type of study: self-contained. 
• 
Data collection: Electronic case report form (eCRF). 
• 
Sampling Schedule (Primary study only): 
 
Cord blood samples collected from all the subjects 
participating in the study, at birth. 
 
Nasal swabs collected from subjects with potential 
LRTI symptoms i.e. RTI symptoms with any signs of 
difficulty in breathing. 
 
Serum collected from the first 2000 enrolled subjects, 
excluding those born at a gestational age of less than 
36 weeks. Refer to Synopsis Table 1. 
Synopsis Table 1 
Blood sample collection (Primary Study only) 
 
Time point 
Seroprevalence sub-cohort: Number of allocated subjects* 
2 months 
200 
4 months 
200 
6 months 
250 
12 months 
300 
18 months 
450 
24 months 
600 
Total 
2000 
Note: Only one blood sample will be withdrawn from each subject in this sub-cohort. 
*Number of subjects selected per time point is calculated based on the required number of subjects for adequate 
analysis considering an accumulating drop-out of subjects. Actual numbers might be less due to drop-outs and 
exclusion of subjects with gestational age < 36 weeks. 
 
• 
Duration of the study: Approximately 2 years for each 
subject enrolled in the primary study and an additional 
(approximately) 3 to 4 years for each subject enrolled in 
the extension study. 
 Epoch 1 (Primary Study): Begins at birth (Visit 1) and 
ends at the age of approximately 2 years (Visit or 
contact at 2 years). 
 Epoch 2 (Extension Study): Begins with the first 
contact for the extension study at approximately age 2 
years; ends with the contact at approximately the sixth 
birthday 

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Synopsis Table 2 
Study groups and epochs foreseen in the study 
 
Study Groups 
Number of subjects 
Age (Min/Max) 
Epoch 1 
Epoch 2 
Primary 
Approximately 2400 
0 days - 2 years 
x 
Extension 
Maximum 2400 
Approximately 2 years to 
6 years of age 
x 
 
 
 
 
 
 
 
 
 
 
Discussion of 
study design 
(Amended 15- 
DEC-2017) 
Surveillance Plan: 
• 
Surveillance for RSV Lower Respiratory Tract Infection (RSV 
LRTI), and wheeze during the Primary Study period. 
• 
Surveillance for wheeze and asthma during the extension study 
period. 
Safety Follow-up: 
Study Procedure related Serious Adverse Events (SAEs) to be 
reported throughout the study. 
The multi-country design of both the primary and extension studies 
will provide robust, multinational estimates of the incidence of RSV- 
associated LRTI during the first two years of life and assess the 
amount of wheeze and asthma that may be attributable to those early 
RSV-LRTI infections. 
The Primary study will determine the incidence and associated 
healthcare utilization of RSV-associated LRTIs in infants from birth 
up to the age of 2 years, and assess the performance of a new LRTI 
case definition and severity scale. Using a cohort representing the 
general population of newborn infants, the study is designed to 
identify RSV-associated LRTI cases at any severity, and will not be 
limited to those that require hospitalization and/or other essential 
medical care. This will provide a comprehensive and accurate measure 
of the overall burden of disease, whereas many previous case-control 
or hospital-based cohort studies were limited to the hospitalized cases 
of RSV-associated LRTI. 
The association of other respiratory viruses with RSV-associated 
LRTI and/or severe LRTI, and the impact of potential RSV risk 
factors on the incidence and severity of RSV-associated LRTI will 
also be explored. In order to assess and adjust for other potential 
confounders in the various analyses, data on the subjects’ 
demography and lifestyle factors will be collected at baseline, and 
followed up quarterly for changes, during the regular follow-up 
contacts. 

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Number of 
subjects 
(Amended 15- 
DEC-2017) 
 
 
Endpoints for 
the Primary 
Study 
(Amended 15- 
DEC-2017) 
At 2nd birthday (on completion of primary study or as soon as possible 
thereafter), surveillance for RSV LRTI will be stopped. Consenting, 
eligible subjects from participating study centers will be enrolled in 
the study extension and followed for the occurrence of wheeze and 
asthma. This will permit an assessment of the proportion of wheeze 
and asthma from birth until the sixth birthday that may be attributable 
to RSV LRTI and RSV infection in the first two years of life. It will 
also test the performance of the different asthma case definitions. 
Target enrollment for the primary study will be 2400 subjects to 
obtain approximately 1920 fully evaluable subjects at primary study 
completion. 
Target enrollment for extension period will be maximum 2400 
subjects (all subjects participating in the primary study, meeting all 
inclusion and no exclusion criteria for the extension). 
Co-Primary 
• 
Occurrence of RSV as confirmed by RT-qPCR. 
• 
Occurrence of different types of healthcare utilization*. 
*Healthcare utilization includes primary, secondary and tertiary care 
settings such as self-care with over-the-counter [OTC] drugs, general 
practitioner (GP) visits, emergency room (ER) visits, hospital visits, 
etc. 
• 
Occurrence of LRTI/severe LRTI as classified by the LRTI case 
definition and severity scale. 
• 
Occurrence of LRTI/severe LRTI as classified by the existing 
comparator LRTI case definition by WHO and by Nokes et al. 
Secondary 
• 
Levels of RSV neutralizing antibodies in the cord blood samples 
collected at birth. 
• 
Levels of RSV neutralizing antibodies in the blood samples 
collected at 2, 4, 6, 12, 18 and 24 months. 
• 
Occurrence of LRTI/severe LRTI cases as classified by the LRTI 
case definition and severity scale, in the subgroups of subjects 
recruited from Months 1-6 and 13-18. 

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Endpoints for 
the extension 
study 
 
(Amended 15- 
DEC-2017) 
Tertiary 
• 
Occurrence of RSV and other respiratory viruses as confirmed by 
xTAG™ RVP Fast assay: 
 
RSV 
 
Influenza A, including subtypes H1 and H3 
 
Influenza B 
 
Parainfluenza virus type 1, 2, 3, and 4 
 
Human Metapneumovirus 
 
Rhinovirus 
 
Adenovirus 
 
Bocavirus 
 
Coronavirus - 229E, OC43, NL63, HKU1 
• 
RSV viral load as determined by RSV RT-qPCR. 
• 
Occurrence of any symptom identified in cases of potential LRTI. 
• 
Cord-blood sample collection variables including collection and 
storage times and temperatures. 
• 
Occurrence of potential risk factors including complications at 
birth, family history of respiratory disease, living environment 
and household composition, breastfeeding, passive smoking and 
day-care attendance. 
Primary: None 
Secondary: 
• 
Occurrence of medically attended wheeze 
• 
Occurrence of wheeze or asthma requiring hospital admission. 
• 
Use of prescription medications for wheeze or asthma. 
Tertiary: 
• 
Number of children with asthma (case definition 1) at age 2, 3, 4, 
5, and 6 years of age 
• 
Number of children with asthma (case definition 2) at age 2, 3, 4, 
5 and 6 years of age. 
• 
Number of children with asthma (case definition 3) at 3, 4, 5 
and 6 years of age. 
• 
Number of children with recurrent wheeze. 

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References 
 
(Amended 15- 
DEC-2017) 
Bisgaard H, et al. J Allergy Clin Immunol. 2011; 127(5):1155-64.e2. 
Jackson DJ, et al. Am J Respir Crit Care Med. 2008; 178 (7):667- 
672. 
Modjarrad K, Giersing B, Kaslow DC, Smith PG, Moorthy VS; 
WHO RSV Vaccine Consultation Expert Group. Vaccine. 
2016;34(2):190-7. doi: 10.1016/j.vaccine.2015.05.093. Epub 2015 
Jun 20. 
Nokes DJ, Okiro EA, Ngama M, et al. Clinical Infectious Diseases. 
2008; 46:50–7. 
Pearce N, Aït-Khaled N, Beasley R, et al. Thorax 2007; 62:758-766. 

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TABLE OF CONTENTS 
 
PAGE 
 
SPONSOR INFORMATION ............................................................................................ 8 
SYNOPSIS ...................................................................................................................... 9 
LIST OF ABBREVIATIONS ........................................................................................... 24 
GLOSSARY OF TERMS (AMENDED 15-DEC-2017) .............................................................. 26 
1. 
INTRODUCTION .................................................................................................... 29 
1.1. 
Background (Amended 15-DEC-2017)........................................................ 29 
1.1.1. 
RSV ............................................................................................. 29 
1.1.2. 
Asthma ........................................................................................ 30 
1.2. 
Rationale for the study (Amended 15-DEC-2017) ....................................... 32 
2. 
OBJECTIVES (AMENDED 15-DEC-2017) ............................................................. 32 
2.1. 
Objectives for the Primary Study (first 2 years) ........................................... 32 
2.1.1. 
Co-Primary objectives .................................................................. 32 
2.1.2. 
Secondary objectives ................................................................... 33 
2.1.3. 
Tertiary objectives ........................................................................ 33 
2.2. 
Objectives for the Extension study (Approximately 2 years of age to 
6th birthday) ................................................................................................ 34 
2.2.1. 
Primary objectives ....................................................................... 34 
2.2.2. 
Secondary objectives ................................................................... 34 
2.2.3. 
Tertiary objectives ........................................................................ 34 
3. 
STUDY DESIGN OVERVIEW (AMENDED 15-DEC-2017) ..................................... 34 
3.1. 
Design Summary ........................................................................................ 34 
3.2. 
Discussion of study design .......................................................................... 38 
3.2.1. 
Primary Study .............................................................................. 38 
3.2.2. 
Extension Study ........................................................................... 38 
4. 
CASE DEFINITIONS (AMENDED 15-DEC-2017) .................................................. 38 
4.1. 
Primary Study ............................................................................................. 38 
4.2. 
Extension Study .......................................................................................... 41 
5. 
STUDY POPULATION (AMENDED 15-DEC-2017) ................................................ 43 
5.1. 
Number of subjects/centres ........................................................................ 43 
5.2. 
Sub-cohorts ................................................................................................ 43 
5.3. 
Inclusion criteria for enrolment .................................................................... 43 
5.3.1. 
Primary study (from birth up to the age of 2 years) ....................... 43 
5.3.2. 
Extension Study (from the age of approximately 2 years 
up to the 6th birthday) ................................................................... 44 
5.4. 
Exclusion criteria for enrollment .................................................................. 44 
5.4.1. 
Primary study (from birth up to the age of 2 years) ....................... 44 
5.4.2. 
Extension Study (from the age of approximately 2 years 
up to the 6th birthday) .................................................................. 45 
6. 
CONDUCT OF THE STUDY .................................................................................. 45 

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6.1. 
Regulatory and ethical considerations, including the informed 
consent process .......................................................................................... 45 
6.2. 
Subject identification ................................................................................... 46 
6.3. 
General study aspects ................................................................................ 46 
6.4. 
Outline of study procedures (Amended 15-DEC-2017)................................ 46 
6.4.1. 
Primary Study (birth to 2 years of age) ......................................... 46 
6.4.2. 
Extension Study (approximately 2 years of age up to the 
6th birthday) ................................................................................. 48 
6.5. 
Detailed description of study procedures for the Primary Study 
period (from birth up to 2 years of age) ....................................................... 51 
6.5.1. 
Informed consent ......................................................................... 51 
6.5.2. 
Check inclusion and exclusion criteria applicable before 
birth ............................................................................................. 51 
6.5.3. 
Subject number allocation and registration in SBIR- 
Screening .................................................................................... 51 
6.5.4. 
Collection of expected birth date .................................................. 51 
6.5.5. 
Collection of cord blood sample ................................................... 51 
6.5.6. 
Check inclusion and exclusion criteria applicable after 
birth and re-sign-off the ICF ......................................................... 52 
6.5.7. 
Collection of medical history, demographic and lifestyle 
characteristics .............................................................................. 52 
6.5.8. 
Collection of data on child at birth and delivery ............................ 52 
6.5.9. 
Registration in SBIR-enrollment ................................................... 52 
6.5.10. 
Distribution of diary cards to record symptoms and 
healthcare utilization .................................................................... 53 
6.5.11. 
Blood sampling ............................................................................ 53 
6.5.12. 
Ascertain RTI symptoms and potential difficulty in 
breathing and assessment of need for examination visit 
(off-site/site) ................................................................................. 53 
6.5.13. 
Recording of data on changes to baseline medical and 
demographic data ........................................................................ 54 
6.5.14. 
Examination during (off-site/site) visit and collection of all 
disease symptoms ....................................................................... 54 
6.5.15. 
Data collection on disease course and healthcare 
utilization before and during the examination visit (off- 
site/site) ....................................................................................... 55 
6.5.16. 
Collection of nasal swab samples ................................................ 56 
6.5.17. 
Return Diary card at completion or at case resolution .................. 56 
6.5.18. 
Confirmation and expansion of data on healthcare 
utilization occurring after the examination visit (off- 
site/site) and collection of any further, relevant data on 
disease course with HCPs involved in subject care ...................... 56 
6.5.19. 
Recording of SAEs related to study procedure ............................. 57 
6.5.20. 
Diary card transcription into eCRF ............................................... 57 
6.5.21. 
End of primary study after 2 years follow-up ................................. 57 
6.6. 
Detailed description of Extension Study procedures .................................... 57 
6.6.1. 
Informed consent ......................................................................... 57 
6.6.2. 
Check inclusion and exclusion criteria .......................................... 58 
6.6.3. 
Collection of demographic data .................................................... 58 
6.6.4. 
Potential  risk  factors  for  /  occurrences  of   wheeze   and 
asthma ......................................................................................... 58 
6.6.4.1. 
Data collected from the parent(s)/LAR(s) .................... 58 

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6.6.4.2. 
Investigator review and assessment ........................... 58 
6.6.5. 
Medications for Wheeze or Asthma .............................................. 59 
6.6.6. 
Recording of SAEs related to study procedures ........................... 59 
6.6.7. 
Study conclusion for the extension ............................................... 59 
6.7. 
Biological sample handling and analysis ..................................................... 59 
6.7.1. 
Use of specified study materials................................................... 60 
6.7.2. 
Biological samples ....................................................................... 61 
6.7.3. 
Laboratory assays ....................................................................... 61 
7. 
SAFETY ................................................................................................................. 62 
7.1. 
Safety definitions ........................................................................................ 63 
7.1.1. 
Definition of an SAE ..................................................................... 63 
7.1.2. 
Clinical laboratory parameters and other abnormal 
assessments qualifying as SAEs ................................................. 63 
7.2. 
Detecting and recording SAEs .................................................................... 64 
7.2.1. 
Time periods for detecting and recording SAEs ........................... 64 
7.2.2. 
Evaluation of SAEs ...................................................................... 64 
7.2.2.1. 
Active questioning to detect SAEs .............................. 64 
7.2.2.2. 
Assessment of causality ............................................. 65 
7.2.2.3. 
Assessment of outcomes ............................................ 65 
7.3. 
Reporting of SAEs ...................................................................................... 65 
7.3.1. 
Prompt reporting of SAEs related to study participation ............... 66 
7.3.2. 
Contact information for reporting SAEs to GSK ..................................... 66 
7.3.3. 
Completion and transmission of SAE reports related to 
study participation to GSK ............................................................ 66 
7.3.3.1. 
Back-up system in case the electronic SAE 
reporting system does not work .................................. 66 
7.3.4. 
Updating of SAE after freezing of the subject’s eCRF .................. 67 
7.3.5. 
Regulatory reporting requirements for SAEs ................................ 67 
7.4. 
Follow-up of SAEs ...................................................................................... 67 
7.4.1. 
Follow-up of SAEs ....................................................................... 67 
7.4.1.1. 
Follow-up during the study .......................................... 67 
7.4.1.2. 
Follow-up after the subject is discharged from 
the study ..................................................................... 67 
8. 
SUBJECT COMPLETION AND WITHDRAWAL (AMENDED 15-DEC-2017) .......... 68 
8.1. 
Subject completion ..................................................................................... 68 
8.2. 
Subject withdrawal ...................................................................................... 68 
9. 
STATISTICAL METHODS (AMENDED 15-DEC-2017) .......................................... 69 
9.1. 
Endpoints for the Primary Study (first 2 years) ............................................ 69 
9.1.1. 
Co-Primary endpoints .................................................................. 69 
9.1.2. 
Secondary endpoints ................................................................... 69 
9.1.3. 
Tertiary endpoints ........................................................................ 69 
9.2. 
Endpoints for the Extension Study .............................................................. 70 
9.2.1. 
Primary: none .............................................................................. 70 
9.2.2. 
Secondary: .................................................................................. 70 
9.2.3. 
Tertiary ........................................................................................ 70 
9.3. 
Determination of sample size ...................................................................... 71 
9.4. 
Study cohorts/ data sets to be analysed ...................................................... 74 
9.4.1. 
Screened cohort .......................................................................... 74 
9.4.2. 
Analysis Cohorts for the Primary study (first 2 years) ................... 74 

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9.4.2.1. 
Total enrolled cohort at Year 2 .................................... 74 
9.4.2.2. 
Per Protocol Set (PPS) cohort at Year 2 ..................... 74 
9.4.2.3. 
Per Protocol Set (PPS) sub-cohort at Year 2 .............. 74 
9.4.3. 
Analysis Cohorts for the Extension Study .................................... 74 
9.4.3.1. 
Total enrolled cohort for extension .............................. 74 
9.4.3.2. 
PPS cohort for extension ............................................ 74 
9.5. 
Derived and transformed data ..................................................................... 75 
9.5.1. 
General considerations for statistical analyses ............................. 75 
9.6. 
Analysis of demographics ........................................................................... 76 
9.7. 
Analysis of Objectives for the Primary Study (birth to 2 years of 
age): ........................................................................................................... 76 
9.7.1. 
Co-primary objectives .................................................................. 76 
9.7.2. 
Secondary objectives ................................................................... 77 
9.7.3. 
Tertiary Objectives ....................................................................... 78 
9.8. 
Analysis of Objectives for the Extension study ............................................ 80 
9.8.1. 
Primary objectives: none .............................................................. 80 
9.8.2. 
Secondary objectives ................................................................... 80 
9.8.2.1. 
To determine the population attributable risk of 
wheeze and asthma from birth to sixth birthday 
due to RSV clinical LRTI in the first two years 
of life........................................................................... 80 
9.8.2.2. 
To determine the population attributable risk 
percent of wheeze and asthma from birth until 
sixth birthday due to RSV clinical LRTI in the 
first two years of life. ................................................... 81 
9.8.3. 
Tertiary objectives ........................................................................ 81 
9.8.3.1. 
To explore the association of RSV clinical LRTI 
in the first two years of life and other potential 
risk factors for wheeze and asthma ............................ 81 
9.8.3.2. 
To explore the performance of asthma case 
definitions. .................................................................. 82 
9.9. 
Interpretation of analyses ............................................................................ 82 
9.10. Conduct of analyses ................................................................................... 82 
9.11. Sequence of analyses ................................................................................. 82 
9.11.1. 
Statistical considerations for the primary study ............................ 83 
9.11.2. 
Statistical considerations for the extension study ......................... 83 
10. ADMINISTRATIVE MATTERS ............................................................................... 83 
10.1. Remote Data Entry instructions................................................................... 84 
10.2. Study monitoring by GSK Biologicals .......................................................... 84 
10.3. Record retention ......................................................................................... 85 
10.4. Quality assurance ....................................................................................... 85 
10.5. Posting of information on publicly available registers and publication 
policy .......................................................................................................... 86 
10.6. Provision of study results to investigators ................................................... 86 
11. COUNTRY SPECIFIC REQUIREMENTS ............................................................... 86 
12. REFERENCES (AMENDED 15-DEC-2017) ........................................................... 87 

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LIST OF TABLES 
 
PAGE 
 
Table 1 
Blood sample collection .......................................................................... 37 
Table 2 
Study groups and epochs foreseen in the study ..................................... 37 
Table 3 
Normal ranges for RR and Sa02 ............................................................ 39 
Table 4 
LRTI case definition and severity scale ................................................... 40 
Table 5 
Case  definitions   of   wheeze   and   asthma   (Amended   15-DEC- 
2017) ...................................................................................................... 42 
Table 6 
Sub-cohort ............................................................................................. 43 
Table 7 
List of study procedures for the primary study (from birth up to 
the age of 2 years) ................................................................................. 47 
Table 8 
List of extension study procedures (from the age of 
approximately 2 years up to  the  6th  birthday)  (Amended  15-DEC- 
2017) ...................................................................................................... 49 
Table 9 
Medication(s) for wheeze or asthma (Amended 15-Dec-2017) ............... 59 
Table 10 
Antibody determination ........................................................................... 61 
Table 11 
Timeframes for submitting SAEs related to study participation ............... 66 
Table 12 
RSV-associated LRTI hospitalization rates in industrialized 
countries (per 1000 children-years) ........................................................ 71 
Table 13 
Precision for expected RSV-associated LRTI hospitalization rate 
during the first year of life (per 1000 children-years) ............................... 72 
Table 14 
Design effect calculated from 1000 simulations and for different 
hypothesis .............................................................................................. 73 
Table 15 
Comparison of two classifications for severe/Non-severe LRTI .............. 77 
Table 16 
GSK Biologicals’ laboratories ................................................................. 91 
Table 17 
Outsourced laboratory ............................................................................ 91 

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LIST OF FIGURES 
 
PAGE 
 
Figure 1 
Study design diagram for the primary study (from birth up to the 
age of 2 years for detection of RSV LRTI) .............................................. 35 
Figure 2 
Study design diagram for the extension (from the age of 
approximately 2 years up to the 6th birthday) for the detection of 
episodes of wheeze and diagnosis of asthma ........................................ 36 
Figure 3 
RSV seasons in Northern and Southern Hemispheres ........................... 93 
Figure 4 
Decision tree for active and passive follow-up contact for the 
primary study ......................................................................................... 98 

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LIST OF APPENDICES 
 
PAGE 
 
APPENDIX A LABORATORY ASSAYS ........................................................................ 90 
APPENDIX B CLINICAL LABORATORIES ................................................................... 91 
APPENDIX C OVERVIEW OF RECRUITMENT PLAN (Primary Study) 
(Amended 15-DEC-2017) ....................................................................... 92 
APPENDIX D Additional Information Regarding Primary Study Visits (Amended 
15-DEC-2017) ........................................................................................ 94 
APPENDIX E Additional Information Regarding LRTI Surveillance, including 
Active Surveillance Contact Schedule (Primary Study) (Amended 
15-DEC-2017) ........................................................................................ 96 
APPENDIX F AMENDMENTS AND ADMINISTRATIVE CHANGES TO THE 
PROTOCOL ......................................................................................... 102 

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LIST OF ABBREVIATIONS 
 
ATP: 
According-To-Protocol 
CI: 
Confidence Interval 
CP: 
Concept Protocol 
DE: 
Design Effect 
eCRF: 
electronic Case Report Form 
ER: 
Emergency Room 
FN: 
False Negative 
FP: 
False Positive 
GCP: 
Good Clinical Practice 
GP: 
General Practitioner 
GSK: 
GlaxoSmithKline 
HIV: 
Human Immunodeficiency Virus 
ICF: 
Informed Consent Form 
ICH: 
International Conference on Harmonization 
IEC: 
Independent Ethics Committee 
ILI: 
Influenza-like Illness 
IRB: 
Institutional Review Board 
LAR: 
Legally Acceptable Representative 
LRTI: 
Lower Respiratory Tract Infection 
mL: 
Milliliter 
NH: 
Northern Hemisphere 
NPV: 
Negative Predictive Value 
OTC: 
Over-The-Counter 
P: 
Percentile 
PCR: 
Polymerase Chain Reaction 
PPV: 
Positive Predictive Value 
RDE: 
Remote Data Entry 
ROC: 
Receiver Operating Characteristics 
RSV: 
Respiratory Syncytial Virus 
RR: 
Respiratory Rate 
RTI: 
Respiratory Tract Infection 
RT-qPCR: 
Reverse transcription-quantitative real time polymerase chain reaction 

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RVP: 
Respiratory Viral Panel 
SAP 
Statistical Analysis Plan 
SAE: 
Serious Adverse Events 
SDV: 
Source Document Verification 
SaO2: 
Blood Oxygen Saturation 
SBIR: 
Randomization System on Internet 
SH: 
Southern Hemisphere 
SPM: 
Study Procedure Manual 
TN: 
True Positive 
TP: 
True Negative 
URTI: 
Upper Respiratory Tract Infection 
US: 
United States 
WHO: 
World Health Organization 

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GLOSSARY OF TERMS (Amended 15-DEC-2017) 
 
According-To-Protocol 
(ATP) cohort: 
This cohort will include all cases enrolled in the study 
who meet the criteria defined in the protocol for the 
considered analysis. 
Active Surveillance: 
A contact with the subject’s parent/LAR, initiated by the 
study physician or by a member of the study staff for the 
purpose of identifying an event of interest. 
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. 
Coded: 
Data from which personal identifier information has been 
removed and replaced by a key. These data are not 
anonymised since a decode listing exists and it is 
therefore possible to identify the patient under certain 
circumstances by an authorised or legally appointed third 
party data custodian, or by the original holder of the data. 
Cohort study: 
A form of epidemiological study where subjects in a 
study population are classified according to their 
exposure status/disease and followed over time 
(prospective/ retrospective) to ascertain the outcome(s). 
Commitment: 
Agreement made with Regulatory Authorities as specific 
condition of regulatory approval and authorization, either 
made at the time of product approval or during the 
lifecycle of the approved product. 
Eligible: 
Qualified for enrollment into the study based upon strict 
adherence to inclusion/exclusion criteria. 
Epidemiological study: 
An observational or interventional study without 
administration of medicinal product(s) as described in a 
research protocol. 
Epoch: 
An epoch is a self-contained set of consecutive time 
points or a single time point from a single protocol. Self- 
contained means that data collected for all subjects at all 
time points within that epoch allows to draw a complete 
conclusion. Typical examples of epochs are retrospective 
data collection and prospective data collection, etc. 

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eTrack: 
GSK Biologicals’ tracking tool for clinical/ 
epidemiological trials. 
Exercise 
Any moderate or vigorous physical activity performed by 
the child 
Evaluable: 
Meeting all eligibility criteria, complying with the 
procedures defined in the protocol, and, therefore, 
included in the According-To-Protocol (ATP) analysis 
(see Section 9.4 for details on criteria for evaluability). 
Health Burden: 
Burden of the disease imposed on the study population in 
terms of incidence of the disease and associated 
healthcare utilization in any healthcare setting. 
Healthcare settings 
(Healthcare Utilization): 
 
 
Interventional Human 
Subject Research: 
Primary, secondary and tertiary care settings such as self- 
care with over-the-counter [OTC] drugs, general 
practitioner (GP) visits, emergency room (ER) visits, 
hospital visits, etc. 
Studies in which participants are administered medical 
care, medicinal products and/or medical/scientific 
procedures as described in a research protocol. 
Passive Surveillance: 
A contact initiated by the subject’s parent/LAR, 
notifying the study physician / site staff of the 
occurrence of an event of interest. 
Population Attributable 
Risk: 
 
 
 
Population Attributable 
Risk Percent: 
Population attributable risk is the portion of the incidence 
of a disease in the population (exposed and unexposed) 
that is due to exposure. It is the incidence of a disease in 
the population that would be eliminated if exposure were 
eliminated. 
Population attributable risk percent is the percent of the 
incidence of a disease in the population (exposed and 
unexposed) that is due to exposure. It is the percent of the 
incidence of a disease in the population that would be 
eliminated if exposure were eliminated. 
Prospective study: 
A study in which the subjects/cases are identified and 
then followed forward in time in order to address one or 
more study objectives. 
Research protocol: 
A document that describes the objective(s), design, 
methodology, statistical considerations, and organization 
of a study. The protocol usually also gives the 
background and rationale for the study, but these could be 
provided in other protocol referenced documents. 
Self-contained study: 
Study with objectives not linked to the data of another 
study. 

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Seroprevalence: 
The total number of cases within the study population at a 
specific time that test positive for the disease based on 
blood serum specimens. 
Site Monitor: 
An individual assigned by the Sponsor who is responsible 
for assuring the proper conduct of epidemiological studies 
at one or more investigational sites. 
Study population: 
Sample of population of interest. 
 
Sub-cohort: 
A subgroup of the total cohort of study subjects for whom 
the planned study procedures are different from those 
planned for the other study subjects. 
Subject: 
Term used throughout the protocol to denote an 
individual who has been contacted in order to participate 
or participates in the epidemiological study or a person 
about whom some medical information has been recorded 
in a database. 
Subject number: 
A unique number identifying a subject, assigned to each 
subject consenting to participate in the study. 
Surveillance: 
The ongoing systematic collection, collation, analysis, 
and interpretation of descriptive epidemiological health 
data on a specific disease. Surveillance can monitor 
incidence and/or prevalence, and/or inform about when 
and where health problems are occurring and who is 
affected. 
xTAG: 
xTAG is an universal tag system that allows easy 
optimization, development and expansion of molecular 
diagnostic assays 

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1. 
INTRODUCTION 
 
1.1. 
Background (Amended 15-DEC-2017) 
 
1.1.1. 
RSV 
 
Respiratory syncytial virus (RSV) is an important cause of respiratory diseases. RSV is a 
highly contagious seasonal pathogen that is transmitted from person-to-person via direct 
or close contact with contaminated secretions, including respiratory droplets or fomites 
[Canducci, 2008]. RSV belongs to the family Paramyxoviridae and is one of the only two 
human pneumoviruses that have been currently recognized (the other being 
metapneumovirus). There are two major genetic RSV subtypes, A and B. These subtypes 
co-circulate, and the predominance of one over the other varies by year and geographic 
location [Graham, 2011]. 
 
RSV is found across the globe with incidences varying between countries and regions 
and even within a country or a region over multiple seasons. In areas of the inner tropics 
with perennial high rainfall, RSV seasonality is less clear-cut. Countries close to the 
equator have a distinct pattern of RSV transmission, with most cases appearing in one 
half of the year, but not in the other. But neither temperature nor rainfall appears to be the 
main determinant of the timing of these outbreaks [Weber, 1998]. Seasonal epidemics of 
RSV occur most frequently in the cold season in regions with temperate and 
Mediterranean climates and in the rainy season in tropical countries with seasonal 
rainfall. Roughly the RSV season runs from October to March in the temperate areas of 
the Northern Hemisphere (NH) and from May to September in the Southern Hemisphere 
(SH). But the exact timing of RSV circulation varies by geographic location and also by 
year [Mullins, 2003; Weber, 1998; Law, 2002]. 
 
RSV infections result in high rates of hospitalization in infants, a large disease burden 
among infants and young children, and excess mortality in the elderly [Graham, 2011]. 
RSV infects 50-70% of infants during the first year of life and essentially all children will 
have had an RSV infection by their third birthday [Hall, 2004]. In the early months of 
life, infants may have protection against RSV through the maternal antibodies transferred 
to them during pregnancy. High titers of maternally derived RSV-neutralizing antibodies 
[Roca, 2002] have been shown to be inversely associated with the incidence of RSV 
associated-acute LRTI during the first 6 months of life, whereas incomplete transfer of 
maternally derived RSV-neutralizing antibodies has been implicated in the increased risk 
of severe RSV infection in preterm infants [de Sierra, 1993]. 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]. 
 
Globally, it is estimated that in children below 5 years of age, RSV causes >30 million 
acute lower respiratory infections (LRTI) each year resulting in more than 3 million 
hospitalizations, making it the most common cause of hospitalization for LRTI or all 
cause from any single pathogen in this age group [Nair, 2010]. RSV is the most common 
cause of bronchiolitis and pneumonia in children less than 1 year of age worldwide, with 

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highest risk in children less than 6 months of age [Nair, 2010; Langley, 2011]. A United 
States (US) based study conducted in children less than 18 years of age, found RSV in 
58% of the hospitalizations for LRTI compared to parainfluenza virus 1-3 in 17%, 
influenza A/B in 21%, adenovirus in 2% and rhinovirus in 2% [Henrickson, 2004]. On a 
community level, a US day-care based study assessing the causes of respiratory tract 
infection (RTI) in children less than 1 year of age found that RSV infection was present 
in 11% of the cases, compared to rhinovirus in 35%, adenovirus in 22%, human 
coronavirus in 15%, parainfluenzavirus in 12%, human meta-pneumovirus in 4% and 
influenza A in 2% [Fairchok, 2010]. This difference between community and hospital 
proportions of RSV related infections indicates the propensity of RSV to cause more 
serious cases of RTI, mainly LRTI, compared to other viruses. 
 
Viral co-infections with RSV are also common. Evidence about the severity of co- 
infections compared to single viral infections is conflicting, as the severity of co-infection 
may depend on the pathogens involved [Fairchok, 2010]. In a study conducted on dual 
respiratory infections it was concluded that dual viral RTIs had higher hospitalization 
rates than single infections [Drews, 1997]. Some examples of viruses which may exist as 
co-pathogens with RSV include, human Metapneumoviruses, human Bocaviruses and 
human Coronaviruses [Canducci, 2008]. 
 
Currently available estimates of RSV disease burden are most often centred on healthcare 
usage, particularly RSV-associated hospitalizations. Also, there is no widely supported 
guideline from regulatory authorities or transnational expert bodies on a case definition of 
RSV-associated LRTI in children. As a result, prospective, cohort-based epidemiological 
studies using a consistent case definition for RSV-associated LRTI are rare and there is 
no obvious case definition to be used uniformly as the outcome measure in clinical trials. 
Although the hospitalized cases represent the most severe cases of RSV disease, variation 
between medical practice policies, quality of the healthcare system and access to 
adequate healthcare can all influence whether a subject with RSV-associated LRTI is 
hospitalized or not. Therefore, hospitalization is not an ideal determinant of the disease 
severity and a more objective scoring system for the disease severity is needed. Several 
studies have attempted to develop a severity score or a model, but this has not lead to a 
validated model, accepted as the universal gold standard [Nokes, 2008]. 
 
The World Health Organization (WHO) has recently updated its RSV-associated LRTI 
case definition [Modjarrad, 2016]. The latter includes clinical features considered to be 
objective, easily standardized, generalizable across settings, and generally accepted 
markers of severe or very severe RSV disease. 
 
1.1.2. 
Asthma 
 
Infant respiratory viral infection and childhood asthma are the most common acute 
and chronic diseases of childhood, respectively. Common clinical features and links 
between these diseases have long been recognized, with early-life RSV LRTIs being 
strongly associated with increased asthma risk. 

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Although asthma is probably a heterogeneous disease or syndrome, three factors 
and/or events consistently emerge for their ability to significantly influence asthma 
inception in the first decade of life: immune response aberrations, which appear to be 
defined best by the concept of cytokine dysregulation; LRTIs, in particular RSV; and 
some form of gene–environment interaction that needs to occur at a critical time- 
period in the development of the immune system or the lung [Lemanske, 2002]. 
 
Population-level contribution of RSV LRTIs is best demonstrated by the population- 
attributable risk for asthma after these early-life LRTIs. Among infants, the cumulative 
incidence of LRTI is approximately 18 to 32% in the first year of life and 
approximately 9 to 17% in the second year of life. Among infants with LRTI, the 
prevalence of RSV can be as high as 80%, especially in the first 3 months of life. Thus, 
the phenotype of asthma after infant RSV LRTI accounts for up to 31% of early 
childhood asthma, with a population-attributable risk estimated at about 13% in 
several diverse populations [Feldman, 2015]. 
 
Numerous longitudinal studies have demonstrated this first important line of evidence 
that RSV LRTIs precede the development of asthma. Several birth cohort studies also 
demonstrate a dose–response relationship between infant respiratory viral infection 
severity and asthma risk, with increasing infant infection severity associated with 
greater childhood asthma risk and asthma severity [Feldman, 2015]. 
 
The Childhood Origins of Asthma (COAST) study was developed to determine and 
define the importance of these three factors on asthma pathogenesis and to test 
different asthma case classifications [Lemanske, 2002; Lemanske, 2005; Bisgaard, 
2011; Jackson, 2008; Jackson, 2012; Bønnelykke, 2015]. These studies have used 
similar albeit slightly different case definitions on asthma diagnosis. The International 
Study of Asthma and Allergies in Childhood (ISAAC) takes a slightly different parent- 
based questionnaire approach toward assessing asthma prevalence in young children. 
 
These definitions are widely used in epidemiological literature of asthma etiology in 
children. The Bisgaard definition [Bisgaard, 2011] has multiple criteria that are 
assessed by the physician from records. Therefore the advantage of this definition is 
that the same objective criteria are applied to ascertain each case of asthma. However, 
its application may be challenging in some settings if routine medical records do not 
fully capture the necessary information in source. The Jackson definition [Jackson, 
2008] includes the criteria of health care provider (HCP) diagnosis of asthma and 
prescription of 2 agonists. This definition is therefore influenced by any differences in 
local practice of asthma diagnosis and management of wheeze. However, its advantage 
is that it captures the reality of diagnosis and treatment. ISAAC uses simple, robust, 
primarily symptom-based questions that are administered solely to the parents. 
ISAAC’s strength is that its definitions are not affected by differences in local asthma 
treatment practices; however, its lack of clinical case confirmation may decrease its 
precision. The ISAAC questionnaire has been used to assess pediatric asthma 
prevalence in at least 42 countries across the globe [Pearce , 2007]. 

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1.2. 
Rationale for the study (Amended 15-DEC-2017) 
This study aims to assess the incidence and associated healthcare utilization of RSV- 
associated, suspected LRTI in a general population of infants from birth up to 2 years of 
age, and also to assess the accuracy of a newly developed LRTI case definition and 
severity scale, compared to two existing scales developed by the World Health 
Organization (WHO) [Modjarrad, 2016] and [Nokes, 2008]. 
This study will also assess the extent to which RSV LRTI in early life (up to 2 years of 
age) accounts for the total burden of wheeze and asthma up to the sixth birthday, and 
test the performance of 3 asthma case definitions – those of Bisgaard, Jackson, and 
ISAAC. 
The LRTI case definition and severity scale to be used in this study has been developed 
as a consensus model derived from existing definitions in the literature, and existing 
guidelines by GlaxoSmithKline (GSK) clinical staff, taking into account the advice of a 
panel of international RSV experts. 
Considering asthma case definitions, this study anticipates that Bisgaard will be more 
specific and Jackson more sensitive. Although it is likely that the ISAAC symptom- 
based case definitions will be the most sensitive and least specific of all three 
definitions [Yang , 2011], its incorporation will facilitate wider international results 
comparisons. Hence, this study will assess the performance of the different case 
definitions since this will help planning for phase 3 clinical trials of RSV vaccines. 
If, in future, a maternal and/or pediatric RSV vaccine is introduced, results of this 
study may be used to evaluate post-vaccination incidence reduction (in RSV LRTI 
and/or wheeze and asthma) and the vaccine’s potential public health impact. 
 
2. 
OBJECTIVES (AMENDED 15-DEC-2017) 
 
In a cohort of infants followed-up from birth up to 2 years of age: 
• 
To determine the total health burden* of RSV-associated RTI with a suspicion of 
involvement of the lower respiratory tract.. 
*Health burden refers to burden of the disease imposed on the study population in terms 
of incidence of the disease and associated healthcare utilization in any healthcare 
setting. 
• 
To assess the performance of the LRTI case definition and severity scale for RSV 
associated cases. 
Refer to Section 4 for the list of clinical parameters included under each LRTI case 
definition under LRTI case definitions for data analysis. 
Co-Primary objectives 
2.1.1. 
Objectives for the Primary Study (first 2 years) 
2.1. 

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Refer to Section 9.1.1 for the definition of the co-primary endpoints. 
 
2.1.2. 
Secondary objectives 
 
In a cohort of infants followed-up from birth up to 2 years of age; 
 
• 
To determine the total health burden of non-RSV-associated RTI with a suspicion of 
involvement of the lower respiratory tract. 
• 
To evaluate the association between RSV-associated LRTI, RSV-associated severe 
LRTI and RSV neutralizing antibodies in the baseline cord blood samples collected 
from subjects, at birth. 
• 
To determine the prevalence of RSV infection, at 2, 4, 6, 12, 18 and 24 months in a 
randomly selected sub-cohort of subjects by assessing antibodies in serum. 
• 
To assess the between calendar year variability in the incidence rates of RSV- 
associated LRTI. 
Refer to Section 9.1.2 for the definition of the secondary endpoints for the primary study. 
 
2.1.3. 
Tertiary objectives 
 
In a cohort of infants followed-up from birth up to 2 years of age: 
 
• 
To explore the association of co-infections with the incidence of RSV-associated 
LRTI and/or severe LRTI (as determined by the LRTI case definition and severity 
scale) using xTAG™ respiratory viral panel (RVP) fast assay. 
• 
To explore the association of RSV and other respiratory viruses with the incidence of 
LRTI and/or severe LRTI (as determined by the LRTI case definition and severity 
scale) using xTAG™ RVP Fast assay. 
• 
To explore the association of RSV viral load with the incidence of RSV-associated 
RTI, LRTI and/or severe LRTI (as determined by the LRTI case definition and 
severity scale). 
• 
To explore the impact of changes to the symptoms and threshold levels of symptoms 
in the LRTI case definition and severity scale. 
• 
To assess the impact of potential RSV risk factors (e.g. complications at birth, family 
history of respiratory disease, living environment and household composition, breast 
feeding, passive smoking, day care attendance) on the incidence and severity of 
RSV-associated LRTI. 
• 
To explore the impact of variations in cord-blood sample collection variables on the 
stability of test results. 
• 
To assess the natural decay of maternal antibody levels using a single follow-up 
blood sample collected from a randomly selected sub-cohort of subjects at 2, 4, 6, 
12, 18 and 24 months. 
Refer to Section 9.1.3 for the definition of the tertiary endpoints for the primary study. 

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2.2. 
Objectives for the Extension study (Approximately 2 years 
of age to 6th birthday) 
 
2.2.1. 
Primary objectives 
 
None 
 
2.2.2. 
Secondary objectives 
 
In a cohort of infants followed-up from birth up to 6 years of age: 
• 
To determine the population attributable risk of recurrent wheeze and asthma from 
birth to sixth birthday associated with RSV clinical LRTI in the first two years of 
life. 
• 
To determine the population attributable risk percent of recurrent wheeze and asthma 
from birth to sixth birthday associated with RSV clinical LRTI in the first two years 
of life. 
Refer to Section 9.2.2 for the definition of the secondary endpoints for the extension 
study. 
 
2.2.3. 
Tertiary objectives 
 
In a cohort of infants followed-up from birth up to 6 years of age: 
 
• 
To explore the association of RSV clinical LRTI in the first two years of life with 
other potential risk factors for wheeze and asthma. 
• 
To explore the performance of asthma case definitions. 
Refer to Section 9.2.3 for the definition of the tertiary endpoints for the extension 
study. 
 
3. 
STUDY DESIGN OVERVIEW (AMENDED 15-DEC-2017) 
 
3.1. 
Design Summary 
In the primary study, subjects were to be followed-up from birth up to the age of 2 years 
for RSV LRTI. Episodes of wheeze and diagnoses of asthma were also documented. 
Refer to Figure 1. 
 
In order to determine the population attributable risk and population attributable risk 
percent of wheeze and asthma from birth to sixth birthday due to RSV clinical LRTI in 
the first two years of life, and to explore the association of RSV clinical LRTI in the first 
two years of life with other potential risk factors for wheeze and asthma, the study will be 
extended and subjects will be followed-up from the age of 2 years up to 6 years to detect 
episodes of wheeze and diagnoses of asthma.* Refer to Figure 2. 

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*Note: The procedures related to primary study surveillance of RSV LRTI will not be 
extended into the extension period. The extension period will survey for occurrence of 
wheeze and asthma. 
 
Figure 1 
Study design diagram for the primary study (from birth up to the age 
of 2 years for detection of RSV LRTI) 
 
V = Visit; D = Day; M = Month 
ICF = Informed Consent Form; CBS = Cord Blood Sample; NS = Nasal Swab; DC = Diary Card; BS = Blood Sample 
1 An examination visit (off-site/site) is to occur for new or worsened, potential LRTI case as identified during active or 
passive follow-up contact. The examination visit needs to occur as soon as possible and no later than 72 hours 
after the potential LRTI was identified during a follow-up contact. Each subject may have none, single or multiple 
examination visits over the course of the study. 
2 A sub-cohort of subjects will be randomized for a single blood draw to occur at one of the six possible time points and 
will have a Visit 3 corresponding to this time point (if still participating at that time); either V3a at 2, V3b at 4, V3c 
at 6, V3d at 12, V3e at 18 or V3f at 24 months. 
* All follow up procedures associated with V2 (e.g. ICF) must be performed within 5 working days after birth. 

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Figure 2 
Study design diagram for the extension (from the age of 
approximately 2 years up to the 6th birthday) for the detection of 
episodes of wheeze and diagnosis of asthma 
 
Annual asthma assessments 
 
 
Quarterly 
surveillance contacts 
 
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the outline of study procedures (Section 6.3), are essential and required for 
study conduct. 
 
• 
Type of design: Prospective, epidemiological, interventional, multi-country, cohort 
study. 
• 
Study population: A cohort of approximately 2400 infants will be included in the 
study at birth and followed-up up to 2 years of age. A maximum of 2400 children 
will be included in the extension and followed up to 6 years of age. 
• 
Type of study: Self-contained. 
• 
Data collection: Electronic case report form (eCRF). 
 
Enrolment visit 
for extension 
(approx. 2 
years of age) 
3 
years 
4 
years 
5 
years 
6 
years 
ICF 
re-consent 
• 
Biological samples (Primary Study only): 
 Cord Blood collected from all participating subjects, at birth. 
 Nasal swabs collected from subjects with potential LRTI. 
 Serum collected from a sub-cohort of subjects, excluding those born at a 
gestational age of less than 36 weeks. Sampling time points for this sub-cohort 
will be randomly allocated as specified in Table 1. 

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Time point 
 
Seroprevalence sub-cohort 
Number of allocated subjects* 
2 months 
200 
4 months 
200 
6 months 
250 
12 months 
300 
18 months 
450 
24 months 
600 
Total 
2000 
Note: Only one blood sample will be withdrawn from each subject in this sub-cohort. 
*Number of subjects selected per time point is calculated based on the required number of subjects for adequate 
analysis considering an accumulating drop-out of subjects. Actual numbers might be less due to drop-outs and 
exclusion of subjects with gestational age <36 weeks. 
• 
Duration of the study: Approximately 2 years for each participant enrolled in the 
primary study and an additional (approximately) 3 to 4 years for each participant 
enrolled in the extension study. 
 
 Epoch 2 (Extension Study): Begins with the first contact for the extension 
study (at approximately age 2 years); ends with the contact at approximately 
the sixth birthday. Table 2 presents the study groups and epochs foreseen in 
the study. 
Table 2 
Study groups and epochs foreseen in the study 
 
Study Groups 
Number of subjects 
Age (Min/Max) 
Epoch 1 
Epoch 2 
Primary 
Approximately 2400 
0 days - 2 years 
x 
Extension 
Maximum 2400 
Approximately 2 years to 6 years 
x 
* Data collection will also occur from medical charts retrospectively for those who have a gap period between the end 
of the primary study and providing re-consent for the extension. 
Surveillance Plan: 
 
 
• 
Surveillance for wheeze and asthma during the extension study period. 
 
 
Safety Follow-up: 
• 
Study procedure related Serious Adverse Events (SAEs) to be reported throughout 
the study. 
Table 1 
Blood sample collection 
 Epoch 1 (Primary Study): Begins at birth (Visit 1) and ends at the age of 
approximately 2 years (Visit or contact at 2 years). 
• 
Surveillance for RSV Lower Respiratory Tract Infection (RSV LRTI), wheeze and 
asthma during the Primary Study period.* 
* Note that discussion of additional primary study visit details has been moved to (new) 
APPENDIX D. Discussion of details regarding Surveillance for RSV Lower 
Respiratory Tract Infection (RSV LRTI), wheeze and asthma during the primary study 
period have been moved to (new) APPENDIX E. 

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3.2. 
Discussion of study design 
The multi-country design of both the primary and extension studies will provide robust, 
multinational estimates of the incidence of RSV-associated LRTI during the first two 
years of life and assess the amount of wheeze and asthma that may be attributable to 
those early RSV-LRTI infections. 
 
 
3.2.2. 
Extension Study 
 
At 2nd birthday (on completion of primary study or as soon as possible thereafter), 
surveillance for RSV LRTI will be stopped. Consenting, eligible subjects from 
participating study centers will be enrolled in the study extension and followed for the 
occurrence of wheeze and asthma (applying 3 different asthma case definitions). This 
will permit an assessment of the proportion of wheeze and asthma from birth until the 
sixth birthday that may be attributable to RSV LRTI and RSV infection in the first two 
years of life. It will also test the performance of the different asthma case definitions 
(Table 5). 
 
4. 
CASE DEFINITIONS (AMENDED 15-DEC-2017) 
 
The Primary study will determine the incidence and associated healthcare utilization of 
RSV-associated LRTIs in infants from birth up to the age of 2 years, and assess the 
performance of a new LRTI case definition and severity scale. Using a cohort 
representing the general population of newborn infants, the study is designed to identify 
RSV-associated LRTI cases at any severity, and will not be limited to those that require 
hospitalization and/or other essential medical care. This will provide a comprehensive 
and accurate measure of the overall burden of disease, whereas many previous case- 
control or hospital-based cohort studies were limited to the hospitalized cases of RSV- 
associated LRTI. 
The association of other respiratory viruses with RSV-associated LRTI and/or severe 
LRTI, and the impact of potential RSV risk factors on the incidence and severity of RSV- 
associated LRTI will also be explored. In order to assess and adjust for other potential 
confounders in the various analyses, data on the subjects’ demography and lifestyle 
factors will be collected at baseline, and followed up quarterly for changes, during the 
regular follow-up contacts. 
Primary Study 
3.2.1. 
DEFINITIONS FOR LRTI SURVEILLANCE: 
During the surveillance for LRTI, a case is defined as; 
A child suffering from a potential LRTI. 
Primary Study 
4.1. 

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Normal ranges for RR and Sa02 
Table 3 
Potential LRTI: 
Suspected involvement of the lower respiratory tract if a child with clinical signs of RTI, 
defined as either a runny nose, blocked nose or cough, is believed to have difficulties in 
breathing in the opinion of the investigator/study staff, based on the symptoms reported 
by the parent(s)/LAR(s) during the surveillance phone contacts. Difficulty in breathing as 
suspected by the investigator/study staff through reported symptoms will then be 
objectively confirmed by the investigator/study staff by means of pulse oximetry and RR 
at an examination visit. If at least one of these parameters is outside of the pre-defined 
normal range (Refer to Table 3), the case will be considered as an LRTI for the 
surveillance part of the study. 
A subject is considered to have difficulty in breathing if he/she shows signs of: 
• 
Wheezing or stridor 
• 
Tachypnea 
• 
Flaring (of nostrils) 
• 
Chest indrawings 
• 
Apnea 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
RR 
Sa02 
 60/min for a child below 2 months of age 
 50/ min for a child aged 2 - 11 months 
 40/min for a child aged 12 - 24 months 
 95%, independent of the age of the child 
RR= Respiratory Rate; SaO2= Blood Oxygen Saturation; min = minutes 
During the surveillance for LRTI, any potential LRTI that is not found to meet the criteria 
for an LRTI may need a subsequent objective assessment by the investigator/study staff. 
Note: The investigator/study staff will do an initial assessment of a case reported for the 
examination visit as either RTI or LRTI, only to determine further study activities. The 
final classification of all the cases reported as either, RTI, LRTI or severe LRTI will be 
done during statistical analyses as per the definitions given below. 
CASE DEFINITIONS FOR DATA ANALYSIS: 
LRTI case definition and severity scale 
During the analysis of the study on the full dataset available for each case, all cases 
identified during the surveillance for LRTI will be definitively classified as either RTI, 
LRTI or severe LRTI according to the LRTI case definition and severity scale described 
in Table 4, and also according to the classification of WHO and the classification used by 
Nokes et al [Modjarrad, 2016; Nokes, 2004] (see below). 

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RTI 
LRTI 
severe LRTI 
Runny nose, OR 
Child with RTI AND 
Child with LRTI AND 
Blocked nose, OR 
SaO2 < 95%*, OR 
SaO2 < 92%*, OR 
Cough 
RR increase: 
Difficulty breathing leading to: 
> 60/min < 2m of age 
Irritability/agitation, OR 
> 50/min 2-11m of age 
Lethargy/sleepiness, OR 
> 40/min 12-24m of age 
Severe chest indrawing, OR 
Reduced/no vocalization, OR 
Apnoea > 20 sec, OR 
Cyanosis, OR 
Stop feeding well/dehydration 
* Measured by oximeter. RR= Respiratory Rate; SaO2= Blood Oxygen Saturation; m = months. 
RTI = Respiratory Tract Infections; LRTI = Lower Respiratory Tract Infections 
Case definition of LRTI and severe LRTI by Nokes et al. 
LRTI is diagnosed when a child has a history of acute cough or difficulty in breathing 
and  1 of the following: 
• 
Fast breathing for age ( 60 breaths/minimum if the child is < 2 months old or  50 
breaths/minimum if the child is 2–11 months old) 
• 
Indrawing, or 
• 
Low oxygen saturation (< 90%) by pulse oxymetry or inability to feed (prostration or 
unconsciousness), when accompanied by a clinical diagnosis of LRTI or 
bronchiolitis. 
Severe LRTI was diagnosed when a child had LRTI meeting second and/or third bullet 
above. 
Case definition of LRTI by WHO (2015) [Modjarrad, 2016] 
LRTI is diagnosed when a child <5 years presents with cough and/or difficulty in 
breathing has the following symptoms: 
• 
Fast breathing, (> 60 per minute in a child < 2 months of age, > 50 per minute in a 
child 2 to 11 months of age and; > 40 per minute in a child 12 to 59 months of age), 
or 
• 
Oxygen saturation < 95% by pulse oximetry. 
Severe LRTI is diagnosed when a child has LRTI and 1 or more of the following features 
of severe disease: 
• 
Oxygen saturation < 93% by pulse oximetry. 
• 
Lower chest wall in-drawing. 
Table 4 
LRTI case definition and severity scale 

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Detection of RSV by reverse transcription-quantitative real time polymerase chain 
reaction (RT-qPCR) in swab sample collected within 72 hours of first identification of a 
potential LRTI by the investigator/study staff during an active or passive surveillance 
study contact. 
 
Start date of the LRTI case: 
 
The start date of the case is defined as the point at which the LRTI was first identified as 
a potential LRTI by the investigator/study staff during an active or passive surveillance 
study contact, and if the LRTI is subsequently confirmed by the investigator/study staff 
(according to the LRTI case definition and severity scale for surveillance) during the 
examination visit (off-site/site). 
 
End date of the LRTI case: 
 
End date of the case is defined as the point at which the subject is considered symptom- 
free of difficulty in breathing, based on the data provided by the parent(s)/LAR(s) in the 
diary card and any additional data obtained from healthcare providers involved in 
management of the case. 
 
New case of LRTI: 
 
A new, single case of LRTI is any occurrence of an LRTI case meeting the LRTI case 
definition and severity scale with an interval of at least 7 symptom free days since the last 
episode of LRTI that was diagnosed. 
 
4.2. 
Extension Study 
Table 5 presents the case definitions of wheeze and asthma. The Bisgaard and Jackson 
case definitions have been updated so as to better account for advances in asthma 
treatment options while still preserving the case definitions’ core intent. 

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Table 5 
Case definitions of wheeze and asthma (Amended 15-DEC-2017) 
 
Definition 
Reference 
Episode of reported wheeze 
Parents report a whistling sound associated with labored 
breathing 
NA 
Medically attended wheeze 
An episode of health care provider confirmed wheeze 
NA 
Wheeze or asthma requiring 
hospital admission 
An episode of health care provider confirmed wheeze 
requiring hospital admission 
NA 
Recurrent wheeze 
This will be defined as four or more episodes of wheeze in 
one year. These episodes may be parent reported wheeze 
or health care provider confirmed wheeze. 
[Morgan 2005] 
Asthma case definition 1 
Asthma will be defined at annual review based on the 
documented presence of one or more of the following 
characteristics in the previous year: 
(1) provider diagnosis of asthma 
(2) Use of a short acting beta agonist (e.g., albuterol) 
for coughing or wheezing episodes as prescribed by a 
health care provider 
(3) use of a daily controller medication 
(4) step-up plan including use of a short acting beta 
agonist (e.g., albuterol) or short-term use of inhaled 
corticosteroids during illness 
(5) use of oral and/or systemic steroids for asthma 
exacerbation 
Based on 
[Jackson, 2008] 
Asthma case definition 2 
Asthma will be defined at annual review based on parent 
interview and review of medical records with the presence 
of all of the following: 
(1) recurrent episodes of troublesome lung symptoms 
(wheeze or whistling sounds, breathlessness, or recurrent 
troublesome cough severely affecting the well-being of the 
infant occurring with a frequency of 5 episodes within 6 
months period or 4 weeks of consecutive symptoms); 
(2) symptoms typical of asthma (recently proposed to be 
termed multitrigger wheeze; e.g., exercise-induced 
symptoms, prolonged nocturnal cough, recurrent cough 
outside the common cold, and symptoms causing 
wakening at night); 
(3) intermittent rescue use of inhaled β2-agonist; 
(4) symptoms controlled by daily inhaled 
corticosteroids 
Based on 
[Bisgaard, 2011] 
Asthma case definition 3 
In the past 12 months: four or more episodes of 
wheeze AND either one or more nights of sleep 
disturbance from wheeze per week, or wheeze that 
was severe enough to limit the child’s speech to only 
one or two words at a time between breaths 
Based on 
[Wong 2013] 

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5. 
STUDY POPULATION (AMENDED 15-DEC-2017) 
 
5.1. 
Number of subjects/centres 
Target enrollment for the primary study will be 2400 subjects to obtain approximately 
1920 fully evaluable subjects at primary study completion. Target enrollment for 
extension period will be a maximum of 2400 subjects. (All subjects participating in the 
primary study whose parent(s)/LAR(s) give re-consent for the extension period and who 
fulfill all relevant inclusion/exclusion criteria may be followed in the extension.) 
 
 
Sub-cohort name 
Description 
Estimated number of subjects 
Seroprevalence 
Blood sample (3.5 mL) collection at a randomly* allocated 
time point (2, 4, 6, 12, 18, 24 months) 
2400 
mL = milliliter 
*Randomization will be performed using randomization system on internet (SBIR). 
The overview of the recruitment plan has been moved to APPENDIX C. 
 
5.3. 
Inclusion criteria for enrolment 
Deviations from inclusion criteria are not allowed because they can potentially jeopardise 
the scientific integrity of the study, regulatory acceptability or subject safety. Therefore, 
adherence to the criteria as specified in the protocol is essential. 
All subjects must satisfy ALL the following criteria at study entry: 
 
5.3.1. 
Primary study (from birth up to the age of 2 years) 
 
Sub-cohort 
Table 6 
The primary study includes a sub-cohort for blood sampling. Refer to Table 6. 
Sub-cohorts 
5.2. 
Before birth: 
• 
Subject whose parent(s)/LAR(s), in the opinion of the investigator, can and will 
comply with the requirements of the protocol (e.g., sample collection, availability for 
examination visits). 
• 
Written informed consent (or witnessed thumb printed consent in case of an 
illiterate subject) (including consent to obtain a cord blood sample at birth) obtained 
from the parent(s)/LAR(s) of the subject 
After Birth: 
• 
Subject for whom updated and re-signed informed consent and confirmation of 
eligibility is available not later than 5 working days after birth. 
• 
Cord blood sample collection of at least 3 mL, at birth. 

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5.3.2. 
Extension Study (from the age of approximately 2 years up to the 
6th birthday) 
• 
Subject is enrolled at a study site that is participating in the extension period 
follow-up. 
• 
Subject whose parent(s)/LAR(s), in the opinion of the investigator, can and will 
comply with the requirements of the protocol (e.g., availability for quarterly 
contacts). 
• 
Written informed consent (or witnessed thumb printed consent in case of an 
illiterate subject) obtained from the parent(s)/LAR(s) of the subject. 
• 
Previous participation in the primary study (from birth up to the age of 2 years). 
 
5.4. 
Exclusion criteria for enrollment 
Deviations from exclusion criteria are not allowed because they can potentially 
jeopardise the scientific integrity of the study, regulatory acceptability or subject safety. 
Therefore, adherence to the criteria as specified in the protocol is essential. 
 
The following criteria should be checked at the time of study entry. If ANY exclusion 
criterion applies, the subject must not be included in the study. 
 
5.4.1. 
Primary study (from birth up to the age of 2 years) 
 
Before birth: 
 
• 
Subject expected to become Child in care 
Please refer to the GLOSSARY OF TERMS for the definition of child in care. 
 
• 
Subjects whose parent(s)/LAR(s) are below the age of 18 or the legal consenting age 
of the respective country if this is higher. 
After Birth: 
 
• 
Child in care. 
Please refer to the GLOSSARY OF TERMS for the definition of child in care. 
 
• 
Newborn with a gestational age of less than 28 weeks. 
• 
Subjects with any congenital condition that will require an expected postnatal stay in 
hospital of more than 12 consecutive weeks. 
• 
Subjects with major congenital defects or serious chronic illness limiting life 
expectancy to less than 5 years. 
• 
Subjects with any confirmed or suspected immunosuppressive or immunodeficient 
condition (including positive infection with human immunodeficiency virus [HIV]), 
based on medical history, physical examination or positive test result. 

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5.4.2. 
Extension Study (from the age of approximately 2 years up to the 
6th birthday) 
 
• 
Child in care. 
 
6. 
CONDUCT OF THE STUDY 
 
6.1. 
Regulatory and ethical considerations, including the 
informed consent process 
The study will be conducted in accordance with the International Conference on 
Harmonization (ICH) Guideline for Good Clinical Practice (GCP) or other applicable 
guidelines, 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 
paediatric population (ICH E11) and all other applicable ethical guidelines. 
 
GSK will obtain favourable opinion/approval to conduct the study prior to a site initiating 
the study in that country or will document that neither a favourable opinion nor an 
approval to conduct the study is needed. 
 
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 Biologicals 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 consent in case of an illiterate 
subject) informed consent must be obtained from each subject’s parent(s)/LAR(s) or the 
impartial witness, as appropriate, prior to participation in the study. 
 
GSK Biologicals will prepare a model Informed Consent Form (ICF) which will embody 
the applicable ICH GCP or other applicable guidelines, and GSK Biologicals required 
elements. While it is strongly recommended that this model ICF 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 

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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 
Subject numbers will be assigned sequentially to subjects whose parent(s)/LAR(s) have 
consented for their child to be included in the study, according to the range of subject 
numbers allocated to each study center. 
 
6.3. 
General study aspects 
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the accompanying Study Procedures Manual (SPM). The SPM provides the 
investigator and the site personnel with administrative and detailed technical information 
that does not impact the safety of the subjects. 
 
6.4. 
Outline of study procedures (Amended 15-DEC-2017) 
 
Table 7 presents the list of study procedures pertaining to the primary study (from birth 
up to the age of 2 years). 
Primary Study (birth to 2 years of age) 
6.4.1. 

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List of study procedures for the primary study (from birth up to the 
age of 2 years) 
Table 7 
 
 
 
 
 
 
 
 
 
Epoch 1 
Prospective data collection 
Visit/Contact 
Visit 1 
Visit 2 
Visit 3 
Surveillance 
contact 1 
Examination visit 2 
Post-Day 
0 7 
As    
randomized 
4 
Time points 
Pre-Day 0 
Regular 5 
Unscheduled 
Informed Consent 
● 
Check inclusion/exclusion criteria 
applicable before birth 
Subject number allocation and 
registration in SBIR-Screening 
● 
● 
Collection of expected birth date 
● 
Collection of cord blood sample (up to 
approximately 10 mL) 
Check inclusion/exclusion criteria 
applicable after birth and re-sign-off ICF 
● 
● 
Collection of family medical history, 
demographic and lifestyle 
characteristics 
● 
Collection of data on child at birth and 
delivery (incl. medical care provided 
immediately after birth) 
● 
Registration in SBIR-enrollment 
● 
Distribution of diary cards to record 
symptoms and healthcare utilization (as 
needed) 
O 
O 
x 
Obtain blood sample at randomized 
time point (approximately 3.5 mL) from 
a sub-cohort of subjects 
● 
Ascertain RTI symptoms and potential 
difficulty in breathing and assessment 
of need for examination visit (off- 
site/site) 
● 
Recording of data on changes to 
baseline medical, demographic and 
lifestyle characteristics data E.g. 
Chronic diseases and changes to living 
conditions 
● 
(quarterly) 
Examination during (off-site/site) visit 
and collection of all disease symptoms 
(including RR and pulse oximetry) 
● 
Data collection on, disease course and 
healthcare utilization before and during 
the examination visit (off-site/site) 3 
● 
Collection of nasal swab samples 
● 
Return of diary cards at completion or 
at case resolution 6 
O 
Confirmation and expansion of data on 
healthcare utilization as recorded in the 
diary card occurring after the 
examination visit (off-site/site) 3 
● 
Recording of SAEs related to study 
procedure throughout study period 
● 
● 
● 
● 

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Epoch 1 
Prospective data collection 
Surveillance 
contact 1 
Visit/Contact 
Visit 1 
Visit 2 
Visit 3 
Examination visit 2 
As    
randomized 
4 
Post-Day 
0 7 
Time points 
Pre-Day 0 
Regular 5 
Unscheduled 
Diary card transcription into eCRF 
● 
● 
End of primary study after 2 years 
follow-up 
● 
● is used to indicate a study procedure that requires documentation in the individual eCRF. 
○ is used to indicate a study procedure that does not require documentation in the individual eCRF. 
SBIR = Randomization System on Internet; mL = milliliter; ICF = Informed Consent Form 
RTI = Respiratory Tract Infection; RR = Respiratory Rate 
eCRF = electronic Case Report Form; SAE = Serious Adverse Events 
1The surveillance contact consists of the following: 
Active surveillance: Follow-up contacts will be made by the investigator/study staff with the parent(s)/LAR(s) of the 
subjects at predefined intervals (to be confirmed based on the local settings) from Visit 2 up to study conclusion. 
Passive surveillance: Follow-up contacts made by the parent(s)/LAR(s) with the study investigator/study staff in case of 
development of RTI symptoms or increase in severity of existing symptoms after the previous reporting of the 
initial symptoms. 
2 The examination visit (off-site/site) will be applicable only for subjects with a suspicion of LRTI. 
3 Whenever required healthcare utilization data should be completed or confirmed with the healthcare provider involved 
in the management of the case. 
4 Selected subjects will be randomized to the time point at which a single blood sample needs to be collected; 2, 4, 6, 
12, 18 or 24 months. The sample can be collected between the intervals of  1 week. E.g. Month 2  1 week, Month 4 
 1 week. Randomization will be done using a second phase application of SBIR. 
5 Refer to APPENDIX E for the active contact schedule. 
6 Diary card can be collected by mail or in person depending on local best practice. 
7 Visit 2 can take place anytime within 5 working days after birth. 
Refer to Section 6.5 for additional details. 
 
6.4.2. 
Extension Study (approximately 2 years of age up to the 6th 
birthday) 
Table 8 presents the list of procedures for the extension study. 
Note that although extension study enrolment ideally occurs at the time of the subjects’ 
second birthdays, enrolment into, and first contact for, the extension study may take 
place at any time between the end of the primary study and the subject’s 6th birthday. 
After the first extension study contact, subjects will be contacted around the time of 
each subject’s birthday and (approximately) quarterly during the intervals between (a) 
first contact and next birthday; (b) subsequent birthdays. 
Site staff may contact subjects more frequently than indicated in Table 8 if consistent 
with the language of the local ICF and considered necessary by the study physician. 
Parents will be encouraged to seek a clinical assessment of their child in between 
quarterly contacts and/or during quarterly contacts whenever their child develops 
wheezing and/or breathing difficulties. 
Refer to Section 6.6 and the SPM for additional details. 

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Table 8 
List of extension study procedures (from the age of approximately 2 years up to the 6th birthday) (Amended 15- 
DEC-2017) 
 
Epoch 2 
Data collection 
Visit/Contact 
First Contact a 
Quarterly Contact b, c 
Annual contact, c, d 
Time points 
Extension study enrolment 
Around the 2d, 3rd, 4th, 5th, and 6th birthdays 
(+ 3 months) 
Perform / document results of these procedures… 
Informed consent for extension 
● 
Check inclusion/exclusion criteria for extension 
● 
Collect demographic data for extension 
● 
Collect data on potential symptoms and risk factors for 
wheeze and asthma 
● 
● 
(applies to Version 1.0 of the 
quarterly contact script) 
● d 
Record episodes of wheeze, asthma, and troublesome 
lungs 
● 
● 
● d 
Collect data about medication used to treat asthma, 
wheeze, or troublesome lung symptoms 
● 
● 
● d 
Review / assess information about asthma diagnoses 
and medication use based on medical record 
abstraction and subject information over approximately 
the past 12 months or longer 
● e 
● e 
Interim analysis after 4th birthday; Final analysis 
after 6th birthday 
● 
Investigator sign-off on eCRF before analysis 
● f 
Study conclusion for extension 
● g 
… and enter data into these eCRF modules 
• 
First Contact 
• 
Annual a 
• 
Quarterly 
• 
Quarterly 
• 
Annual 
● indicates a study procedure that requires documentation in the individual eCRF. 
a At the time of first contact, if delayed, all missed annual assessments of asthma will be completed retrospectively by the Investigator. 
b At approximately 3, 6 and 9 months (+/- 1.5 months), between consecutive birthdays. There should be at least one month between each Quarterly Contact 
c Both Quarterly parent/LAR interview AND Annual investigator review/assessment data to be collected and reported. 

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d To accurately complete investigator-targeted asthma questions, up-to-date information about all asthma, wheeze, and troublesome lung episodes as well as a review of 
any and all potential asthma medications that were taken by the subject will be needed for the accurate completion of the investigator assessment. Refer to Section 6.6.4.2. 
e The investigator will supplement information from parents with review of routine medical records/ consultation with routine health care provider(s), as appropriate. 
f After completion of 4th birthday annual contact (for interim analysis), and at study conclusion 
g Study conclusion for the extension will be at the last contact, at child’s 6th birthday. 

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6.5. 
Detailed description of study procedures for the Primary 
Study period (from birth up to 2 years of age) 
 
6.5.1. 
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. 
 
• 
In case of anticipated twins (or other multiple births), an ICF needs to be signed for 
each expected child before the start of delivery. 
• 
In case of unexpected twins (or other multiple births), only the children for whom an 
ICF has been signed before birth can be enrolled. This should occur as per the birth 
order. 
 
6.5.2. 
Check inclusion and exclusion criteria applicable before birth 
 
Check all applicable inclusion and exclusion criteria applicable before birth as described 
in Sections 5.3.1 and 5.4.1 before enrollment. A pre-selected child who does not meet the 
eligibility criteria should be considered a screening failure. 
 
6.5.3. 
Subject number allocation and registration in SBIR-Screening 
 
Subject numbers will be assigned sequentially to subjects whose parent(s)/LAR(s) have 
consented for their child participation in the study, according to the range of subject 
numbers allocated to each study center. 
 
• 
In case of anticipated twins (or other multiple births), a subject number will be 
assigned sequentially to each child for whom the consent has been obtained, as per 
the birth order, where the first born will be associated with the lowest subject 
number, the second born with the successive subject number, etc. 
After obtaining the ICF and confirming eligibility, the subject needs to be entered in to 
the SBIR screening module. SBIR will control the recruitment rate as per an allocated 
target. 
 
6.5.4. 
Collection of expected birth date 
 
Record the expected delivery date as required in the subject’s eCRF. 
 
6.5.5. 
Collection of cord blood sample 
 
Refer to the Module on Biospecimen Management in the SPM for general handling of 
blood samples. 
 
A volume of up to approximately 10 mL of whole cord blood sample will be collected 
from all subjects at birth, which should yield up to approximately 3 mL of serum. In case 

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less than 3 mL of whole blood is collected, the subject will be considered a screening 
failure and the sample collected needs to be discarded according to local procedure. 
 
Details of the sample collection such as duration of processing steps and storage 
conditions need to be collected and recorded in the eCRF in order to allow adjustment for 
these variables in the primary analyses and to explore the impact of collection variables 
on the measured antibody titer. 
 
Cord blood samples collected will provide RSV- antibody levels in the child, at birth. 
 
6.5.6. 
Check inclusion and exclusion criteria applicable after birth and 
re-sign-off the ICF 
 
Check all applicable inclusion and exclusion criteria applicable after birth as 
described in Sections 5.3.1 and 5.4.1 before enrollment. 
 
The informed consent should be updated with relevant personal identifiers as applicable 
by local requirements. The ICF should be re-signed off by the investigator/study staff and 
subject’s parent(s)/LAR(s) and witness (when required) not later than 5 working days 
after the birth of the subject. 
 
Any pre-selected subject not meeting the eligibility criteria should be considered a 
screening failure, and the cord blood sample collected should be discarded. 
 
6.5.7. 
Collection of medical history, demographic and lifestyle 
characteristics 
 
Obtain the family medical history, demographic and lifestyle characteristics of the subject 
as required by the eCRF, by interviewing parent(s)/LAR(s) and/or reviewing the medical 
records and record data collected in the subject’s eCRF. This includes family history of 
respiratory disease, living environment and household composition, breastfeeding, 
passive smoking and day-care attendance. 
 
6.5.8. 
Collection of data on child at birth and delivery 
 
Information about the delivery and the newborn (including medical care provided 
immediately after birth and planned to be provided subsequently) should be collected 
from the parents/LAR and completed and/or confirmed from an original source accessed 
through a person involved in the delivery of the subject or from any authorized person 
representing the healthcare organization that is in charge of the source and the collected 
data should be recorded in the subject’s eCRF. 
 
6.5.9. 
Registration in SBIR-enrollment 
 
After obtaining the updated ICF and confirming eligibility, the subject needs to be 
entered in to the SBIR enrollment module. SBIR will randomize the subject to a time 
point for blood sample collection if the subject is part of the sub-cohort the 
parent(s)/LAR(s) should be informed about this allocation. 

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6.5.10. 
Distribution of diary cards to record symptoms and healthcare 
utilization 
 
The investigator/study staff will provide diary cards to the subject’s parent(s)/LAR(s) as 
needed to record relevant symptoms and healthcare system utilization during the course 
of the case. The diary card provided needs to be filled by the parent(s)/LAR(s) only in 
case the investigator/study staff concludes that their child has developed an RTI with 
suspicion of difficulty breathing, leading to an examination visit (off-site/site) during the 
study follow-up period. 
 
6.5.11. 
Blood sampling 
 
Refer to the Module on Biospecimen Management in the SPM for general handling of 
blood samples. 
 
A volume of approximately 3.5 mL of whole blood sample will be collected from a sub- 
cohort of subjects at randomly allocated time points to obtain approximately 1 mL of 
serum. 
 
Selected subjects will be randomized to the time point 2, 4, 6, 12, 18 or 24 months at 
which a single blood sample should be collected from them. The sample should be 
collected between the intervals of  1 week e.g. Month 2  1 week, Month 4  1 week in 
order for the subjects to be included in the analyses. Subjects born at a gestational age of 
less than 36 weeks will be excluded from this blood sampling. Randomization will be 
done using a second phase application of SBIR. 
 
Blood samples collected will be used to assess RSV antibody levels in the subjects. 
 
6.5.12. 
Ascertain RTI symptoms and potential difficulty in breathing and 
assessment of need for examination visit (off-site/site) 
 
During each active or passive follow-up contact, the investigator/study staff should 
confirm with the parent(s)/LAR(s) of the subject, if the subject developed new RTI 
symptoms (cough, runny nose, blocked nose), and any signs of difficulty in breathing 
(during and between contacts). In case there is any current sign or suspicion of difficulty 
in breathing in a child with symptom(s) of RTI at the time of the contact, the 
investigator/study staff should instruct the parent(s)/LAR(s) to start completing the diary 
card and schedule an examination visit (off-site/site) as soon as possible, 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 
an optimal biological sample for detection of RSV. Active surveillance contacts required 
by the surveillance schedule and each passive surveillance contact, whether or not it 
triggers an examination visit, will be recorded in the site’s source documentation and in 
the eCRF. Parent(s)/LAR(s) will be instructed to contact the study team as soon as 
possible if the severity of the already existing symptoms in the child increases, or if the 
child who did not have signs of difficulty breathing develops the symptom. 

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The active and passive surveillance contacts can also be made with person designated by 
the parent(s)/LAR(s) (e.g. grandparents, nanny) as long as the parent(s)/LAR(s) have 
approved the same. If needed, a field worker can also be assigned to support the 
parent(s)/LAR(s) and/or person designated by the parent(s)/LAR(s) in completing the 
diary card. 
 
The investigator/study staff should also collect any further identifying data (e.g. official 
name, social security number) that becomes available for a subject during the course of 
the study at regular surveillance contacts, and record it in a supporting site document. 
 
6.5.13. 
Recording of data on changes to baseline medical and 
demographic data 
 
On a quarterly basis, the investigator/study staff should expand a regular surveillance 
contact by asking the parents/LARs for changes to the baseline medical, demographic 
and lifestyle characteristics data collected at Visit 2. This includes at least; 
 
• 
diagnosis of chronic diseases 
• 
medical events requiring hospitalization 
• 
vaccinations received (on disease level, not full vaccination details) 
• 
start/stop attendance of day-care and other changes in daily care 
• 
start/stop breastfeeding 
• 
changes to household composition and/or living conditions 
This data will be recorded in a quarterly surveillance eCRF. 
 
6.5.14. 
Examination during (off-site/site) visit and collection of all 
disease symptoms 
 
The examination visit can be an on-site or off-site visit. An off-site visit is preferred in 
order to avoid influencing the pattern of healthcare utilization for the disease. 
Parent(s)/LAR(s) of the subjects can however be requested to bring their child to the 
study center for the site examination visit e.g. if this would be the normal standard of care 
to provide given the situation, if this will significantly expedite the timing of the visit, or 
if it is unlikely that the off-site examination visit can occur at all within the required 
timeframe. 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. ER) and an examination visit could be scheduled to take place there at a 
suitable time. During the examination visit (off-site/site), the investigator/study staff 
should objectively confirm the RTI and difficulty breathing experienced by the subject 
and if the symptoms meet the LRTI case definition for surveillance. Data should be 
collected on all the clinical symptoms present in the child including a measurement of the 
temperature, RR and pulse oximetry. The data collected should be recorded in the 
subject’s eCRF. 

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For any case for which an examination visit is done (off-site/site), at least the following 
characteristic but not limited to, will be reported in the eCRF: 
 
• 
Date of telephone contact. 
• 
Date of visit. 
• 
Start and end date of the case. 
• 
Nasal swab sample number. 
• 
Clinical symptoms (Eg: irritability, cyanosis) as assessed by the investigator/study 
staff during examination visit (off-site/site), and as subsequently assessed from the 
diary card, and/or confirmed with any healthcare provider involved, during disease 
course. 
• 
SaO2 as assessed by investigator/study staff during the examination visit (off- 
site/site), and as subsequently assessed by any healthcare provider involved, during 
disease course. 
• 
Temperature as measured by the investigator/study staff during the examination visit 
(off-site/site), and as subsequently assessed from the diary card, and/or confirmed 
with any healthcare provider involved, during course of the disease. 
• 
RR as assessed by investigator/study staff during the examination visit (off-site/site), 
and as subsequently assessed by any healthcare provider involved, during disease 
course. 
• 
Healthcare utilization during disease course as assessed from the diary card and/or 
confirmed with any healthcare provider involved. 
Note: 
 
Healthcare utilization (or healthcare setting availed) refers to self-care with OTC drugs, 
GP visits, ER visits, hospital visits, etc. 
 
Data from healthcare providers (such as temperature, RR, SaO2, symptoms and 
diagnosis) is to be regarded as a valuable, but optional extra, if this data is available and 
shared by the applicable healthcare provider. 
 
A case eCRF needs to be created for each scheduled examination visit and data collected 
up to case resolution will be entered. Cases will be allocated with a unique case number 
that is a sequential number per subject. 
 
6.5.15. 
Data collection on disease course and healthcare utilization 
before and during the examination visit (off-site/site) 
 
Data on disease course recorded by the subject’s parent(s)/LAR(s) in the diary card until 
the examination visit should be assessed and recorded by the investigator/study staff in 
the subject’s eCRF. 
 
Data provided by the parent(s)/LAR(s) in the diary card on healthcare utilization should 
be confirmed by direct contact of the investigator/study staff with the healthcare 

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providers involved in management of the case (e.g. GP, hospital staff), and recorded in 
the eCRF. Where possible, the data on healthcare utilization should be made more 
complete so as to best capture the healthcare utilization in the eCRF. Any clinical 
diagnoses for the respiratory infection (e.g. pneumonia, bronchiolitis) made by the 
contacted healthcare providers, should be collected and recorded in the eCRF as well as 
the symptoms assessed in support of this diagnosis (especially measured RR and SaO2). 
 
Note: In case of any discrepancies between healthcare utilization data recorded in the 
diary card and as provided (and supported with source documentation) by the HCPs, the 
data from the HCP will be used in the eCRF. 
 
Data from healthcare providers (such as temperature, RR, SaO2, symptoms and 
diagnosis) is to be regarded as a valuable, but optional extra, if this data is available and 
shared by the applicable healthcare provider. 
 
6.5.16. 
Collection of nasal swab samples 
 
• 
Nasal sampling: Cells and secretions from the nose will be collected by using sterile 
swabs for all the subjects who are reported for an examination visit (off-site/site) 
(this includes subjects with no confirmed LRTI). 
Full details for obtaining nasal swabs are provided in the Module on Biospecimen 
Management in the SPM accompanying this protocol. 
 
6.5.17. 
Return Diary card at completion or at case resolution 
 
The diary card will be collected at completion. 
 
• 
Regular completion is after the standard diary card duration of 14 days. 
• 
If a surveillance case eCRF is ‘closed’ due to a subsequent examination visit for the 
same case, the diary card relating to the ‘closed’ eCRF is stopped prematurely and a 
new 14-day diary card is started (see also Section 3-examination visit). 
If the subject is not free of the symptoms asked for in the diary card at the end of Day 14, 
the parent(s)/LAR(s) should continue to assess the symptoms until no more symptoms are 
present, and record in the diary card, the date at which no more symptoms were observed 
in the child. 
 
6.5.18. 
Confirmation and expansion of data on healthcare utilization 
occurring after the examination visit (off-site/site) and collection 
of any further, relevant data on disease course with HCPs 
involved in subject care 
 
Data on disease course recorded by the subject’s parent(s)/LAR(s) in the diary card until 
diary card completion/case resolution should be assessed and recorded by the 
investigator/study staff in the subject’s eCRF. 

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Data provided by the parent(s)/LAR(s) in the diary card on healthcare utilization should 
be confirmed by direct contact of the investigator/study staff with the healthcare 
providers involved in management of the case (e.g. GP, hospital staff), and recorded in 
the eCRF. Wherever possible, the data on healthcare utilization should be made more 
complete so as to best capture the healthcare utilization in the eCRF. Any clinical 
diagnoses for the respiratory infection (e.g. pneumonia, bronchiolitis) made by the 
contacted healthcare providers should be collected and recorded in the eCRF as well as 
the symptoms assessed in support of this diagnosis (especially measured RR and SaO2). 
 
Note: In case of any discrepancies between healthcare utilization data recorded in the 
diary card and as provided (and supported with source documentation) by the HCPs, the 
data from the HCP will be used in the eCRF. 
 
Data from healthcare providers (such as temperature, RR, SaO2, symptoms and 
diagnosis) is to be regarded as a valuable, but optional extra, if this data is available and 
shared by the applicable healthcare provider. 
 
6.5.19. 
Recording of SAEs related to study procedure 
 
• 
Refer to Section 7.2 for procedures for the investigator to record SAEs. Refer to 
Section 7.3 for guidelines on how to submit 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. 
 
6.5.20. 
Diary card transcription into eCRF 
 
The investigator/study staff will transcribe the collected information into the eCRF in 
English. 
 
6.5.21. 
End of primary study after 2 years follow-up 
 
The investigator/study staff will: 
 
• 
review all the data collected to ensure accuracy and completeness. 
• 
complete the Study Conclusion screen in the eCRF. 
6.6. 
Detailed description of Extension 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 participation in the extension. Refer to Section 6.1 for the 
requirements on how to obtain informed consent. 

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6.6.2. 
Check inclusion and exclusion criteria 
 
Check all applicable inclusion and exclusion criteria for the extension as described in 
Sections 5.3.2 and 5.4.2. 
 
6.6.3. 
Collection of demographic data 
 
Record gender and ethnicity in the subject’s eCRF. 
 
6.6.4. 
Potential risk factors for / occurrences of wheeze and asthma 
 
6.6.4.1. 
Data collected from the parent(s)/LAR(s) 
 
The following data are to be collected by interviewing the parent(s)/LAR(s). Refer to 
the SPM for additional details 
 
Genetic History 
 
Family history of asthma 
 
Family history of allergies 
Child/subject variables of interest 
 
Past or current allergies 
 
Exposure to environmental/household or other risk factors for asthma 
 
Child’s activity levels 
 
Potential signs/symptoms of asthma 
 
Episodes of wheeze, asthma, or troublesome lung symptoms since the end of the 
primary study and their associated care 
 
Medications taken to prevent or treat asthma, wheeze or troublesome lung 
symptoms 
 
6.6.4.2. 
Investigator review and assessment 
 
Investigators will review each subject’s data to assess whether the subject met the 
protocol defined case definition(s) of asthma at the 2d, 3d, 4th, 5th and 6th birthdays. The 
assessments will be based on: 
 
• 
Review of information gathered at the first extension study contact with the subject’s 
parent(s) / LAR(s) about past wheeze, asthma, and troublesome lung symptoms, and 
the medications used to treat them. 
• 
Review of information about any applicable primary study episodes of wheeze and 
troublesome lung symptoms, and history of asthma medication use. 
• 
Review of the subject’s routine medical records (where these exist and are 
available), as needed to verify/clarify study information. 

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• 
Consultation with the subject’s health care provider(s), as needed to verify/clarify 
study information. 
 
Note that all information about all asthma, wheeze, and troublesome lung episodes as 
well as a review of any and all potential asthma medications that were taken by the 
subject will be needed for the accurate completion of the investigator assessment. (Refer 
to Section 4 for case definitions of asthma). 
 
To this end, quarterly contact information about asthma, wheeze, and troublesome 
lung episodes as well as the medications used to treat them should all be brought up-to- 
date at the time of each annual contact. 
 
Refer to the SPM for additional details. 
 
6.6.5. 
Medications for Wheeze or Asthma 
 
Table 9 presents a list of medications for wheeze or asthma that should be identified 
during parent/LAR interviews and investigator review / assessment (Section 6.6.4), and 
recorded in the eCRF. These medications are usually prescribed by a health care 
provider. 
Table 9 
Medication(s) for wheeze or asthma (Amended 15-Dec-2017) 
 
 
6.6.6. 
Recording of SAEs related to study procedures 
 
Refer to Section 7.2 and Section 7.3. There is no biological sample collection during 
the extension study. 
 
6.6.7. 
Study conclusion for the extension 
 
The investigator/study staff will: 
 
• 
Review all the data collected to ensure accuracy and completeness. 
• 
Complete the Study Conclusion screen in the eCRF. 
 
Oral steroids 
Systemic (intramuscular or intravenous) steroids 
Inhaled steroids (ICS) 
Combination inhalers containing steroids and long-acting beta agonists 
Long-acting beta agonists (LABA) 
Short-acting beta agonists (SABA) 
Leukotriene modifiers or receptor antagonists 
Theophyline 
Anti-IgE therapy (e.g.,Omalizumab) 
Please refer to the SPM for details of biospecimen management (handling, storage and 
shipment). 
Biological sample handling and analysis 
6.7. 

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Samples will not be labelled with information that directly identifies the subjects but will 
be coded with the identification number for the subject (subject number). 
 
• 
Collected samples will be used for protocol mandated research. In addition, these 
samples may be used to perform research 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 invited to give another specific 
consent to allow GSK or a contracted partner use the samples for future research 
including development of tests and their quality assurance. 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). 
 
Collected samples will be stored for a maximum of 20 years (counting from when the last 
subject performed the last study contact), 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 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 According-To-Protocol (ATP) analysis (See Section 9.4 for the 
definition of study cohorts/data sets 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 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 
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The following samples will be collected, as a part of the primary study: 
 
• 
Cord blood sample (up to approximately 10 mL) at birth from all the subjects. 
• 
Nasal swab samples within 72 hours from the first identification of a potential LRTI 
case by the investigator/study staff during an active or passive surveillance study 
contact. 
• 
Single blood sample (approximately 3.5 mL) from a sub-cohort of subjects, at the 
time point allocated through randomization (2, 4, 6, 12, 18 or 24 months). Children 
who are born with a gestational age of less than 36 weeks will be excluded from this 
sub-cohort. 
No additional samples will be collected during the extension period. 
 
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 C for the address of the clinical laboratories 
used for sample analysis. 
 
The samples collected will be shipped to the study reference laboratory for testing. 
 
The following assays will be performed at GSK Biologicals’ laboratory or in a laboratory 
designated by GSK Biologicals using standardized and validated procedures. 
 
For cord blood and sub-cohort blood samples: 
 
• 
Serum neutralization assay to assess RSV antibody [Table 10]. 
Table 10 Antibody determination 
 
System  
Component    
Method 
 
Kit/ 
Manufacturer 
Unit  Cut-off** 
  
Laboratory 
 
 Serum 
  Anti-RSV-A 
  Neutralization 
  In house 
  ED60   8 
 GSK Biologicals* and/or 
designated laboratory 
 Serum 
  Anti-RSV-B 
  Neutralization 
  In house 
  ED60   6 
 GSK Biologicals* and/or 
designated laboratory 
*GlaxoSmithKline Biologicals laboratory refers to the Clinical Laboratory Sciences (CLS) in Rixensart, Belgium; Wavre, 
Belgium. 
** Unit and cut-off for the RSV-A and/or RSV-B neutralization assay may be subject to change 
RSV = Respiratory Syncytial Virus; ED = Effective Dose 

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7. 
SAFETY 
SAEs, which in the opinion of the investigator are related to the study procedures (e.g. 
blood sample and nasal swab sample collection), will be recorded throughout the study 
period. 
 
The investigator or study staff is/are responsible during the study for the detection and 
documentation of events meeting the criteria and definition of an 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/ of concern or indicating a change in their health status. 
For nasal swab samples: 
• 
RT-qPCR assay for the detection of RSV and determination of RSV subtype (A/B). 
• 
xTAG™ RVP Fast assay for the detection of the following 17 viruses and subtypes. 
 
RSV 
 
Influenza A, including subtypes H1 and H3 
 
Influenza A H1N1 2009 
 
Influenza B 
 
Parainfluenza virus type 1, 2, 3, and 4 
 
Human Metapneumovirus 
 
Enterovirus/Rhinovirus 
 
Adenovirus 
 
Bocavirus 
 
Coronavirus - 229E, OC43, NL63, HKU1 
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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7.1. 
Safety definitions 
 
7.1.1. 
Definition of an SAE 
 
An SAE is any untoward medical occurrence that: 
 
a. 
Results in death, 
b. Is life-threatening, 
NB: 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 an existing hospitalization, 
NB: 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 SAE. 
d. Results in disability/incapacity, 
NB: The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions. This definition is not intended to include experiences 
of relatively minor medical significance such as uncomplicated headache, nausea, 
vomiting, diarrhoea, influenza like illness, and accidental trauma (e.g., sprained 
ankle) which may interfere or prevent everyday life functions but do not constitute a 
substantial disruption. 
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 ER 
or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result 
in hospitalization. 
 
7.1.2. 
Clinical laboratory parameters and other abnormal assessments 
qualifying as SAEs 
 
In absence of diagnosis, abnormal laboratory findings (e.g., clinical chemistry, 
haematology, urinalysis) or other abnormal assessments that are judged by the 

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investigator to be clinically significant will be recorded as SAEs if they meet the 
definition of an SAE (refer to Section 7.1.1). 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 SAEs. However, clinically 
significant abnormal laboratory findings or other abnormal assessments that are 
associated with the disease being studied, unless judged by the investigator as more 
severe than expected for the subject’s condition, or that are present or detected at the start 
of the study and do not worsen, will not be reported as 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. 
 
7.2. 
Detecting and recording SAEs 
 
7.2.1. 
Time periods for detecting and recording SAEs 
 
SAEs related to study participation will be collected and recorded from the time of the 
first study visit until the subject is discharged from the study. 
 
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) will be collected and recorded from the time when the subject parent(s)/ LAR(s) 
have consented their child’s/children’s participation in the study until she/he is 
discharged from the study. 
 
7.2.2. 
Evaluation of SAEs 
 
7.2.2.1. 
Active questioning to detect SAEs 
 
Each subject’s parent(s)/LAR(s) will be instructed to contact the investigator immediately 
should the subject manifest any signs and symptoms (s) they perceive as serious. 
 
All SAEs either observed by the investigator or his/ her staff or reported by the subject’s 
parent(s)/LAR(s) spontaneously or in response to a direct question will be evaluated by 
the investigator. The nature of each event, date and time of onset, outcome, intensity and 
possible relationship to the study procedures should be established. 
 
When an 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 the 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. 

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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 SAE and not the individual signs/symptoms. 
 
7.2.2.2. 
Assessment of causality 
 
The investigator should assess the causality of each SAE. The investigator will use 
clinical judgement to determine the relationship between the SAEs and study 
participation. Alternative causes, such as natural history of the underlying diseases, other 
concomitant therapy and other risk factors will be considered and investigated. 
 
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 SAE 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. 
 
If an event meets the criteria to be considered as ‘serious’ (see section 7.1.1), additional 
examinations/tests will be performed by the investigator in order to determine ALL 
possibly contributing factors to each SAE. 
 
Possibly contributing factors include: 
 
• 
Medical history. 
• 
Concomitant medication. 
• 
Protocol required procedure. 
• 
Other procedure not required by the protocol. 
• 
Other cause (specify). 
 
7.2.2.3. 
Assessment of outcomes 
 
The investigator will assess the outcome of all SAEs recorded during the study as: 
 
• 
Recovered/resolved. 
• 
Recovering/resolving. 
• 
Not recovered/not resolved. 
• 
Recovered with sequelae/resolved with sequelae. 
• 
Fatal (SAEs only). 
 
7.3. 
Reporting of SAEs 
All SAEs occurring up to 30 days after the study procedure and considered related to 
study participation must be recorded on the SAE form, irrespective of intensity. 

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PPD 
PPD 
7.3.1. 
Prompt reporting of SAEs related to study participation 
 
SAEs that occur in the time period defined in Section 7.2.1 will be reported promptly to 
GSK within the timeframes described in Table 11 once the investigator determines that 
the event meets the protocol definition of an SAE. 
 
Table 11 Timeframes for submitting SAEs related to study participation 
 
Type of event 
Initial reports 
Follow-up of relevant information 
on a previous report 
Timeframe 
Documents 
Timeframe 
Documents 
SAEs related to 
study 
participation 
24 hours* 
electronic expedited adverse 
event report 
24 hours* 
electronic expedited adverse 
event report 
* Timeframe allowed after receipt or awareness of the information. 
 
7.3.2. 
Contact information for reporting SAEs to GSK 
 
 
 
 
7.3.3. 
Completion and transmission of SAE reports related to study 
participation to GSK 
 
Once an investigator becomes aware that an SAE has occurred in a study subject, the 
investigator (or designee) must complete the information in the electronic SAE report 
WITHIN 24 HOURS. The SAE report will always be completed as thoroughly as 
possible with all available details of the event. Even if the investigator does not have all 
information regarding an SAE, the report should still be completed within 24 hours. Once 
additional 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. 
 
7.3.3.1. 
Back-up system in case the electronic SAE reporting system does not 
work 
 
If the electronic SAE reporting system does not work, the investigator (or designee) must 
complete, then date and sign a paper SAE report and fax it to the GSK Biologicals 
Clinical Safety and Pharmacovigilance department within 24 hours. 
 
This back-up system should only be used if the electronic SAE reporting system is not 
working and NOT if the system is slow. As soon as the electronic SAE reporting system 
is working again, the investigator (or designee) must complete the electronic SAE report 
Back-up Study Contact for Reporting SAEs 
Study Contact for Reporting SAEs 
Refer to the local study contact information document. 
24/24 hour and 7/7 day availability: 
GSK Biologicals Clinical Safety & Pharmacovigilance 
Fax: + 
or + 

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within 24 hours. The final valid information for regulatory reporting will be the 
information reported through the electronic SAE reporting system. 
 
7.3.4. 
Updating of SAE after freezing of the subject’s eCRF 
 
When additional SAE information is received after freezing of the subject’s eCRF, new 
or updated information should be recorded on a paper report, with all changes signed and 
dated by the investigator. The updated report should be faxed to the GSK Biologicals 
Clinical Safety and Pharmacovigilance department or to the Study Contact for Reporting 
SAEs (see the Sponsor Information) within the designated reporting time frames 
specified in Table 11. 
 
7.3.5. 
Regulatory reporting requirements for SAEs 
 
The investigator will promptly report all SAEs to GSK Biologicals in accordance with 
the procedures detailed in Section 7.3.1. 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 epidemiological 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. 
 
7.4. 
Follow-up of SAEs 
 
7.4.1. 
Follow-up of SAEs 
 
7.4.1.1. 
Follow-up during the study 
 
After the initial SAE report, the investigator is required to proactively follow each subject 
and provide further relevant information on the subject’s condition to GSK Biologicals 
(within 24 hours for SAEs, refer to Table 11). 
 
All SAEs documented at a previous visit/ contact and recorded as not recovered/ not 
resolved or recovering/ resolving will be reviewed at subsequent visits/ contacts until the 
end of the study. 
 
7.4.1.2. 
Follow-up after the subject is discharged from the study 
 
The investigator will follow-up subjects: 
 
• 
With SAEs until the event has resolved, subsided, stabilized, 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 SAE report. 

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GSK Biologicals may request that the investigator performs or arranges for the conduct 
of additional clinical examinations/ tests and/ or evaluations to elucidate as fully as 
possible the nature and/ or causality of the SAE. The investigator is obliged to assist. If a 
subject dies during participation in the study or during a recognized follow-up period, 
GSK Biologicals will be provided with any available post-mortem findings, including 
histopathology. 
 
8. 
SUBJECT COMPLETION AND WITHDRAWAL 
(AMENDED 15-DEC-2017) 
 
8.1. 
Subject completion 
 
 
A subject who is available for the concluding contact foreseen in the protocol for the 
extension study is considered to have completed the extension study. 
 
8.2. 
Subject withdrawal 
Subjects who are withdrawn from the study because of study procedure related SAEs 
must be clearly distinguished from subjects who are withdrawn for other reasons. 
Investigators will follow subjects who are withdrawn from the study as the result of a 
study procedure related SAE until resolution of the event (see Section 7.4.1.2). 
Withdrawals will not be replaced. 
From an analysis perspective, a ‘withdrawal’ from the study refers to any subject who 
was not available for the concluding contact foreseen in the protocol. 
 
All data collected until the date of 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. 
 
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, by the subject’s parent(s) or LAR(s), or by the investigator, as well as which of the 
following possible reasons was responsible for withdrawal: 
 
• 
SAE. 
• 
Non-serious AE. 
• 
Protocol violation (specify). 
• 
Consent withdrawal, not due to an AE*. 
A subject who is available for the concluding contact foreseen in the protocol for the 
primary study is considered to have completed the primary study. 

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• 
Moved from the study area. 
• 
Lost to follow-up**. 
• 
Other (specify). 
*In case a subject is withdrawn from the study because the subject’s parent(s)/ LAR(s) 
has/have withdrawn consent, the investigator will document the reason for withdrawal of 
consent, if specified by the subject’s parent(s)/LAR(s), in the CRF. 
 
**Details concerning the definition of “lost to follow up” are presented in the SPM. 
 
9. 
STATISTICAL METHODS (AMENDED 15-DEC-2017) 
 
9.1. 
Endpoints for the Primary Study (first 2 years) 
 
9.1.1. 
Co-Primary endpoints 
 
• 
Occurrence of RSV as confirmed by RT-qPCR. 
• 
Occurrence of different types of healthcare utilization*. 
* Healthcare utilization includes primary, secondary and tertiary care settings such as 
self-care with OTC drugs, GP visits, ER visits, hospital visits, etc. 
 
• 
Occurrence of LRTI/severe LRTI as classified by the LRTI case definition and 
severity scale. 
• 
Occurrence of LRTI/severe LRTI as classified by the existing comparator LRTI case 
definition by WHO and by Nokes et al. 
 
9.1.2. 
Secondary endpoints 
 
• 
Levels of RSV neutralizing antibodies in the cord blood samples collected at birth. 
• 
Levels of RSV neutralizing antibodies in the blood samples collected at 2, 4, 6, 12, 
18 and 24 months. 
• 
Occurrence of LRTI/severe LRTI cases as classified by the LRTI case definition and 
severity scale, in the subgroups of subjects recruited from Months 1-6 and 13-18. 
 
9.1.3. 
Tertiary endpoints 
 
• 
Occurrence of RSV and other respiratory viruses as confirmed by xTAG™ RVP Fast 
assay: 
 
 
Parainfluenza virus type 1, 2, 3, and 4 
 
Human Metapneumovirus 
 
Rhinovirus 
 
Adenovirus 

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9.2. 
Endpoints for the Extension Study 
 
9.2.1. 
Primary: none 
 
9.2.2. 
Secondary: 
 
• 
Occurrence of medically attended wheeze 
• 
Occurrence of wheeze or asthma requiring hospital admission. 
• 
Use of prescription medications for wheeze or asthma. 
 
9.2.3. 
Tertiary 
 
• 
Number of children with asthma (case definition 1) at age 2, 3, 4, 5, and 6 years of 
age 
• 
Number of children with asthma (case definition 2) at age 2, 3, 4, 5 and 6 years of 
age. 
• 
Number of children with asthma (case definition 3) at 3, 4, 5 and 6 years of age. 
• 
Number of children with recurrent wheeze. 
 
Bocavirus 
 
Coronavirus - 229E, OC43, NL63, HKU1 
 
RSV 
 
Influenza A, including subtypes H1 and H3 
 
Influenza B 
• 
RSV viral load as determined by RSV RT-qPCR. 
• 
Occurrence of any symptom identified in cases of potential LRTI. 
• 
Cord-blood sample collection variables including collection and storage times and 
temperatures. 
• 
Occurrence of potential risk factors including complications at birth, family history 
of respiratory disease, living environment and household composition, breastfeeding, 
passive smoking and day-care attendance. 

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Source 
Region 
0-5 months 
6-11 months 
12-23 months 
[Hall, 2009] 
USA 
16.9 
5.1 
2.7 
[Holman, 2004] 
USA 
41.9 
12.8 
- 
[Iwane, 2004] 
NY/ Tennessee 
18.5 
7.4 
0.4 
[Boyce, 2000] 
Tennessee 
44.1 
15.0 
3.7 
[Despande, 2003] 
UK 
36.0 
11.3 
- 
[Vicente, 2003] 
Spain 
36.8 
14.2 
- 
USA = United States of America 
UK = United Kingdom 
Table 13 shows the exact 95% confidence interval (CI) (Poisson exact distribution and 
normal approximation of the Poisson distribution accounting for a design effect of 4.18) 
for a range of expected incidence rates of RSV that we can reasonably estimate between 
10 and 50 per 1000 children-years in the first year of birth. With an overall sample size of 
about 320 evaluable subjects by country during the first year of enrollment and with a 
follow-up period of 1 year after the last subject is recruited, the CI for an expected RSV- 
associated LRTI hospitalization rate of 20 cases per 1000 children-years is respectively 
[6.9; 40.8] for the exact Poisson distribution and [0; 51.7] for the normal approximation 
with design effect of 4.18. 
RSV-associated LRTI hospitalization rates in industrialized countries 
(per 1000 children-years) 
Table 12 
Different RSV-associated LRTI hospitalization rates have been reported in industrialized 
countries. We observe incidence rates between 16.9 and 44.1 per 1000 children-years in 
the age group of infants below 6 months of age, between 5.1 and 14.2 per 1000 children- 
years in the age group of infants between 6-11 months and between 0.4 and 3.7 per 1000 
children-years in the age group of children between 12-23 months [Table 12]. These rates 
are similar to the ones measured in several studies conducted in developing countries 
[Nair, 2010]. 
Determination of sample size 
9.3. 

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Precision for expected RSV-associated LRTI hospitalization rate 
during the first year of life (per 1000 children-years) 
Table 13 
 
 
 
 
 
 
 
 
 
Number of 
  Number 
 of cases 
RSV-associated 
LRTI rate (per 1000 
children-years) 
95% CI 
Poisson 
Exact 
95% CI Normal 
approx. with DE 
children-years 
First year of enrollment (analysis will be performed 1 year after the last subject is recruited) 
 Country/region level    
320 
   
3 
   
10 
     [1.9; 27.4] 
   
[0; 32.4] 
 
  
320 
   
6 
   
20 
     [6.9; 40.8] 
   
[0; 51.7] 
 
  
320 
   
10 
   
30 
    [13.9; 55.4]  
  
[0; 68.8] 
 
  
320 
   
13 
   
40 
    [20.5; 67.5]  
  
[0; 84.8] 
 
  
320 
   
16 
   
50 
    [28.6; 81.2]  
  
[0; 100.1] 
 
 Overall 
   
1280 
   
13 
   
10 
     [5.1; 16.9] 
   
[0; 21.2] 
 
  
1280 
   
26 
   
20 
    [13.0; 29.3]  
  
[4.2; 35.8] 
 
  
1280 
   
38 
   
30 
    [21.0; 40.7]  
  
[10.6; 49.4] 
 
  
1280 
   
51 
   
40 
    [29.7; 52.4]  
  
[17.6; 62.4] 
 
  
1280 
   
64 
   
50 
    [38.5; 63.8]  
  
[25.0; 75.0] 
 
  
Second year of enrollment (analysis will be performed 1 year after the last subject is recruited) 
 
 Country/region level    
160 
   
2 
   
10 
     [0.7; 40.1] 
   
[0; 41.7] 
 
  
160 
   
3 
   
20 
     [3.9; 54.8] 
   
[0; 64.8] 
 
  
160 
   
5 
   
30 
     [8.4; 68.5] 
   
[0; 84.9] 
 
  
160 
   
6 
   
40 
    [13.8; 81.6]  
  
[0; 103.4] 
 
  
160 
   
8 
   
50 
    [21.6; 98.5]  
  
[0; 120.8] 
 
 Overall 
   
640 
   
6 
   
10 
     [3.4; 20.4] 
   
[0; 25.8] 
 
  
640 
   
13 
   
20 
    [10.2; 33.7]  
  
[0; 42.4] 
 
  
640 
   
19 
   
30 
    [17.9; 46.4]  
  
[2.6; 57.4] 
 
  
640 
   
26 
   
40 
    [25.9; 58.6]  
  
[8.3; 71.7] 
 
  
640 
   
32 
   
50 
    [34.2; 70.6]  
  
[14.6; 85.4] 
 
CI = Confidence Interval; RSV = Respiratory Syncytial Virus; 
LRTI = Lower Respiratory Tract Infection; DE = Design Effect 
The design effect measures the increase in the standard error of the estimate due to the 
sampling design. The following formula will be used to estimate the design effect in the 
simulation [Bennett, 1991]: 
 
With 
 
 

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Design effect calculated from 1000 simulations and for different 
hypothesis 
Table 14 
Each simulation consists of creating ‘c’ clusters whose size and incidence vary around a 
given value. Then the above formula was applied to estimate the design effect in the 
simulation. Table 14 shows the median result of 1000 simulations (with 5th and 95th 
percentile). The design effect [Bennett, 1991] can be estimated as following once the 
intra-cluster correlation value is known or can be assumed: 
DE = 1 + (b – 1) ρ 
Where, ρ is the intra-cluster correlation and b is the average number of subjects sampled 
per cluster. According to the results of simulations, we could assume that the intra-cluster 
correlation of 0.02 (See Table 14 below) and considering 12 clusters of 160 subjects, we 
expect that the design effect will take a value of 4.18. 
Where, ‘c’ is the number of clusters, ‘xi’, and ‘yi’ are number of children-years and 
number of cases, respectively in the ‘ith’ cluster, ‘n’ is the total number of children-years 
and ‘p’ is the overall proportion ‘∑ yi/∑xi’. 
The intra-cluster correlation ‘ρ’ may then be estimated as: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hypothesis of the 
simulation (Number of 
clusters; Overall 
number of children- 
years; incidence) 
Results of 1000 simulations 
Number of 
children-years by 
cluster (P5; 
Median; P95) 
Proportion of 
cases by cluster 
(P5; Median; P95) 
DE : Design Effect 
(P5; Median; P95) 
ρ : intra-cluster 
correlation (P5; 
Median; P95) 
  
9; 2400; 0.03 
   
136; 266; 401 
 
    0; 0.028; 0.086  
    2.51; 6.46; 13.67  
  0.006; 0.021; 0.047  
12; 2400; 0.03 
100; 201; 300 
0; 0.027; 0.087 
2.57; 5.13; 9.49 
0.008; 0.021; 0.042 
15; 2400; 0.03 
81; 160; 239 
0; 0.027; 0.088 
2.29; 4.34; 7.74 
0.008; 0.021; 0.042 
18; 2400; 0.03 
68; 133; 199 
0; 0.026; 0.091 
2.08; 3.89; 6.69 
0.009; 0.022; 0.043 
P = Percentile 
Few active studies reported the overall RSV-associated LRTI incidence rates (with or 
without hospitalization). According to the results observed in a birth cohort conducted in 
Kenya [Nokes, 2008] we expect that the RSV-associated LRTI rate will be 8 times 
greater than the hospitalization rate. 
As the subjects may dropout from the study due to a variety of reasons, e.g. migration 
from the study area, the sample size has been increased to accommodate the same. 
Assuming a drop-out rate of about 20% during the course of follow-up approximately 
400 subjects by country/region and 2400 subjects overall will need to be recruited. 

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9.4. 
Study cohorts/ data sets to be analysed 
 
9.4.1. 
Screened cohort 
 
The screened cohort will include all subjects screened for the study. All the aggregated 
information (anonymous) for these subjects will be collected in a logbook. 
 
 
9.4.3. 
Analysis Cohorts for the Extension Study 
 
9.4.3.1. 
Total enrolled cohort for extension 
 
The total enrolled cohort will include all subjects enrolled in the extension study. 
 
9.4.3.2. 
PPS cohort for extension 
 
The PPS cohort for the Extension study will include all subjects meeting all eligibility 
criteria up to the time of their censoring, either at study completion or prematurely as 
drop-out (e.g. withdrawn consent or lost-to-follow-up). 
• 
The PPS sub-cohort at Year 2 will include subjects in the PPS cohort at Year 2 for 
whom a blood sample result will be available (at Month 2, 4, 6, 12, 18 or 24). 
Analyses will be done on the ATP sub-cohort from the total cohort defined in section 
9.4.2 as well as from the ATP cohort defined in section 9.4.2.2. 
Per Protocol Set (PPS) sub-cohort at Year 2 
9.4.2.3. 
The PPS cohort will include all subjects enrolled in the primary study meeting all 
eligibility criteria up to the time of their censoring, either at completion of epoch 1 or 
prematurely as drop-out (e.g. withdrawn consent, lost-to-follow-up, lack of compliance). 
Additional details are provided in the Statistical Analysis Plan (SAP). 
Per Protocol Set (PPS) cohort at Year 2 
9.4.2.2. 
The total enrolled cohort will include all subjects enrolled in the primary study. 
Total enrolled cohort at Year 2 
9.4.2.1. 
Analysis Cohorts for the Primary study (first 2 years) 
9.4.2. 

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9.5. 
Derived and transformed data 
Data transformations and derived variables will be described in the SAP. However, 
they may include the following: 
 
• 
Age of the subject at time of the LRTI case will be expressed in months and will be 
computed as the difference between the start date of the LRTI case and the date of 
birth. 
• 
Age of the subject at time of blood sample collection will be expressed in months 
and will be computed as the difference between the sample collection date and the 
date of birth. 
• 
Age of the mother at the time of childbirth will be expressed in years and will be 
computed as the difference between the birth date of the subject and the birth date of 
the mother. 
• 
Duration of the study for each subject will be computed as the difference between 
the date of last contact (i.e., active or passive surveillance contact or the date of the 
censoring) and the date of enrollment (date when ICF was first signed by the 
subject’s parent[s]/LAR[s]). 
 
• 
All potential LRTI cases identified during the surveillance period will be classified 
as RTI, LRTI or severe LRTI according to the LRTI case definition and severity 
scale (refer to Section 4). The cases will also be classified according to the 
classification of WHO and by Nokes et al [Modjarrad, 2016; Nokes, 2004]. First 
time, the classification will be done at visit level, i.e. according to the data collected 
at the initial visit and, if applicable, at each additional examination visit. Finally, a 
classification at case level will be done considering the most severe classification 
from all visits. 
 
9.5.1. 
General considerations for statistical analyses 
 
The primary analyses will at least be performed on the PPS cohort or sub-cohort. If more 
than 5% of the subjects are eliminated from the total enrolled cohort, then all analyses 
may also be performed on the total enrolled cohort in addition to the PPS cohort or sub- 
cohort. 
 
When mentioned below in the upcoming analyses sections, analysis by subgroups may 
include: 
 
• 
Age categories 
• 
Hemisphere/Region/Country 
• 
Birth on-season or off-season 
• 
Collection time of swabs (72 hours/48 hours from the start date of the case (date of 
the call), 72 hours/48 hours from the reported onset of symptoms). 

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• 
For all incidence rate calculations, the 95% CI using the exact Poisson distribution 
will be estimated, as well the 95% CI using the normal approximation of the Poisson 
distribution, accounting for a design effect (after having derived the design effect 
from the real data). 
 
9.6. 
Analysis of demographics 
The distribution of subjects enrolled among the study sites may be tabulated overall, by 
hemisphere, country, region, center and/or by other relevant grouping. The 
demographic and lifestyle characteristics collected for the enrolled subjects may be 
summarized overall, by hemisphere, country, region, center, and/or other relevant 
grouping. 
 
• 
Frequency tables will be generated as appropriate, for categorical variables such as 
center. 
• 
Mean, median, standard error will be provided as appropriate, for continuous data 
such as age. 
 
9.7. 
Analysis of Objectives for the Primary Study (birth to 2 
years of age): 
 
9.7.1. 
Co-primary objectives 
 
• 
To determine the total health burden of RSV-associated RTI with a suspicion of 
involvement of the lower respiratory tract. 
Incidence rates will be calculated as the number of RSV-associated RTI with a suspicion 
of involvement of the lower respiratory tract over the number of children-years 
observations, overall and by subgroups. 
 
Descriptive statistics of the different types of healthcare utilization from all healthcare 
settings will be provided (proportions, duration, etc.) among RSV-associated RTI with a 
suspicion of involvement of the lower respiratory tract, overall and by subgroups. 
 
• 
To assess the performance of the LRTI case definition and severity scale for 
RSV-associated cases. 
Incidences rates will be calculated as the number of RSV-associated LRTI/severe LRTI 
as classified by the LRTI case definition and severity scale and also as classified by the 
comparator case definitions (WHO and Nokes, et al [Modjarrad, 2016; Nokes, 2004]), 
over the number of children-years observations, overall and by subgroups. 
 
Descriptive statistics of the different types of healthcare utilization will be provided 
(proportions, duration, etc.) among RSV-associated LRTI/severe LRTI as classified by 
the LRTI case definition and severity scale and also as classified by the comparator case 
definitions (WHO and Nokes, et al [Modjarrad, 2016; Nokes, 2004]), overall and by 
subgroups. 

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Comparison of two classifications for severe/Non-severe LRTI 
Table 15 
Statistical analysis of agreement will be performed to compare the different case 
definitions of RSV-associated LRTI/severe LRTI and key healthcare utilization and 
health outcomes (the hospitalization status, (P) intensive care unit [ICU] attendance, 
clinical diagnosis of bronchiolitis or pneumonia, death) overall and by age categories. 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
RSV-associated cases 
 
Classification of reference 
(severe/Non-severe) 
Hospitalized 
Not hospitalized 
Alternative 
classification (severe / 
Non-severe) 
Severe LRTI 
(LRTI case definition and severity scale) 
   True positive (TP)  
    False positive (FP)  
Non-severe LRTI 
(LRTI case definition and severity scale) 
  False negative (FN)     True Negative (TN)  
 
2x2 contingency tables such as Table 15 will be provided and the following measures of 
agreement (with 95% CI) will be calculated: 
 
• 
Sensitivity: TP/ (TP+FN) 
• 
Specificity: TN/ (TN+FP) 
• 
Positive predictive value (PPV): TP/ (TP+FP) 
• 
Negative predictive value (NPV): TN/ (TN+FN) 
• 
Proportion of overall agreement, which is the proportion of cases similarly classified: 
(TP + TN)/ (TP+FP+FN+TN). 
• 
Cohen’s kappa coefficient. The magnitude of the kappa coefficient represents the 
proportion of agreement greater than that expected by chance. 
The same analysis will at least be performed for all the following combinations 
(reference vs. alternative classification): 
 
• 
Health/healthcare utilization outcome vs. LRTI case definition and severity scale. 
• 
Health/healthcare utilization outcome vs. WHO case definition [Modjarrad, 2016]. 
• 
Health/healthcare utilization outcome vs. Nokes, et al case definition [Nokes, 2004]. 
• 
WHO case definition [Modjarrad, 2016] vs. LRTI case definition and severity scale. 
• 
Nokes, et al case definition [Nokes, 2004] vs. LRTI case definition and severity 
scale. 
 
9.7.2. 
Secondary objectives 
 
• 
To determine the total health burden of non-RSV-associated RTI with a 
suspicion of involvement of the lower respiratory tract. 
Incidence rates will be calculated as the number of non-RSV-associated RTI with a 
suspicion of involvement of the lower respiratory tract over the number of children-years 
observations, overall and by subgroups. 

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Descriptive statistics of the different types of healthcare utilization will be provided 
(proportions, duration, etc.) among non-RSV-associated RTI with a suspicion of 
involvement of the lower respiratory tract, overall and by subgroups. 
 
• 
To evaluate the association between RSV-associated LRTI, RSV-associated 
severe LRTI and RSV neutralizing antibodies in the baseline cord blood 
samples collected from subjects, at birth. 
The impact of the level of RSV neutralizing antibodies in the baseline cord blood samples 
on the risk of having a RSV-associated LRTI and RSV-associated severe LRTI will be 
assessed through a statistical model. 
 
Incidence rates will be calculated overall and by level of antibodies in the cord blood 
sample, as the number RSV-associated LRTI/severe LRTI as classified by the case 
definition and severity scale over the number of children-years observations. 
 
• 
To determine the prevalence of RSV infection, at 2, 4, 6, 12, 18 and 24 months in 
a randomly selected sub-cohort of subjects by assessing antibodies in serum. 
The primary analysis will be based on ATP sub-cohort for this objective. 
 
Infection by RSV will be assessed (with 95% CI) by time point as the proportion of 
samples with a positive score of antibody titer after adjusting for baseline antibody results 
over the total number of samples. 
 
Scores will be determined based on the measured antibody titer vs. the expected antibody 
level at the time of sampling based on the individual baseline (cord blood) value and the 
average, modelled decay rate. 
 
• 
To assess the between calendar year variability in the incidence rates of RSV- 
associated LRTI. 
Incidences rates will be calculated as the number of RSV-associated LRTI/severe LRTI 
as classified by the case definition and severity scale, over the number of children-years 
observations, in the subgroups of subjects recruited from months 1-6 and from months 
13-18. 
 
9.7.3. 
Tertiary Objectives 
 
• 
To explore the association of co-infections with the incidence of RSV-associated 
LRTI and/or severe LRTI (as determined by the LRTI case definition and 
severity scale) using xTAG™ RVP Fast assay. 
For each of the other respiratory viruses, incidence rates will be calculated as the number 
of RSV-associated LRTI/severe LRTI cases associated co-infected with the virus over the 
number of children-years observations. 
 
• 
To explore the association of RSV and other respiratory viruses with the 
incidence of LRTI and/or severe LRTI (as determined by the LRTI case 
definition and severity scale) using xTAG™ RVP Fast assay. 

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For each of the respiratory viruses, incidence rates will be calculated as the number of 
LRTI/severe LRTI cases associated with the virus over the number of children-years 
observations. 
 
• 
To explore the association of RSV viral load with the incidence of RSV- 
associated RTI, LRTI and/or severe LRTI (as determined by the LRTI case 
definition and severity scale). 
Descriptive analyses (mean, median, min, max) of viral load assessed by the RSV RT- 
qPCR of RSV RTI, RSV LRTI and severe LRTI cases will be tabulated. 
 
• 
To explore the impact of changes to the symptoms and threshold levels of 
symptoms in the LRTI case definition and severity scale. 
Frequency tables will summarize the proportion of RSV-associated LRTI/ severe LRTI 
cases associated with a list of symptoms and clinical parameters, overall and by age 
categories. 
 
This will help us to determine potential areas of improvement of the LRTI case definition 
and severity scale. Incidence rates of RSV-associated LRTI/severe LRTI will be 
calculated for any proposal of modification of the LRTI case definition and severity 
scale. 
 
• 
To explore the impact of variations in cord-blood sample collection variables on 
the stability of test results. 
The measured maternal antibody levels will be assessed versus variability in sample 
collection variables. This involves assessment versus various continuous and categorical 
variables and an overall comparison between samples as classified ‘according to 
recommended procedure’ and ‘not according to recommended procedure’. 
 
The measured maternal antibody levels by duration of the processing step and overall 
process duration will be analysed graphically and by log-linear regression. 
 
The measured maternal antibody levels by storage condition or tube type will be analysed 
graphically and by group statistics (mean, 95% CI). Group means will be compared by t- 
test to assess the statistical significance of differences. 
 
The measured maternal antibody levels in samples collected ‘according to recommended 
procedure’ and ‘not according to recommended procedure’ will be analysed graphically 
and by group statistics (mean, 95% CI). Group means will be compared by t-test to assess 
the statistical significance of any difference. 
 
• 
To assess the impact of potential RSV risk factors (e.g. complications at birth, 
family history of respiratory disease, lifestyle characteristics and household 
composition, breast feeding, passive smoking, day care attendance) on the 
incidence and severity of RSV-associated LRTI. 
The incidence of any, severe, non-severe RSV-associated LRTI will be analysed using a 
Poisson regression model including potential risk factors. 

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9.8. 
Analysis of Objectives for the Extension study 
 
9.8.1. 
Primary objectives: none 
 
9.8.2. 
Secondary objectives 
 
Data for secondary endpoints may be pooled across the primary and extension periods. 
Additional details are provided in the SAP. 
 
9.8.2.1. 
To determine the population attributable risk of wheeze and asthma 
from birth to sixth birthday due to RSV clinical LRTI in the first two 
years of life. 
 
The incidence rate of medically attended wheeze, wheeze or asthma requiring hospital 
admission, and prescription of medications for wheeze or asthma may be calculated 
and stratified by country. 
 
The population attributable risk may be calculated by subtracting the incidence rate in the 
subjects who did not have RSV clinical LRTI in the first two years of life from the 
incidence rate in all subjects including both who had and who did not have RSV clinical 
LRTI in the first two years of life. 
 
Details will be provided in the SAP. An example follows. 
 
The population attributable risk of medically attended wheeze may be calculated as: 
• 
To assess the natural decay of maternal antibody levels using a single follow-up 
blood sample collected from a randomly selected sub-cohort of subjects at 2, 4, 
6, 12, 18 and 24 months. 
The primary analysis will be based on ATP sub-cohort for this objective. 
The decay of maternal antibody levels over time will be analysed graphically and by a 
log-linear regression. A true, natural decay curve will be explored by stochastically 
reducing the sample to uninfected subjects only. The following steps will be taken to 
identify, confirmed and suspected infected subjects to eliminate these from the sample; 
• 
Subjects with an RSV positive nasal swab during the study before time of sampling 
will be eliminated. 
• 
A sensitivity analysis of the decay curve will be explored in sub-sample consisting of 
the subjects born ‘off-season’ as these have the lowest likelihood of having been 
infected. 
• 
Subjects with an antibody titer at the sampling time that is more than 2-fold above 
the expected value based on their baseline (cord blood) value and the established 
decay curve will be considered to have been infected, eliminated and the decay curve 
refined. 
• 
Step 3 is repeated up to 5 times until the most accurate decay curve is established. 

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Ip-Iu 
 
Where Iu is the incidence rate of medically attended wheeze in subjects who did not have 
RSV clinical LRTI in the first two years of life, and Ip is the incidence rate of medically 
attended wheeze in all subjects including both who had and who did not have RSV 
clinical LRTI in the first two years of life. The above population attributable risk 
formula may be further adapted to best accommodate the data and their required 
analytic assumptions (e.g., a modified formula may be used for population attributable 
risk calculations involving recurrent outcomes). 
 
9.8.2.2. 
To determine the population attributable risk percent of wheeze and 
asthma from birth until sixth birthday due to RSV clinical LRTI in the 
first two years of life. 
 
The population attributable risk percent together with 95% CI of medically attended 
wheeze, wheeze or asthma requiring hospital admission, and prescription of medications 
for wheeze and asthma may be calculated overall and by age strata (0-2 years, 2-4 years 
and 5-6 years), respectively. 
 
The population attributable risk percent may be calculated by dividing the population 
attributable risk by the incidence rate in all the subjects including both who had and who 
did not have RSV clinical LRTI in the first two years of life. 
 
For example, the population attributable risk percent of medically attended wheeze may 
be calculated as: 
 
(Ip-Iu)/Ip*100 
 
Where Iu is the incidence rate of medically attended wheeze in subjects who did not have 
RSV clinical LRTI in the first two years of life, and Ip is the incidence rate of medically 
attended wheeze in all subjects including both who had and who did not have RSV 
clinical LRTI in the first two years of life. As with the population attributable risk, the 
above formula may be adapted, as appropriate, to best suit the data. 
 
The detail for calculating the CI for both population attributable risks and population 
attributable risk percent will be provided in the SAP. 
 
9.8.3. 
Tertiary objectives 
 
9.8.3.1. 
To explore the association of RSV clinical LRTI in the first two years of 
life and other potential risk factors for wheeze and asthma 
 
Endpoints such as medically attended wheeze, wheeze or asthma requiring hospital 
admission, and prescription of medications for wheeze or asthma may be calculated as 
recurrent events and stratified by country. 
 
Occurrence/recurrence rates will be calculated overall and by subgroups for each of the 
outcomes, as relevant. Multivariable Poisson regression or other appropriate models 

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including RSV clinical LRTI in the first two years of life and other potential risk factors 
such as, but not limited to, family history of asthma, and/or allergies, contact with pets, 
child history of allergy, eczema or atopic dermatitis, etc., will be explored, respectively. 
 
9.8.3.2. 
To explore the performance of asthma case definitions. 
 
The number and percentage of children with diagnosis of asthma (case definitions 1, 2, 
and 3 will be described for each applicable age; the number and percentage of children 
with recurrent wheeze at each applicable age will be described overall and by country in 
frequency tables. 
 
The risk of asthma at the age of 6 years using case definitions 1, 2 and 3 (occurring from 
2nd to the 6th birthday) will be analyzed using multivariable logistic regression model 
including RSV clinical LRTI in the first two years of life and other potential risk factors 
listed above, respectively. 
 
• 
Statistical analysis of agreement will be performed to compare asthma case 
definitions 1, 2, and 3 to each other. 
• 
Cohen’s kappa (or other appropriate) coefficient may be used for the comparisons. 
The magnitude of the kappa coefficient represents the proportion of agreement 
greater than that expected by chance. 
 
9.9. 
Interpretation of analyses 
All analyses will be descriptive with the aim to characterise overall occurrences, patterns 
and potential differences between groups in the endpoints related to the objectives. 
The tertiary objective ‘To explore the impact of changes to the symptoms and threshold 
levels of symptoms in the LRTI case definition and severity scale’ will be assessed if we 
detect potential areas of improvement of the LRTI case definition and severity scale, such 
as clearly under or overestimated incidence rates of LRTI/ severe LRTI compared to the 
rates in the literature or a lack of discriminative power between severe and non-severe 
cases. This decision will not be taken on specific pre-defined thresholds. 
 
9.10. 
Conduct of analyses 
Analytic plans may be modified as appropriate to accommodate final sample sizes and 
data distributions. 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. 
 
9.11. 
Sequence of analyses 
An interim analysis will be performed after data lock at the end of recruitment (expected 
after 18 months) or in June 2015 whichever occurs first, on the data collected for the 
subjects recruited in the first year of the study (approximately 1600). This interim 
analysis will be performed to obtain preliminary indications of the results in very young 
infants. These preliminary results will be used for potential adjustment of the LRTI Case 

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Definition and Severity Scale before final analysis, and to provide data for other relevant 
decision making, as soon as possible.* The results pertaining to this analysis will be 
descriptively reported in an interim statistical report. 
 
*Based on the preliminary results of the interim analyses it was decided that the 
incidence rate would be more robust if all subjects completed the primary study until 2 
years of age. 
 
Final analysis will be performed on all the data collected and cleaned in the study, at the 
end of the extension period which is expected to occur 7 years after study start. An 
integrated study report presenting the consolidated analysis for the entire study duration 
(primary and extension study period [as applicable]) will be written and made available 
to the investigators. 
 
 
9.11.2. 
Statistical considerations for the extension study 
 
All statistical analyses pertaining to the extension study will be performed on data 
collected and cleaned for the subjects who re-consented for the extension. 
 
An interim analysis for the extension study will be conducted near the midway point of 
extension study data collection, after all subjects have reached four years of age (and 
completed their annual contact, or passed the window for that contact). The interim 
analysis will be purely descriptive, no adjustment of the type I error is foreseen. 
 
Final extension study analysis will be conducted after all subjects have reached six 
years of age (and completed their annual contact, or passed the window for that 
contact). 
 
10. 
ADMINISTRATIVE MATTERS 
To comply with ICH GCP or other applicable guidelines administrative obligations 
relating to data collection, monitoring, archiving data, audits, confidentiality, ownership 
and publications must be met. 
Statistical analyses for the interim analysis will be performed on all the data collected and 
cleaned for the subjects recruited in the first year of the study, at the end of recruitment 
(expected after 18 months) or in June 2015 whichever occurs first. 
The interim analysis will be purely descriptive, no adjustment of the type I error is 
foreseen. 
Statistical considerations for the primary study 
9.11.1. 

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10.1. 
Remote Data Entry instructions 
Remote Data Entry (RDE), a validated computer application, will be used as the method 
for data collection. 
 
In all cases, subject initials will not be collected nor transmitted to GSK. Subject data 
necessary for analysis and reporting will be entered/transmitted into a validated database 
or data system. Clinical data management will be performed in accordance with 
applicable GSK standards and data cleaning procedures. 
 
While completed eCRFs are reviewed by a GSK Biologicals’ Site Monitor at the study 
site, omissions or inconsistencies detected by subsequent eCRF review may necessitate 
clarification or correction of omissions or inconsistencies with documentation and 
approval by the investigator or appropriately qualified designee. In all cases, the 
investigator remains accountable for the study data. 
 
Once the database is archived and the clinical study report is complete and approved by 
all parties, each participating investigator will be provided with a CD-ROM of the final 
version of the data generated at his/her investigational site. 
 
10.2. 
Study monitoring by GSK Biologicals 
GSK will monitor the study to verify that, amongst others, the: 
 
• 
Data are authentic, accurate, and complete. 
• 
Safety and rights of subjects are being protected. 
• 
Study is conducted in accordance with the currently approved protocol, any other 
study agreements, GCP and all applicable regulatory requirements. 
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents. 
 
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 RDE review and a Source Document 
Verification (SDV). By SDV we understand verifying RDE 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 RDE. This document should be completed and signed by the site monitor and 
investigator and should be filed in the monitor’s and investigator’s study file. Any data 
item for which the RDE will serve as the source must be identified, agreed and 
documented in the source documentation agreement form. 
 
For RDE, the monitor will mark completed and approved screens at each visit. 

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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. 
 
10.3. 
Record retention 
Following closure of the study, the investigator must maintain all site study records 
(except for those required by local regulations to be maintained elsewhere) in a safe and 
secure location. The records must be easily accessible, when needed (e.g., audit or 
inspection), and must be available for review in conjunction with assessment of the 
facility, supporting systems, and staff. Where permitted by applicable laws/regulations or 
institutional policy, some or all of these records can be maintained in a validated format 
other than hard copy (e.g., microfiche, scanned, electronic); however, caution needs to be 
exercised before such action is taken. The investigator must ensure that all reproductions 
are legible and are a true and accurate copy of the original and meet accessibility and 
retrieval standards, including re-generating a hard copy, if required. Furthermore, the 
investigator must ensure that an acceptable back-up of the reproductions exists and that 
there is an acceptable quality control procedure in place for making these reproductions. 
 
GSK will inform the investigator/institution of the time period for retaining these records 
to comply with all applicable regulatory requirements. However, the 
investigator/institution should seek the written approval of the Sponsor before proceeding 
with the disposal of these records. The minimum retention time will meet the strictest 
standard applicable to a particular site, as dictated by ICH GCP or other applicable 
guidelines, any institutional requirements or applicable laws or regulations, or GSK 
standards/procedures; otherwise, the minimum retention period will default to 15 years. 
 
The investigator/institution must notify GSK of any changes in the archival 
arrangements, including, but not limited to, archival at an off-site facility and transfer of 
ownership of the records in the event the investigator leaves the site. 
 
10.4. 
Quality assurance 
To ensure compliance with GCP or other applicable guidelines and all applicable 
regulatory requirements, GSK may conduct a quality assurance audit. Regulatory 
agencies may also conduct a regulatory inspection of this study. Such audits/inspections 
can occur at any time during or after completion of the study. If an audit or inspection 
occurs, the investigator and institution agree to allow the auditor/inspector direct access 
to all relevant documents and to allocate his/her time and the time of his/her staff to the 
auditor/inspector to discuss findings and any relevant issues. 

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10.5. 
Posting of information on publicly available registers and 
publication policy 
Study information from this protocol will be posted on public registers before enrollment 
of subjects begins/before start of the analyses. 
 
Interventional studies that do not evaluate vaccines/products are progressed for 
publication in the scientific literature when the results provide important scientific or 
medical knowledge. 
 
10.6. 
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 Biologicals site or other 
mutually-agreed location. 
 
GSK Biologicals will also provide the investigator with the full summary of the study 
results. The investigator is encouraged to share the summary results with the study 
subjects, as appropriate. 
 
11. 
COUNTRY SPECIFIC REQUIREMENTS 
Not applicable. 

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12. 
REFERENCES (AMENDED 15-DEC-2017) 
Bennett S, et al. A simplified general method for cluster-sample surveys of health in 
developing countries. World Heath Statistics Quarterly. 1991; 44 (3) 98-106. 
 
Bisgaard H, et al. Endotyping early childhood asthma by quantitative symptom 
assessment. J Allergy Clin Immunol. 2011; 127(5):1155-64.e2. 
 
Bønnelykke K, et al. Association between respiratory infections in early life and later 
asthma is independent of virus type. J Allergy Clin Immunol. 2015; 136(1):81-86.e4. 
 
Boyce TG, Mellen BG, Mitchel EF, et al. Rates of hospitalization for respiratory 
syncytial virus infection among children in Medicaid. J Pediatr. 2000; 137:865-70. 
 
Canducci F, Debiaggi M, Sampaolo M, et al. Two-year prospective study of single 
infections and co-Infections by respiratory syncytial virus and viruses identified recently 
in infants with acute respiratory disease. J. of Medical Virology. 2008; 80:716-723. 
 
de Sierra TM, Kumar ML, Wasser TE, et al. Respiratory syncytial virus-specific 
immunoglobulins in preterm infants. J Pediatr. 1993 May; 122(5 Pt 1):787-91. 
 
Despande SA, 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; 88:1065–1069 detected in children by polymerase chain 
reaction. Pediat.r Infec.t Dis. J. 2004; 23:S11-18. 
 
Drews AL, Atmar RL, Glezen WP, et al. Dual respiratory virus infections. Clin. Infect. 
Dis. 1997; 25: 1421-9. 
 
Fairchok MP, Martin ET, Chambers S, et al. Epidemiology of viral respiratory tract 
infections in a prospective cohort of infants and toddlers attending daycare. J. of Clinical 
Virology. 2010; 49; 16-20. 
 
Feldman AS, He Y, Moore ML, Hershenson MB, Hartert TV. Toward primary 
prevention of asthma. Reviewing the evidence for early-life respiratory viral infections 
asmodifiable risk factors to prevent childhood asthma. Am J Respir Crit Care Med. 2015; 
191(1):34-44. 
 
Graham BS. Biological challenges and technological opportunities for respiratory 
syncytial virus vaccine development. Immunological reviews. 2011; 239:149-166. 
 
Hall CB, McCarthy CA. Respiratory syncytial virus. In: Mandell GL, Bennett JE, Dolin 
R, editors. Principles and practices of infectious disease. Philadelphia: Elsevier Churchill 
Livingstone; 2004. p. 2008–26. 
 
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. 

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88
Henrickson KJ, Hoover S and Sue Kehl K. National disease burden of respiratory viruses. 
Pediatr Infect Dis J. 2004 Jan;23(1 Suppl):S11-8. 
 
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. 
 
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 June 6; Vol. 113. 
 
Jackson DJ, et al. Wheezing rhinovirus illnesses in early life predict asthma development 
in high-risk children. Am J Respir Crit Care Med. 2008; 178 (7):667-672. 
 
Jackson DJ, et al. Evidence for a causal relationship between allergic sensitization and 
rhinovirus wheezing in early life. Am J Respir Crit Care Med. 2012; 185(3):281-5. 
 
Krilov LR. Respiratory syncytial virus disease: update on treatment and prevention. 
Expert Rev. Anti. Infect. Ther. 2011; 9(1), 27–32. 
 
Langley GF and Anderson LJ. Epidemiology and prevention of respiratory syncytial 
virus infections among infants and young children. Pediatr. Infect. Dis. 2011; 30: 510- 
517. 
 
Law BJ, Estrany C and Simoes EA. An update on respiratory syncytial virus 
epidemiology: a developed country perspective. Respiratory Medicine. 2002; Vol.96 
(Supplement B), S1-S7. 
 
Lemanske RF Jr. The Childhood Origins of Asthma (COAST) study. Pediatr Allergy 
Immunol 2002; 13 (Suppl. 15): 38–43. 
 
Lemanske RF Jr, et al. Rhinovirus illnesses during infancy predict subsequent childhood 
wheezing. J Allergy Clin Immunol 2005;116:571–577. 
 
Modjarrad K, Giersing B, Kaslow DC, Smith PG, Moorthy VS; 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. doi: 10.1016/j.vaccine.2015.05.093. Epub 2015 Jun 20. 
 
Morgan WJ, et al. Outcome of asthma and wheezing in the first 6 years of life: follow-up 
through adolescence. Am J Respir Crit Care Med. 2005;172(10):1253-8. 
 
Mullins JA, Lamonte AC, Bresee JS, et al. Substantial variability in community 
respiratory syncytial virus season timing. PIDJ. 2003; 22(10):857-863. 
 
Nair H, Nokes JD, Gessner BD, et al. Global burden of acute lower respiratory infections 
due to respiratory syncytial virus in young children: a systematic review and meta- 
analysis. Lancet. 2010; 375:1545-55. 

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89
Nokes DJ, Okiro EA, Ngama M, et al. Respiratory Syncytial Virus Epidemiology in a 
Birth Cohort from Kilifi District, Kenya: Infection during the First Year of Life. J Infect 
Dis. 2004; 190 (10): 1828-1832. 
 
Nokes DJ, Okiro EA, Ngama M, et al. Respiratory Syncytial Virus Infection and Disease 
in Infants and Young Children Observed from Birth in Kilifi District, Kenya. Clinical 
Infectious Diseases. 2008; 46:50–7. 
 
Pearce N, Aït-Khaled N, Beasley R, et al. Worldwide trends in the prevalence of 
asthma symptoms: phase III of the International Study of Asthma and Allergies in 
Childhood (ISAAC). Thorax 2007;62:758-766. 
 
Roca A, Abacassamo F, Loscertales MP, et al. Prevalence of respiratory syncytial virus 
IgG antibodies in infants living in a rural area of Mozambique. J Med Virol. 2002; 67, pp. 
616–623. 
 
Simoes EAF. Respiratory syncytial virus infection. Lancet. 1999; 354: 847–52. 
 
Vicente D, Montes M, Cilla G, et al. Hospitalization for respiratory syncytial virus in the 
paediatric population in Spain. Epidemiol. Infect. 2003; 131, 867–872. 
 
Weber MW, Mulholland EK and Greenwood BM. Respiratory syncytial virus infection 
in tropical and developing countries. Tropical Med. and Int. Health. 1998; volume 3 no 4 
pp 268–280. 
 
Wong, G, Brunekreef B, Ellwood P, et al. Cooking fuels and prevalence of asthma: a 
global analysis of phase three of the International Study of Asthma and Allergies in 
Childhood (ISAAC). Lancet Respir Med. 2013; 1: 386–94. 
 
Yang CL, To T, Foty RG, Stieb DM, Dell SD. Verifying a questionnaire diagnosis of 
asthma in children using health claims data. BMC Pulmonary Medicine. 2011;11:52. 
doi:10.1186/1471-2466-11-52. 

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APPENDIX A 
LABORATORY ASSAYS 
Neutralization assay 
 
The Serum Neutralization assay is a functional assay that measures the ability of serum 
antibodies to neutralise the cytopathic effects of RSV (for example, strains A and B) on 
the host cell line, hence RSV replication. In the first step of the assay, a specific quantity 
of a replication capable RSV virus and a defined dilution of serum are mixed and 
incubated. Each serum dilution is tested in duplicates. During the second step, the virus- 
serum reaction mixture is transferred on the host cells and only non-neutralized virus is 
able to infect and replicate in the host cells. This leads to the formation of a given number 
of plaque forming units (PFU) on the cell monolayer that can be detected using a 
fluorochrome-tagged anti-RSV antibody. The neutralising titer is determined by 
calculating the serum dilution inducing a 60% inhibition in PFUs compared to a cell 
monolayer infected with virus alone, without serum. 
 
RT-qPCR assay 
 
Briefly, RSV A and RSV B ribonucleic acids (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 (cDNA) 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. 
 
xTAG™ RVP Fast assay 
 
xTAG™ RVP Fast assay is a qualitative nucleic acid multiplex tests intended for the 
simultaneous detection and identification of multiple respiratory virus nucleic acids in 
nasal/nasopharyngeal swabs from individuals suspected of respiratory tract infections. A 
multiplexed PCR reaction is performed to amplify the regions of interest in the target 
human or infectious agent genes. The PCR reaction is treated to remove excess 
nucleotides and primers. The PCR reaction is then subjected to a primer extension step 
that is specific for the allele or the infectious agent that is being analyzed: Allele Specific 
Primer Extension (ASPE) or Target Specific Primer Extension (TSPE). The 5’ end of the 
ASPE or TSPE primers is attached to an xTAG universal tag sequence. The 5’ universal 
tag sequence is hybridized to the complementary anti-tag sequence coupled to a particular 
xMAP bead set. The hybridized beads are read by the xMAP system and results are 
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APPENDIX B 
CLINICAL LABORATORIES 
Table 16 
GSK Biologicals’ laboratories 
 
Laboratory 
Address 
GSK Biologicals Clinical Laboratory Sciences, 
Rixensart 
Biospecimen Reception - B7/44 
Rue de l'Institut, 89 - B-1330 Rixensart - Belgium 
GSK Biologicals Clinical Laboratory Sciences, Wavre- 
Nord Noir Epine 
Avenue Fleming, 20 - B-1300 Wavre - Belgium 
 
 
Table 17 
Outsourced laboratory 
 
Laboratory 
Address 
NÉOMED-LABS Inc. 
525, Cartier Ouest Laval, 
Quebec 
Canada H7V 3S8 

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APPENDIX C 
OVERVIEW OF RECRUITMENT PLAN (PRIMARY 
STUDY) (AMENDED 15-DEC-2017) 
• 
Subjects will be pre-selected to be enrolled in the study, by obtaining the informed 
consent from the parent(s)/LAR(s) during pregnancy, after 20 weeks of gestation 
and before the start of delivery, to include their child in the study at birth. On 
obtaining the consent, the subjects will be checked for inclusion and exclusion 
criteria applicable before birth. A pre-selected child not meeting the inclusion and 
exclusion criteria will be considered a screening failure. 
• 
On receiving consent, subject numbers will be assigned sequentially to each 
subject, according to the range of subject numbers allocated to each study center. 
• 
After birth, the final inclusion and exclusion criteria will be checked and the 
informed consent will be updated with, time and date of birth and any other 
potentially relevant identifiers as applicable by local requirements and re-signed. 
Any pre-selected subject not meeting the eligibility criteria will be considered a 
screening failure. 
• 
Subject recruitment is intended to occur over a period 18 months or until the 
planned target enrollment has been met. Assuming no delays in recruitment, two- 
thirds of the subjects (1600) will be recruited in Year 1 and the remaining one- 
third of the subjects (800) in the first half of Year 2 of the study. In case of any 
delays in recruitment for the first two-thirds of the subjects, the study duration will 
be extended until all these subjects have completed follow-up to 2 years of age. 
Delays in the recruitment of the last one-third of the subjects will be absorbed by a 
shorter follow-up period for these subjects, unless the decision is taken after the 
interim analysis to extend the study to allow all subjects to complete 2 years of 
follow-up. 
• 
The recruitment will be performed using a first application of SBIR where subjects 
will be entered on obtaining ICF and recruitment is controlled on the monthly 
recruitment rate. The aim is to attain a reasonably stable number of subjects per 
month over the full recruitment period in order to achieve an equal spread in the 
age of subjects at first exposure to an RSV season. Recruitment will be actively 
controlled through the SBIR system on country level according to agreed targets, 
actual recruitment rates, and further recruitment potential, so as to achieve a 
sufficient population on a regional level. With concurrent recruitment across the 
globe (with different seasonality) and an intended, steady recruitment over 18 
months, the following population is to be included; 
 
Subjects from NH during first 6 months 
 
Subjects from SH during first 6 months 
 
Subjects from NH during second 6 months 
 
Subjects from SH during second 6 months 
 
Subjects from NH during third 6 months; repeat of first 6 months NH 
 
Subjects from SH during third 6 months; repeat of first 6 months SH 

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 
In case recruitment is extended beyond 18 months, subjects recruited in the 
fourth 6 month period are a repeat to those recruited during the second 6 
month period 
NH=Northern hemisphere, SH=Southern Hemisphere. Figure assumes equal recruitment targets on both hemispheres 
(which is not a requirement for the study). 
Figure A represents recruitment in the NH and assumes RSV seasons running from November to April relative to a 
currently estimated time point 0 in Nov 2013. 
Figure B represents recruitment in the SH and assumed RSV seasons running from May to October relative to a 
currently estimated time point 0 in Nov 2013. 
Recruitment on both Hemispheres will include a period of ‘On Season’ recruitment and a period of ‘Off Season’ 
recruitment and a third period of recruitment matching the first period. 
An interim analysis data lock is scheduled after 1.5 years or in June 2015, whichever occurs first. 
RSV seasons in Northern and Southern Hemispheres 
Figure 3 

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APPENDIX D 
ADDITIONAL INFORMATION REGARDING 
PRIMARY STUDY VISITS (AMENDED 15-DEC- 
2017) 
 
 
 
 
 
• 
Eligibility criteria applicable before birth will be assessed. A pre-selected child who 
does not meet the eligibility criteria will be considered a screening failure. 
• 
The expected delivery date will be collected as required by the eCRF. 
• 
After obtaining the ICF and confirming eligibility, the subject needs to be entered 
into the randomization system on internet (SBIR) screening module. SBIR will 
control the recruitment rate as per an allocated target. 
• 
The study site will contact the pregnant mother at their own discretion to monitor 
the status of the pregnancy. 
Visit 2 (enrollment visit commencing at birth): 
• 
During this visit, and before any study follow-up procedures are performed (no 
later than 5 working days after birth of the subject), the informed consent will be 
updated with relevant personal identifiers as applicable by local requirements and 
re-signed by the parent(s)/LAR(s), investigator and witness (when required). The 
investigator/study staff should also collect any further identifying data (e.g. official 
name, social security number) that becomes available for a subject during the 
course of the study, at regular surveillance contacts and record it in a supporting 
document. 
 
In case of anticipated twins (or other multiple births), an ICF needs to be 
signed for each expected child before the start of delivery. A subject number 
will be assigned sequentially to each child as per the birth order, where the 
first born will be associated with the lowest subject number, the second born 
with the successive subject number, etc. 
 
In case of unexpected twins (or other multiple births), only the children for 
whom an ICF was signed and subject number was assigned before birth can 
be enrolled. This should again occur as per the birth order. 
Study visit schedule related to the primary study (from birth up to the age of 2 years): 
Visit 1 (screening visit): 
• 
Informed consent will be obtained by the investigator/study staff for each subject 
from the parent(s)/LAR(s) of the subjects during pregnancy, after at least 20 weeks 
of gestation and before the start of delivery, to include their child in the study, at 
birth. 
• 
On obtaining the consent, one subject number will be assigned to each unborn 
child and recorded in the ICF and the copy of the ICF will be provided to the 
parent(s)/LAR(s). A sequential allocation of subject numbers will be assigned 
according to the range of subject numbers allocated to each study center. 

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• 
A baseline cord blood sample of up to approximately 10 mL will be collected at 
birth from all live born infants recruited at Visit 1 in the study. 
• 
Eligibility of the infants for the study will be confirmed as per the inclusion and 
exclusion criteria that can be assessed only after birth. If the subject is found to be 
ineligible during this assessment, the cord blood sample that was collected will be 
discarded and the subject will be considered a screening failure. Eligibility 
(including the updated ICF) needs to be definitively confirmed not later than 5 
working days after the birth or the subject will automatically become a screening 
failure. Eligibility also needs to be definitively confirmed before any other study 
procedure is performed. 
Refer to section 5.3 and 5.3.2 for details on the inclusion and exclusion criteria. 
 
• 
After obtaining the updated ICF and confirming eligibility, the subject needs to be 
entered in to the SBIR enrollment module. SBIR will randomize the subject to a 
time point for blood sample collection. If the subject is part of the sub-cohort, 
parent(s)/LAR(s) should be informed about this allocation. 
• 
Information about the delivery and the newborn (including medical care provided 
immediately after birth and planned to be provided subsequently) will be collected 
by the study team from the parents/LAR, and if possible, completed and/or 
confirmed with an original source accessed through a person involved in the 
delivery of the subject or from any authorized person representing the healthcare 
organization that is in charge of the source. 
• 
The parent(s)/LAR(s) will be interviewed to obtain information on the family 
medical history and demographic and lifestyle characteristics of the subject as 
required by the eCRF. 
• 
Parent(s)/LAR(s) of the subjects will be instructed when to contact the 
investigator/study staff and will be provided with diary cards to record symptoms 
and healthcare utilization over the course of the disease when instructed to do so 
by the investigator/study staff. For details refer to ‘surveillance contacts (active 
and passive surveillance)’ below. 
Visit 3 (blood sample collection): 
 
• 
This visit will be applicable only for a sub-cohort of subjects. At the time point 
randomly allocated to each subject selected for a blood draw (2, 4, 6, 12, 18 or 24 
months), an off-site or site visit needs to be scheduled and a single follow-up blood 
sample of 3.5 mL should be collected from the subjects between the intervals of  1 
week, to be included in the analyses e.g. Month 2  1 week, Month 4  1 week. For 
details refer to Table 1. Children who are born with a gestational age of less than 
36 weeks will be excluded from this sub-cohort. 

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APPENDIX E 
ADDITIONAL INFORMATION REGARDING LRTI 
SURVEILLANCE, INCLUDING ACTIVE 
SURVEILLANCE CONTACT SCHEDULE 
(PRIMARY STUDY) (AMENDED 15-DEC-2017) 
Surveillance contacts (ACTIVE AND PASSIVE SURVEILLANCE) 
 
In order to optimize the reporting procedures of suspected LRTI cases and to ensure 
that the maximum number of cases are timely identified and reported to the study sites, 
both active and passive surveillance will be conducted. 
 
• 
Passive surveillance by ‘self’-report of symptoms by parent(s)/LAR(s) of the 
subjects is key for timely identification of a potential LRTI case. Parent(s)/LAR(s) 
need to contact the investigator/study staff as soon as the child experiences new 
RTI symptoms (cough, runny nose, blocked nose), irrespective of the appearance 
of signs of difficulty in breathing, which will be determined by the 
investigator/study staff on contact. 
• 
For the active surveillance, parent(s)/LAR(s) of all the subjects will be contacted 
by the investigator/study staff on a regular basis (active follow-up schedule will be 
confirmed based on the local settings and seasonality) to identify any potential 
LRTI case and to remind the parent(s)/LAR(s) of the subjects to report any new 
sign of RTI symptoms (cough, runny nose, blocked nose) as soon as possible 
themselves. 
Note: A child experiencing RTI symptoms (cough, runny nose, blocked nose) with any 
signs of difficulty in breathing will be considered a potential LRTI case. 
 
During each active or passive follow-up contact, the investigator/study staff will: 
 
• 
Confirm with the parent(s)/LAR(s) of the subject, if the subject developed new RTI 
symptoms (cough, runny nose, blocked nose) and if he/she has developed any signs 
of difficulty in breathing (during and between contacts). 
 
 
 
In case there is any current sign or suspicion of difficulty in breathing in a 
child with symptom(s) of RTI at the time of the contact, the investigator/study 
staff will instruct the parent(s)/LAR(s) to start completing the diary card and 
will schedule an examination visit as soon as possible, 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 an optimal biological sample for the detection of RSV. 
The examination visit can be an on-site or off-site visit. An off-site visit is 
preferred in order to avoid influencing the pattern of healthcare 
utilization for the disease. Parent(s)/LAR(s) of the subjects can however 
be requested to bring their child to the study center for the site 
examination visit e.g. if this would be the normal standard of care to 
provide given the situation, if this will significantly expedite the timing of 
the visit, or if it is unlikely that the off-site examination visit can occur at 

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all within the required timeframe. 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 [ER]) and an examination visit could be scheduled to 
take place there at a suitable time. 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
If during the contact, the investigator/study staff schedules an examination visit 
(off-site/site), the parent(s)/LAR(s) are instructed to start completion of the diary 
card. Parent(s)/LAR(s) need to fill the diary card until Day 14 from the day the 
investigator/study staff have instructed them to initiate the diary card, unless the 
investigator/study staff informs them otherwise (e.g. in case of a second 
examination visit). If the symptoms last for more than 14 days the 
parent(s)/LAR(s) should continue to assess the symptoms until no more symptoms 
are present, and record in the diary card, the date at which no more symptoms 
were observed in the child. 
• 
For any reported illness, the investigator/study staff should assess the need for any 
intervention and provide the same as part of regular healthcare or instruct/advise 
the parent(s)/LAR(s) where to obtain this care. 
• 
The active and passive surveillance contacts and completion of diary card can also 
be made by/with person designated by the parent(s)/LAR(s) (e.g. grandparents, 
nanny) as long as the parent(s)/LAR(s) have approved the same. If needed, a field 
worker can also be assigned to support the parent(s)/LAR(s) and/or person 
designated by the parent(s)/LAR(s) in completing the diary card. 
• 
On a quarterly basis, an active surveillance contact will be expanded to obtain 
updated information on the demographic, lifestyle and general medical 
characteristics of the subject as required by the eCRF. 
Refer to phone script provided along with the protocol for details. 
Examination visit (off-site/site): 
• 
A case eCRF needs to be created for each scheduled examination visit and data 
collected up to case resolution will be entered. Examination visits will be allocated 
with a unique visit number that is a sequential number per subject. 
• 
During the examination visit (off-site/site), the investigator/study staff will 
objectively confirm the RTI and difficulty breathing (i.e. involvement of lower 
 
The surveillance contact and the decision that an examination visit is 
indicated should be recorded in the eCRF. Refer to ‘examination visit’ for 
next steps. 
 
In case the symptoms do not include current signs of RTI and difficulty in 
breathing, this surveillance/episode will be recorded in the site’s source 
documentation and in the eCRF, but no examination visit will be scheduled. 
Parent(s)/LAR(s) will be instructed to contact the study team as soon as 
possible if the severity of the already existing symptoms in the child increases 
or if the child who did not have signs of difficulty breathing develops the 
symptom. 

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RTI = Respiratory Tract Infection; 72h = 72 hours; RR = Respiratory Rate; SaO2 = Blood Oxygen Saturation 
eCRF = electronic Case Report Forms; LRTI = Lower Respiratory Tract Infections; HCP = Healthcare Provider 
** Parent(s)/LAR(s) need fill in the diary card until Day 14 from the day the investigator/study staff have 
instructed them to initiate the diary card. 
respiratory tract) experienced by the subject. Data will be collected on all the 
clinical symptoms present in the child including a measurement of the respiratory 
rate (RR) and blood oxygen saturation [SaO2] by pulse oximetry and recorded in 
the eCRF. The investigator/study staff will consider whether the symptoms meet 
the LRTI case definition for surveillance. Refer Section 4 for details on symptoms 
to be recorded. If the symptoms are not (yet) considered to be an LRTI, a potential 
additional examination visit (off-site/site) in case of worsening of symptoms may 
be needed (Refer to Figure 4 for the decision model). 
Figure 4 
Decision tree for active and passive follow-up contact for the 
primary study 

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Note: The investigator/study staff will do an initial assessment of a case reported for 
the examination visit as either RTI or LRTI, only to determine further study activities. 
The final classification of all the cases reported as either RTI, LRTI or severe LRTI 
will be done during statistical analyses (as per the LRTI case definition and severity 
scale and comparative scales). 
 
• 
Nasal swabs will be collected for all the subjects who are reported for an 
examination visit (off-site/site) (this includes subjects with no confirmed LRTI). 
• 
Data on disease course and healthcare utilization recorded by the subject’s 
parent(s)/LAR(s) in the diary card until the examination visit will be reviewed and 
recorded by the investigator/study staff in the subject’s eCRF. 
• 
During subsequent regular surveillance contacts (active and passive) after an 
examination visit, the status and evolution of the case will be followed, and 
parent(s)/LAR(s) will be reminded to complete the diary card for the full period or 
until case resolution, if after. Data provided by the parent(s)/LAR(s) in the diary 
card on healthcare utilization should ideally be confirmed by direct contact of the 
investigator/study staff with the healthcare providers involved in management of 
the case (e.g. General Practitioner [GP], hospital staff) and recorded in the eCRF. 
Where possible, the data on healthcare utilization should be made more complete 
as to best capture the healthcare utilization in the eCRF. Any clinical diagnoses 
for the respiratory infection (e.g. pneumonia, bronchiolitis) made by the contacted 
healthcare providers should be collected and recorded in the eCRF as well as the 
symptoms assessed in support of this diagnosis (especially measured RR and 
SaO2). 
• 
A new diary card and case eCRF will be initiated for each scheduled examination 
visit. Any ongoing eCRF for that case from previous examination visits will be 
closed and further data recorded in the new case eCRF. If a surveillance case 
eCRF is ‘closed’ due to a subsequent examination visit for the same case, the diary 
card relating to the ‘closed’ eCRF is stopped prematurely and a new 14-day diary 
card is started (see also Section 3-examination visit). 
• 
Collection of the completed diary cards will be done at resolution by mail or in 
person depending on local best practice. 
 
ACTIVE SURVEILLANCE CONTACT SCHEDULE to identify any potential LRTI 
case 
 
Active surveillance is aimed at confirming that a case is/was not missed due to lack of 
reporting by parent(s)/LAR(s) and to remind parent(s)/LAR(s) to report cases of RTI 
symptoms as soon as possible themselves. 
 
Active surveillance is allowed to occur through various media (e.g. text messaging, 
email, telephone, and in-person) based on local possibilities 
 
• 
Requirements for non-live media (e.g., text messaging and email) are that; 
 
They meet GSK, local and international requirements with regards to the 
validity of the system used and data privacy and security. 

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Active surveillance is to occur at a defined frequency dependent on the known RSV 
seasonality. 
 
• 
RSV has a typical winter/monsoon seasonality. The peak rates of RSV occur at 
different times on the Northern and Southern Hemisphere. The tropical regions 
are generally known to have little or no seasonality. 
 
For this reason, an active surveillance schedule will usually be applied based on the 
known or expected RSV seasonality for each study country/site. 
 
• 
12 annual contacts - One monthly contact in all the regions. 
• 
At least 4 seasonal contacts – An intermediate contact in the four known/expected 
peak months, depending on the RSV seasons in the country/site. More 
intermediate contacts may be scheduled if deemed necessary by the investigator. 
 
Outside the scheduled active surveillance contacts, each country/site can employ 
additional activities to enforce active and passive surveillance at their discretion. These 
activities can be tailored to best meet the local situation (e.g. reminders, community 
consultation sessions, additional in-person subject support visits, etc.). 
 
TIMING AND REQUIREMENTS FOR CONTACT 
 
• 
Active surveillance contacts are scheduled compared to the calendar week (Sat- 
Sun) of enrollment into the study. So regardless of the day of birth, the first 
Sunday after birth is Week 1 in the surveillance schedule. 
 
• 
Seasonal contacts can occur anytime during the season they are scheduled to 
occur. A minimum of three attempts, occurring on at least two different working 
days should be made. 
 
• 
Monthly contacts should occur in the first two weeks of the calendar month. A 
minimum of six attempts, occurring on at least four different working days spread 
over two subsequent weeks should be made to make contact for monthly 
surveillance contacts. 
 
DISCONTINUATION OF ACTIVE SURVEILLANCE 
 
All reasonable efforts should be made to conduct all active surveillance contacts in line 
with the schedule mentioned above. However, subjects’ parent(s)/LAR(s) of the subject 
may not be available for active surveillance for a period of time. 
 
At least one live (e.g., telephone or in-person) contact occurs every quarter. 
 
An adequate response is obtained on non-live contact (e.g. return text message 
or return email). Any non-live contact that is not responded to after a 
maximum of 2 reminders within the course of 2 days should be followed up 
with a live contact. 

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• 
During active contacts, investigator/study staff should request the parent(s)/LAR(s) 
of the subject if they will unavailable for a scheduled period (e.g. due to holiday). 
If so, the active surveillance contacts can then be actively planned differently or 
cancelled compared to the regular schedule. No more than 2 consecutive active 
surveillance contacts and/or a period of more than 1 month can be cancelled. 
• 
Active surveillance should be suspended after there has been no contact for more 
than 3 planned contacts and/or no contact for more than 2 months and a final 
attempt has been made by mail or a live visit. If the parent(s)/LAR(s) of the subject 
contact the investigator/study staff at a later point in time through passive 
surveillance, the case should be followed up, data should be collected at 
intermittent period and active surveillance could be reinitiated. 

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PPD 
PPD 
PPD 
PPD 
PPD 
PPD 
PPD 
PPD 
APPENDIX F 
AMENDMENTS AND ADMINISTRATIVE 
CHANGES TO THE PROTOCOL 
 
GlaxoSmithKline Biologicals 
Vaccine Value & Health Science (VVHS) 
Protocol Amendment 1 
eTrack study number and Abbreviated Title 
200150 (EPI-RSV-005 BOD) 
Amendment number: 
1 
Amendment date: 
27 November 2013 
Co-ordinating author: 
PPD 
, Scientific writer 
Rationale/background for changes: 
In order to reduce study complexity and manage the global study budget the study 
design has been amended as follows. 
• 
The sample size has been reduced from 3,000 subjects to 2,400 subjects to balance 
recruitment of approximately 400 subjects in each geographic/climatic area. 
Reducing the sample size will affect the precision of the estimates obtained, but 
will be sufficient to meet the study objectives with a sample size of 2,400 subjects. 
• 
The maximum number of active surveillance contacts has been fixed to 16 per year 
per subject. Reducing active surveillance impacts the probability to detect cases of 
LRTI. To balance the risk of missing cases of LRTI, the study sites will also 
perform passive surveillance. The study procedure manual will outline passive 
surveillance methods that could be implemented in country settings e.g. social 
media applications in developed countries versus regular (weekly) person-to- 
person community visits in less developed countries. 
• 
In addition, some minor editorial changes have been made. 
Amended text has been included in bold italics and deleted text in strikethrough in 
the following sections: 
Title page: 
List of contributing authors: 
• 
, Senior Manager, Epidemiologisty, Discovery and Early Development 
• 
, Global Study Delivery Manager, Harrison Clinical Research 
Benelux n.v. a SynteractHCR, Inc Company for GlaxoSmithKline Biologicals 
• 
, Study Delivery Lead 
• 
, Study Delivery Manager, Novellas Healthcare for 
GlaxoSmithKline Biologicals 
• 
,Project Delivery Lead 
• 
, Vaccine Supply Co-ordinator 
• 
, Project Manager, Global Study Management Study Delivery Lead 
• 
, Lead Statistician Senior Manager, Biometrics 

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Synopsis (Tertiary objectives): 
 
• 
To explore the association of other respiratory viruses with the incidence of LRTI 
and/or severe LRTI (as determined by the LRTI case definition and severity scale) 
using xTAG™ RVP Fast assay. 
• 
To explore the impact of variations in cord-blood sample collection variables on 
the stability of test results. 
• 
To assess the natural decay of maternal antibody levels using a single follow-up 
blood sample collected from a randomly selected sub-cohort of subjects at 2, 4, 6, 
12, 18 and 24 months. 
 
Synopsis and Section 3. (Study design overview): 
 
Study population: A cohort of approximately 3000 2400 infants will be included in the 
study at birth and followed-up to a maximum of 2 years of age. 
 
• 
Subjects will be recruited and followed up through active and passive surveillance 
for a maximum of 2 years. The study involves the following visit and contact 
schedule: 
 
Visit 1 (screening visit) 
 
Visit 2 (enrollment visit, commencing at birth) 
 
Assuming no delays in recruitment, two-thirds of the subjects (approximately 
20001600) will be recruited in Year 1 of the study and will be followed-up up to 
2 years of age, resulting in a total study duration of 3 years. The remaining 
subjects (approximately 1000800) will be recruited in the first half of Year 2 of 
the study and will be followed up till the end of Year 3. 
Table 2 
Study groups and epochs foreseen in the study 
 
Study 
Groups 
Number of 
subjects 
Age (Min/Max) 
Epoch 1 
Prospective 
Approximately 
3000 2400 
At birth-maximum of 2 
years 
x 
Synopsis and Section 3.1 (Discussion of study design): 
 
The first 2000 subjects (ideally recruited in the first year of recruitment) enrolled in the 
study will be randomized at recruitment to a time point at which a single blood sample 
will be collected from these subjects if they are still participating in the study at that 
time. 
 
Synopsis (Number of subjects): 
 
Target enrollment will be 30002400 subjects to obtain approximately 24001920 fully 
evaluable subjects at study completion. 

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Section 5.1. Number of subjects/centers:Target enrollment will be 30002400 subjects to 
obtain approximately 24001920 fully evaluable subjects at study completion. 
 
Subject recruitment is intended to occur over a period 18 months or until the planned 
target enrollment has been met. Assuming no delays in recruitment, two-thirds of the 
subjects (20001600) will be recruited in Year 1 and the remaining subjects (1000800) in 
the first half of Year 2 of the study (See Figure 3). 
 
Synopsis and Section 9.1.3 (Tertiary endpoints): 
Cord-blood sample collection variables including collection and storage times and 
temperatures. 
 
Section 2.3 Tertiary objectives: 
To explore the impact of variations in cord-blood sample collection variables on the 
stability of test results. 
 
Section 3 Study Design Overview: 
Figure 1 Study design diagram: 
Footnote added – “* All follow up procedures associated with V2 (e.g. ICF) must be 
performed within 5 working days after birth.” 
 
Study visit schedule:Visit 1 (screening visit) 
The study site will contact the pregnant mother at their own discretion to monitor the 
status of the pregnancy. 
 
Visit 2 (enrollment visit commencing at birth): 
Information about the delivery and the newborn (including medical care provided 
immediately after birth and planned to be provided subsequently) will be collected by the 
study team from the parents/LAR, and if possible, completed and/or confirmed with an 
original source accessed through a person involved in the delivery of the subject or from 
any authorized person representing the healthcare organization that is in charge of the 
source. 
Data provided by the parent(s)/LAR(s) in the diary card on healthcare utilization should 
ideally be confirmed by direct contact of the investigator/study staff with the healthcare 
providers involved in management of the case (e.g. General Practitioner [GP], hospital 
staff) and recorded in the eCRF. 
Refer to APPENDIX C for active and passive contact schedule. 
 
Examination visit (off-site/site): 
Data provided by the parent(s)/LAR(s) in the diary card on healthcare utilization should 
ideally be confirmed by direct contact of the investigator/study staff with the healthcare 
providers involved in management of the case (e.g. General Practitioner [GP], hospital 
staff) and recorded in the eCRF. 

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Section 3 (Figure 2 Decision tree for active and passive follow-up contact) 

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Section 3.1: 
Proper passive surveillance is important in order to identify potential cases as early as 
possible. The active surveillance is mostly aimed at reinforcing the passive surveillance 
as the chance of picking up a (developing) case at the exact time of the active 
surveillance contact is limited. 
In between scheduled active surveillance contacts, the study staff can employ activities 
to solicit passive surveillance according to local practices, e.g. reminder emails or text 
messages up to regular community centre visits. 
Where possible, tThe study team will confirm and expand relevant healthcare utilization 
with the healthcare provider involved in the management of the case. 
Section 4 Case definition: 
• 
Aapnea 
Section 5.2 Inclusion criteria for enrolment: 
• 
Subject for whom updated and re-signed informed consent and confirmation of 
eligibility is available not later than 5 working days, after birth. 
• 
New born male or female. 
• 
Cord Bblood cord sample collection of at least 3 mlL, at birth. 
Section 5.3: 
Subjects with any confirmed or suspected immunosuppressive or immunodeficient 
condition at time of enrollment (including positive infection with human 
immunodeficiency virus [HIV]), based on medical history, physical examination or 
positive test result. 
Section 6.4: 
Table 6 
List of study procedures 
Only the amended rows have been added here: 
 
Time points 
Pre - Day 
0 
At 
birthPost 
- Day 0† 
As 
randomized
Regular& 
Unscheduled 
Examination during (off-site/site) 
visit and collection of all disease 
symptoms (including temperature, 
RR and pulse oximetry) 
● 
† Visit 2 can take place anytime within 5 working days after birth. 
Section 6.5.5: 
In case less than 3 mlL of whole blood is collected, the subject will be considered a 
screening failure and the sample collected needs to be discarded according to local 
procedure. 
Details of the sample collection such as duration of processing steps and storage 
conditions need to be collected and recorded in the eCRF in order to allow adjustment 

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for these variables in the primary analyses and to explore the impact of collection 
variables on the measured antibody titer. 
Section 6.5.8: 
Information about the delivery and the newborn (including medical care provided 
immediately after birth and planned to be provided subsequently) should be collected 
from the parents/LAR and completed and/or confirmed from an original source 
accessed through a person involved in the delivery of the subject or from any authorized 
person representing the healthcare organization that is in charge of the source and the 
collected data should be recorded in the subject’s eCRF. 
Section 6.5.12: 
Each aActive surveillance contacts required by the surveillance schedule and each 
passive surveillance contact, whether or not it triggers an examination visit, will be 
recorded in the site’s source documentation and in the eCRF. 
Section 6.5.13: 
On a quarterly basis, the investigator/study staff should expand a regular surveillance 
contact by asking the parents/LARs for changes to the baseline medical, demographic 
and lifestyle characteristics data collected at Visit 2. 
• 
vaccinations received (on disease level, not full vaccination details) 
Section 6.5.14: 
Data should be collected on all the clinical symptoms present in the child including a 
measurement of the temperature, RR and pulse oximetry. 
Temperature as measured by the investigator/study staff during the examination visit 
(off-site/site), and as subsequently assessed from the diary card, and/or confirmed with 
any healthcare provider involved, during course of the disease. 
Note: 
Hhealthcare utilization (or healthcare setting availed) refers to self-care with OTC 
drugs, GP visits, ER visits, hospital visits, etc. 
Data from healthcare providers (such as RR, SaO2, symptoms and diagnosis) is to be 
regarded as a valuable, but optional extra, if this data is available and shared by the 
applicable healthcare provider. 
Section 6.5.15 and Section 6.5.18 (Note): 
Data from healthcare providers (such as RR, SaO2, symptoms and diagnosis) is to be 
regarded as a valuable, but optional extra, if this data is available and shared by the 
applicable healthcare provider. 
Section 9.2: 
Table 10 shows the exact 95% confidence interval (CI) (Poisson exact distribution and 
normal approximation of the Poisson distribution accounting for a design effect of 4.18) 
for a range of expected incidence rates of RSV that we can reasonably estimate between 
10 and 50 per 1000 children-years in the first year of birth. With an overall sample size of 
about 400320 evaluable subjects by country during the first year of enrolment and with a 

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follow-up period of 1 year after the last subject is recruited, the CI for an expected RSV- 
associated LRTI hospitalization rate of 20 cases per 1000 children-years is respectively 
[8.66.9; 39.440.8] for the exact Poisson distribution and [0; 53.751.7] for the normal 
approximation with design effect of 4.18. 
Table 10 
Precision for expected RSV-associated LRTI hospitalization rate 
during the first year of life (per 1000 children-years) 
 
Number of 
children- 
years 
Number 
of cases 
RSV-associated 
LRTI rate (per 
1000 children- 
years) 
95% CI Poisson Exact 95% CI Normal 
approx. with DE 
First year of enrolment (analysis will be performed 1 year after the last subject is recruited) 
Country/region 
400320 
43 
10 
[2.7; 25.6] [1.9; 27.4] 
[0.0; 32.2] 
level 
[0; 32.4] 
400320 
86 
20 
[8.6; 39.4] [6.9; 40.8] 
[0.0; 51.4] 
[0; 51.7] 
400320 
1210 
30 
[15.5; 52.4] [13.9; 55.4] 
[0.0; 68.4] 
[0; 68.8] 
400320 
1613 
40 
[22.9; 65.0] [20.5; 67.5] 
[0.0; 84.4] 
[0; 84.8] 
400320 
2016 
50 
[30.5; 77.2] [28.6; 81.2] 
[0.4; 99.6] 
[0; 100.1] 
Overall 
16001280 
1613 
10 
[5.7; 16.2] [5.1; 16.9] 
[0.0; 21.1] 
[0; 21.2] 
16001280 
3226 
20 
[13.7; 28.2] [13.0; 29.3] 
[4.3; 35.7] 
[4.2; 35.8] 
16001280 
4838 
30 
[22.1; 39.8] [21.0; 40.7] 
[10.8; 49.2] 
[10.6; 49.4] 
16001280 
6451 
40 
[30.8; 51.1] [29.7; 52.4] 
[17.8; 62.2] 
[17.6; 62.4] 
16001280 
8064 
50 
[39.6; 62.2] [38.5; 63.8] 
[25.2; 74.8] 
[25.0; 75.0] 
Second year of enrolment (analysis will be performed 1 year after the last subject is recruited) 
Country/region 
200160 
2 
10 
[1.2; 36.1] [0.7; 40.1] 
[0.0; 41.4] 
level 
[0; 41.7] 
200160 
43 
20 
[5.4; 51.2] 
[0.0; 64.4] 
[3.9; 54.8] 
[0; 64.8] 
200160 
65 
30 
[11.0; 65.3] 
[0.0; 84.4] 
[8.4; 68.5] 
[0; 84.9] 
200160 
86 
40 
[17.3; 78.8] 
[0.0; 102.8] 
[13.8; 81.6] 
[0; 103.4] 
200160 
108 
50 
[24.0; 92.0] 
[0.0; 120.2] 
[21.6; 98.5] 
[0; 120.8] 
Overall 
800640 
86 
10 
[4.3; 19.7] 
[0.0; 25.7] 
[3.4; 20.4] 
[0; 25.8] 
800640 
1613 
20 
[11.4; 32.5] 
[0.0; 42.2] 
[10.2; 33.7] 
[0; 42.4] 
800640 
2419 
30 
[19.2; 44.6] 
[2.8; 57.2] 
[17.9; 46.4] 
[2.6; 57.4] 
800640 
3226 
40 
[27.4; 56.5] 
[8.6; 71.4] 
[25.9; 58.6] 
[8.3; 71.7] 
800640 
4032 
50 
[41.5; 59.8] [34.2; 70.6] 
[14.9; 85.1] 
[14.6; 85.4] 
CI = Confidence Interval; RSV = Respiratory Syncytial Virus; 
LRTI = Lower Respiratory Tract Infection; DE = Design Effect 

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The design effect measures the increase in the standard error of the estimate due to the 
sampling design. The following formula will be used to estimate the design effect in the 
simulation [Bennett, 1991] 
 
Each simulation consists of creating ‘c’ clusters whose size and incidence vary around a 
given value. Then the above formula was applied to estimate the design effect in the 
simulation. Table 11 shows the median result of 1000 simulations (with 5th and 95th 
percentile). The design effect [Bennett, 1991] can be estimated as following once the 
intra-cluster correlation value is known or can be assumed: 
 
DE = 1 + (b – 1) ρ 
 
Where, ρ is the intra-cluster correlation and b is the average number of subjects 
sampled per cluster. According to the results of simulations, we could assume that the 
intra-cluster correlation of 0.02 (See Table 11 below) and considering 12 clusters of 
200160 subjects, we expect that the design effect will take a value of 4.18between 2.57 
and 9.49. A median value of 5.13 was used for the CIs described in Table 9. 
 
Assuming a drop-out rate of about 20% during the course of follow-up approximately 
6400 subjects by country/region and 30002400 subjects overall will need to be recruited. 
Section 9.3.3 ATP cohort: 
The ATP cohort will include all subjects meeting all eligibility criteria up to the time of 
their censoring, either at study completion or prematurely as drop-out (e.g. withdrawn 
consent, losst-to-follow-up, lack of compliance). 
Section 9.8 Analysis of tertiary objectives: 
• To explore the impact of variations in cord-blood sample collection variables on the 
stability of test results. 
 
The measured maternal antibody levels will be assessed versus variability in sample 
collection variables. This involves assessment versus various continuous and 
categorical variables and an overall comparison between samples as classified 
‘according to recommended procedure’ and ‘not according to recommended 
procedure’. 
 
The measured maternal antibody levels by duration of the processing step and overall 
process duration will be analysed graphically and by log-linear regression. 
 
The measured maternal antibody levels by storage condition or tube type will be 
analysed graphically and by group statistics (mean, 95% CI). Group means will be 
compared by t-test to assess the statistical significance of differences. 
 
The measured maternal antibody levels in samples collected ‘according to 
recommended procedure’ and ‘not according to recommended procedure’ will be 
analysed graphically and by group statistics (mean, 95% CI). Group means will be 
compared by t-test to assess the statistical significance of any difference. 

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Section 9.9 Interpretation of analyses: 
 
The second tertiary objective ‘To explore the impact of changes to the symptoms and 
threshold levels of symptoms in the LRTI case definition and severity scale’ will be 
assessed if we detect potential areas of improvement of the LRTI case definition and 
severity scale, such as clearly under or overestimated incidence rates of LRTI/ severe 
LRTI compared to the rates in the literature or a lack of discriminative power between 
severe and non-severe cases. 
 
Section 9.10.1 Sequence of analyses: 
 
An interim analysis will be performed after data lock at the end of recruitment (expected 
after 18 months) or in June 2015 whichever occurs first, on the data collected for the 
subjects recruited in the first year of the study (approximately 20001600). 
 
APPENDIX C Active surveillance contact schedule: 
 
• 
Requirements for the non-live media chosen are that; 
 
At least one in three subsequent live contacts is done by phoneoccurs every 
quarter. 
 
An adequate response is obtained on non-live contact (e.g. return text message 
or return email). Any non-live contact that is not responded to after a maximum 
of 2 reminders within the course of 2 1 days should be followed up with a 
phone calllive contact. 
RSV has a typical winter/monsoon seasonality. 
For this e above mentioned reasons, an active surveillance schedule will be applied 
based on the known or expected RSV seasonality for each study country/site.is to occur 
according to the following schedule per geographic area (each study site will be allocated 
to a schedule based on geography and known data on seasonality pattern); 
• 
12 annual contacts - One monthly contact in all the regions. 
• 
4 seasonal contacts – An intermediate contact in the four known/expected peak 
months, depending on the RSV seasons in the country/site. 
• 
Outside the scheduled active surveillance contacts, each country/site can employ 
additional activities to enforce passive surveillance at their discretion. These 
activities can be tailored to best meet the local situation (e.g. reminders, 
community consultation sessions etc.). 
• 
Northern Hemisphere 
 
Every two weeks in October 
 
Every weekin November to February 
 
Every two weeks in March 
 
Every month in April to September 
• 
Southern Hemisphere 

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 
Every two weeks in May 
 
Every week in June to August 
 
Every two weeks in September 
 
Every month in October to April 
• 
Tropical region 
Every two weeks all year 
Weekly and two-weekly surveillance Seasonal contacts can occur anytime during the 
week season they are scheduled to occur. A minimum of three attempts, occurring on at 
least two different working days should be made to make contact for weekly and two- 
weekly surveillance contacts. 
 
Active surveillance should be suspended after there has been no contact for more than 3 
planned contacts and/or no contact for more than 2 months and a final attempt has been 
made by mail or a live visit. 

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GlaxoSmithKline Biologicals 
Vaccine Value & Health Science (VVHS) 
Protocol Amendment 2 
eTrack study number and Abbreviated Title 
200150 (EPI-RSV-005 BOD) 
Amendment number: 
Amendment 2 
Amendment date: 
06 July 2016 
Co-ordinating author: 
PPD 
writer 
, Scientific 
Rationale/background for changes: 
Infant respiratory viral infection and childhood asthma are the most common acute and 
chronic diseases of childhood, respectively. Common clinical features and links 
between these diseases have long been recognized, with early-life respiratory syncytial 
virus (RSV) lower respiratory tract infections (LRTIs) being strongly associated with 
increased asthma risk with no direct link to causality. 
World Health Organization (WHO) has recently updated its RSV-associated LRTI case 
definition. The latter includes clinical features considered to be objective, easily 
standardized, generalizable across settings, and generally accepted markers of severe or 
very severe RSV disease. 
Although asthma is probably a heterogeneous disease or syndrome, three factors and/or 
events consistently emerge for their ability to significantly influence asthma inception 
in the first decade of life: immune response aberrations, which appear to be defined 
best by the concept of cytokine dysregulation; LRTIs, in particular RSV; and some 
form of gene–environment interaction that needs to occur at a critical time-period in the 
development of the immune system or the lung [Lemanske, 2002]. 

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The Childhood Origins of Asthma (COAST) study was developed to determine and 
define the importance of these three factors on asthma pathogenesis and to test different 
asthma case classifications [Lemanske, 2002, Lemanske, 2005, Bisgaard, 2011, 
Jackson, 2008, Jackson, 2012, Bønnelykke, 2015]. These studies have used similar 
albeit slightly different case definitions on asthma diagnosis. These definitions are 
widely used in epidemiological literature of asthma etiology in children. The Bisgaard 
definition [Bisgaard, 2011] has multiple criteria that are assessed by the physician from 
records. Therefore the advantage of this definition is that the same objective criteria are 
applied to ascertain each case of asthma. However, its application may be challenging 
in some settings if routine medical records do not fully capture the necessary 
information in source. The Jackson definition [Jackson, 2008] includes the criteria of 
HCP diagnosis of asthma and prescription of 2 agonists. This definition is therefore 
influenced by any differences in local practice of asthma diagnosis and management of 
wheeze. However, its advantage is that it captures the reality of diagnosis and 
treatment. This study anticipates that Bisgaard will be more specific and Jackson more 
sensitive. Hence, this study will assess the performance of these two case definitions 
since this will help planning for phase 3 clinical trials of RSV vaccines. 
 
Numerous longitudinal studies have demonstrated this first important line of evidence 
that RSV LRTIs precede the development of asthma. Several birth cohort studies also 
demonstrate a dose–response relationship between infant respiratory viral infection 
severity and asthma risk, with increasing infant infection severity associated with 
greater childhood asthma risk and asthma severity [Feldman, 2015]. 
 
Population-level contribution of RSV LRTIs is best demonstrated by the population- 
attributable risk for asthma after these early-life LRTIs. Among infants, the prevalence 
of LRTI is approximately 18 to 32% in the first year of life and approximately 9 to 
17% in the second year of life. 
 
Among infants with LRTI, the prevalence of RSV can be as high as 80%, especially in 
the first 3 months of life. Thus, the phenotype of asthma after infant RSV LRTI 
accounts for up to 31% of early childhood asthma, with a population-attributable risk 
estimated at about 13% in several diverse populations [Feldman, 2015]. 
 
This cohort study provides us an opportunity to evaluate a potential association and the 
disease burden in the population due to RSV LRTI (exposure) early in life and the 
development of recurrent wheeze and asthma later in life (outcome). Derived 
calculations of incidence of recurrent wheeze and asthma among RSV LRTI positive 
and negative subjects and the calculation of population attributable risk percent will be 
able to potentially demonstrate a measurement of potential public health impact if a 
successful maternal and/or pediatric vaccine introduced and exposure (RSV) 
eliminated/reduced. 

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Hence, the protocol is being amended to reflect the following changes: 
 
• 
All subjects enrolled in the study will now be followed up from 2 years of age up 
to 6 years of age to capture episodes of wheeze and the diagnosis of asthma. 
• 
Additional secondary and tertiary objectives are being included in order to support 
exploratory analysis of the extent the early life experience of RSV LRTI is 
accounting for the total burden of wheeze and asthma from birth up to 6 years of 
age. 
• 
To perform an exploratory analysis and test of asthma case definitions and case 
classification performance based on well defined and commonly used case 
definitions from epidemiological studies. 
• 
To update LRTI case definitions and severity scale (according to WHO, 2015 
[Modjarrad, 2016]). 
• 
Information from this study will now be used to infer the potential benefit in terms 
of disease burden reduction and health care utilization of successful 
implementation of vaccination against RSV and measurement of potential public 
health impact and potential incidence reduction if a maternal and/or pediatric 
vaccine introduced and exposure (RSV) eliminated. 
• 
Overall, the new objectives aim to support the fact that successful maternal and 
paediatric vaccines that would be introduced would provide protection through the 
first two years of life against RSV LRTI and thus would reduce the burden of 
recurrent wheeze and asthma associated RSV from birth until the sixth birthday. 
Amended text has been included in bold italics and deleted text in strikethrough in 
the following sections: 
Title page: 
 
Title: 
 
A prospective, epidemiological study to assess the disease burden of respiratory syncytial 
virus (RSV) associated, suspected lower respiratory tract infections (LRTIs) in newborns, 
from birth up to 2 years of age from 0 to 2 years and population attributable risk 
percent of RSV LRTI on the development of recurrent wheeze and asthma from 0 to 6 
years. 
 
Detailed title: 
 
A prospective, epidemiological, interventional, multi-country based, cohort study to 
assess the disease burden of respiratory syncytial virus (RSV) associated, suspected lower 
respiratory tract infections (LRTIs) in newborns, from birth up to 2 years of age and 
population attributable risk percent of RSV LRTI on the development of recurrent 
wheeze and asthma from birth up to 6 years of age. 

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PPD 
PPD 
PPD 
PPD 
PPD 
PPD 
PPD 
PPD 
List of contributing authors: 
• 
, Senior Epidemiology Lead 
• 
, Global Vaccines Clinical Laboratory, Laboratory Project Manager 
Clinical Read-Out Team Leader 
• 
, Project Delivery Lead 
• 
, Clinical Laboratory Sciences Study Manager 
• 
, Clinical Laboratory Sciences Study Manager 
• 
; Project Data Manager 
• 
, Project Data Manager 
• 
, Study Data Manager 
Copyright 2013-2016 of the GlaxoSmithKline group of companies. All rights 
reserved. Unauthorized copying or use of this information is prohibited. 
Protocol Amendment 2 Sponsor Signatory Approval: 
Adrian Cassidy 
Director, 
VVHS Epidemiology, GSK Biologicals 
Amanda Leach 
Clinical and Epidemiology R&D Project Leader 
RSV Program, GSK Biologicals 
 
Glossary of terms: 
 
Exercise: Any moderate or vigorous physical activity performed by the child. 
 
Population Attributable Risk: Population attributable risk is the portion of the 
incidence of a disease in the population (exposed and unexposed) that is due to 
exposure. It is the incidence of a disease in the population that would be eliminated if 
exposure were eliminated. 
 
Population Attributable Risk Percent: Population attributable risk percent is the 
percent of the incidence of a disease in the population (exposed and unexposed) that is 
due to exposure. It is the percent of the incidence of a disease in the population that 
would be eliminated if exposure were eliminated. 
 
Synopsis and section 1.2 
Rationale for the study 
 
Infant respiratory viral infection and childhood asthma are the most common acute 
and chronic diseases of childhood, respectively. Common clinical features and links 
between these diseases have long been recognized, with early-life RSV LRTIs being 
strongly associated with increased asthma risk. 
 
World Health Organization (WHO) has recently updated its RSV-associated LRTI case 
definition [Modjarrad, 2016]. The latter includes clinical features considered to be 
objective, easily standardized, generalizable across settings, and generally accepted 
markers of severe or very severe RSV disease. 

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Although asthma is probably a heterogeneous disease or syndrome, three factors 
and/or events consistently emerge for their ability to significantly influence asthma 
inception in the first decade of life: immune response aberrations, which appear to be 
defined best by the concept of cytokine dysregulation; LRTIs, in particular RSV; and 
some form of gene–environment interaction that needs to occur at a critical time- 
period in the development of the immune system or the lung [Lemanske, 2002]. 
 
The Childhood Origins of Asthma (COAST) study was developed to determine and 
define the importance of these three factors on asthma pathogenesis and to test 
different asthma case classifications [Lemanske, 2002; Lemanske, 2005; Bisgaard, 
2011; Jackson, 2008; Jackson, 2012; Bønnelykke, 2015]. These studies have used 
similar albeit slightly different case definitions on asthma diagnosis. These definitions 
are widely used in epidemiological literature of asthma etiology in children. The 
Bisgaard definition [Bisgaard, 2011] has multiple criteria that are assessed by the 
physician from records. Therefore the advantage of this definition is that the same 
objective criteria are applied to ascertain each case of asthma. However, its application 
may be challenging in some settings if routine medical records do not fully capture the 
necessary information in source. The Jackson definition [Jackson, 2008] includes the 
criteria of HCP diagnosis of asthma and prescription of 2 agonists. This definition is 
therefore influenced by any differences in local practice of asthma diagnosis and 
management of wheeze. However, its advantage is that it captures the reality of 
diagnosis and treatment. This study anticipates that Bisgaard will be more specific and 
Jackson more sensitive. Hence, this study will assess the performance of these two case 
definitions since this will help planning for phase 3 clinical trials of RSV vaccines. 
Numerous longitudinal studies have demonstrated this first important line of evidence 
that RSV LRTIs precede the development of asthma. Several birth cohort studies also 
demonstrate a dose–response relationship between infant respiratory viral infection 
severity and asthma risk, with increasing infant infection severity associated with 
greater childhood asthma risk and asthma severity [Feldman, 2015]. 
 
Population-level contribution of RSV LRTIs is best demonstrated by the population- 
attributable risk for asthma after these early-life LRTIs. Among infants, the prevalence 
of LRTI is approximately 18 to 32% in the first year of life and approximately 9 to 17% 
in the second year of life. Among infants with LRTI, the prevalence of RSV can be as 
high as 80%, especially in the first 3 months of life. Thus, the phenotype of asthma 
after infant RSV LRTI accounts for up to 31% of early childhood asthma, with a 
population-attributable risk estimated at about 13% in several diverse populations 
[Feldman, 2015]. 
 
This cohort provides us an opportunity and information to evaluate a potential 
association between RSV LRTI (exposure) early in life and the development of 
recurrent wheeze and asthma later in life (outcome). In other words, this study will 
assess to what extent this early life experience of RSV LRTI is accounting for the total 
burden of wheeze and asthma from birth until sixth birthday. Moreover, this study will 
also test the performance of asthma case definition. This study will be able to 
potentially demonstrate a measurement of potential public health impact and potential 

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incidence reduction if a successful maternal and/or pediatric vaccine introduced and 
exposure (RSV) eliminated/reduced. 
 
Synopsis and section 2.1 
Co-Primary objectives 
 
In a cohort of infants followed-up from birth up to a maximum of 2 years of age: 
• 
To determine the total health burden* of RSV-associated RTI with a suspicion of 
involvement of the lower respiratory tract. 
Synopsis and section 2.2 
Secondary objectives: 
 
In a cohort of infants followed-up from birth up to a maximum of 2 years of age; 
• 
To evaluate the association between RSV-associated LRTI, RSV-associated severe 
LRTI and RSV neutralizing antibodies in the baseline cord blood samples collected 
from subjects, at birth. 
• 
To determine the prevalence of RSV A and B infection, at 2, 4, 6, 12, 18 and 24 
months in a randomly selected sub-cohort of subjects by assessing antibodies in 
serum. 
Objectives pertaining to the amendment related to wheeze and asthma: 
In a cohort of infants followed-up from birth up to 6 years of age: 
• 
To determine the population attributable risk of wheeze and asthma from birth to 
sixth birthday associated with RSV clinical LRTI in the first two years of life. 
• 
To determine the population attributable risk percent of wheeze and asthma from 
birth until sixth birthday associated with RSV clinical LRTI in the first two years 
of life. 
 
Synopsis and section 2.3 
Tertiary objectives: 
 
• 
To explore the association of RSV and other respiratory viruses with the incidence of 
LRTI and/or severe LRTI (as determined by the LRTI case definition and severity 
scale) using xTAG™ RVP Fast assay. 
• 
To explore the association of RSV viral load with the incidence of RSV-associated 
RTI, LRTI and/or severe LRTI (as determined by the LRTI case definition and 
severity scale). 
Objective pertaining to the amendment related to wheeze and asthma 
In a cohort of infants followed-up from birth up to 6 years of age: 
• 
To explore the association of RSV clinical LRTI in the first two years of life and 
other potential risk factors for wheeze and asthma. 
 
• 
To explore the performance of asthma case definitions. 

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Synopsis and section 3 
Study design overview: 
 
In the primary study subjects were to be followed-up from birth up to the age of 2 years 
for RSV LRTI. In order to determine the population attributable risk and population 
attributable risk percent of wheeze and asthma from birth to sixth birthday due to RSV 
clinical LRTI in the first two years of life, and to explore the association of RSV 
clinical LRTI in the first two years of life with other potential risk factors for wheeze 
and asthma, the study will be extended and subjects will be followed-up from the age of 
2 years up to 6 years to detect episodes of wheeze and diagnoses of asthma.* 
 
*Note: The procedures related to primary study (surveillance of RSV LRTI) will not be 
extended into the extension period. The extension period will survey for occurrence of 
wheeze and asthma. Data about wheeze and asthma were also collected in the primary 
study (documented at an examination visit or extracted from all treatments that were 
recorded during the examination visits, see Section 9.8). 
 
Epidemiological cohort studies have some limitations. It is possible that study dropouts 
might occur leading to differential lost to follow up and bias study. Moreover, it is 
possible that a selection bias might occur. Factors pertaining to enrollment of subjects 
into this prospective cohort study would not introduce selection bias. In order to 
introduce bias, selection has to be related to both exposure and outcome. But in this 
study, subjects are enrolled in prospective cohort before they experience the outcome of 
interest. 
 
Another potential limitation of this study is the occurrence of confounding especially 
with potential risk factors. A possible alternative would be to match within a cohort 
study. But this can reduce the efficiency of a cohort study even when there is no 
sample-size reduction and even when the matching variable is a confounder. 
Furthermore, albeit cohort matching prevents confounding by the matched variable, it 
is not considered an advantage of matched designs since in an unmatched study 
confounding by the covariates can be removed by analytical methods. Hence, in order 
to deal with the confounding factors stratification analysis will be used for each 
confounder. Multivariate logistic regression will also be used to adjust to confounders 
after selection from the univariate logistic regression. All possible confounding factors 
such as gender, geographic ancestry, pets, parental smoking and previous maternal or 
siblings history of asthma will be analyzed first in stratification and then in logistic 
regression (univariate and multivariate). 
 
Figure 1 shows the study diagram for the primary study (from birth up to the age of 2 
years for detection of RSV LRTI). 
 
Figure 2 describes the extension (from the age of approximately 2 years up to the age 
of 6 years for the detection of episodes of wheeze and diagnosis of asthma). 
 
Figure 1 
Study design diagram for the primary study (from birth up to the age of 
2 years for detection of RSV LRTI) 

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Figure 2 
Study design diagram for the extension (from the age of approximately 2 
years up to the age of 6 years) for the detection of episodes of wheeze and diagnosis of 
asthma 
 
 
 
Quarterly 
surveillance contacts 
 
• 
Parent(s)/legally acceptable representative(s) (LARs) of the subject will be contacted 
during the pregnancy in order to be informed about the study and to request consent 
for their child’s participation in the primary study. 
 
The parent(s)/LAR(s) will be requested to provide consent during pregnancy, 
after at least 20 weeks gestation, to enrol their child into the study, at birth. 
 
The child will be checked for eligibility criteria applicable before birth. 
 
The remaining eligibility criteria applicable after birth will be assessed as soon 
as possible, and the child’s participation in the study will be confirmed through 
an updated and resigned informed consent form (ICF) (including any other 
potentially relevant identifiers as applicable by local requirements) , not later 
than 5 working days after the birth of the subject. 
At the end of primary study (from birth up to the age of 2 years), parent(s)/LARs) will 
be asked for re-consent for their child’s participation in the extension (from 
approximately 2 years of age up to 6 years of age), pertaining to the amendment related 
to wheeze and asthma. 
 
• 
Study population: A cohort of approximately 2400 infants will be included in the 
study at birth and followed-up up to a maximum of 2 years of age. Maximum 2400 
children will be included in the extension and followed-up up to 6 years of age. 
Enrolment visit 
for extension 
(approx. 2 
years of age) 
3 
years 
4 
years 
5 
years 
6 
years 
ICF 
re-consent 

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• 
Biological samples: 
 Serum derived from up to approximately 10 milliliters (mL) of cord blood 
samples collected from all the subjects participating in the study, at birth. 
 Nasal swabs collected from subjects with potential LRTI symptoms i.e. RTI 
symptoms with any signs of difficulty in breathing. 
 Serum derived from a single blood sample of approximately 3.5 mL collected 
from a sub-cohort of subjects. This sub-cohort consists of the first 2000 enrolled 
subjects, from which those born at a gestational age of less than 36 weeks will be 
excluded from this blood sampling. Sampling time points for this sub-cohort will 
be randomly allocated as specified in Table 1. 
 No biological samples will be collected during the extension (from 
approximately 2 years of age up to 6 years of age). 
• 
Duration of the study: The entire duration of the primary study will be 
approximately 3 years. 
 
Assuming no delays in recruitment, two-thirds of the subjects (approximately 
1600) will be recruited in Year 1 of the study and will be followed-up up to 2 
years of age, resulting in a total primary study duration of 3 years. The 
remaining subjects (approximately 800) will be recruited in the first half of Year 
2 of the study and will be followed up till the end of Year 3. The follow-up 
period for subjects recruited in Year 2 will thus be 1.5 to 2 years.* Refer to 
Figure 4 for more details. 
 
In case of any delays in recruitment for the first two-thirds of the subjects in the 
study, the study duration will be extended until all these subjects have 
completed follow-up up to 2 years of age. Delays in the recruitment of the last 
one-third of the subjects will be absorbed by a shorter follow-up time for these 
subjects. 
 
Based on the preliminary results of the interim analyses including any delays 
incurred in the recruitment at that time, a decision will be taken whether to 
complete the study as currently described in this protocol, or to extend study 
completion to allow all subjects to complete 2 years of follow-up.* 
 
*Note: Based on the preliminary results of the interim analyses it was decided 
that the incidence rate would be more robust if all subjects completed the 
study as described above. 
The duration of the extension period will be approximately 4 years. Subjects will 
be followed-up from approximately 2 years of age up to 6 years of age. 
 
Epoch 1: Prospective data collection starting at birth up to a maximum of 2 
years of age on episodes of RSV LRTI.* 
 
Epoch 2: Prospective and retrospective data collection starting at the age of 
approximately 2 years and up to 6 years of age on episodes of wheeze and 
asthma. 

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*Data about wheeze and asthma were also collected in the primary study 
(documented at an examination visit or extracted from all treatments that were 
recorded during the examination visits, see Section 9.8). 
Table 2 presents the study groups and epochs foreseen in the study. 
Table 2 
Study groups and epochs foreseen in the study 
 
Study Groups 
Number of 
subjects 
Age (Min/Max) 
Epoch 1 
Epoch 2 
ProspectivePrimary 
Approximately 
2400 
At birth0 days - 
maximum of 2 years 
x 
Extension 
Maximum 2400 
Approximately 2 
years to 6 years of 
age 
x 
* Data collection will also occur from medical charts retrospectively for those who 
have a gap period between the end of the primary study and providing re-consent 
for the extension. 
• 
Serious adverse events (SAEs) related to study procedures (E.g. blood sample and 
nasal swab sample collection) as determined by the investigator will be collected 
throughout the primary study period. 
Study visit schedule related to the primary study (from birth up to the age of 2 years): 
 
Surveillance contacts (active and passive surveillance) [Epoch 1]: 
 
Examination visit (off-site/site): 
Study visit/contact schedule related to the extension (from the age of approximately 2 
years up to the age of 6 years) [Epoch 2]: 
 
Enrollment visit for extension (at 2nd birthday [on completion of primary study or as 
soon as possible thereafter]): 
 
• 
Eligibility of the children for the study will be confirmed as per the inclusion and 
exclusion criteria for the extension. Refer to Sections 5.4 and 5.5 for details on the 
inclusion and exclusion criteria for the extension. 
• 
The parent(s)/LAR(s) will asked for re-consent for their child’s participation in the 
extension (from approximately 2 years of age up to 6 years of age), pertaining to 
the amendment related to wheeze and asthma. 
• 
The parent(s)/LAR(s) will be interviewed to obtain complementary information on 
demographic characteristics of the subject. They will also be interviewed to obtain 
information on potential risk factors for wheeze and asthma, and on data about 
wheeze and asthma. In addition, the investigator will assess whether a child meets 
the protocol defined criteria of asthma based on information of parents and review 
of routine medical records /consultation with routine health care provider. 
• 
Data collection will also occur from medical charts retrospectively for those who 
have already completed 2 years of life prior to providing re-consent for the 
extension(for any gap period between end of primary study and start of extension 
period). 

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Quarterly surveillance contacts: 
• 
The parent(s)/LAR(s) will be interviewed to obtain information on potential risk 
factors for wheeze and asthma, and on data about wheeze and asthma. The 
investigator will supplement information from parents with review of routine 
medical records /consultation with routine health care provider. 
• 
In addition, the investigator will on annual basis assess whether a child meets the 
protocol defined criteria of asthma based on information of parents and review of 
routine medical records /consultation with routine health care provider. 
Refer to Section 6.6 for details on procedures related to the extension. 
 
Figure 3 
Decision tree for active and passive follow-up contact for the primary 
study 
 
Synopsis and section 3.1 
Discussion of the study design 
 
The association of other respiratory viruses with RSV-associated LRTI and/or severe 
LRTI, and the impact of potential RSV risk factors on the incidence and severity of RSV- 
associated LRTI will also be explored. The influence of other respiratory viruses in co- 
infections will be assessed by testing selected samples for the occurrence of other viruses 
after the primary analyses are completed. In order to assess and adjust for other potential 
confounders in the various analyses, data on the subjects’ demography and lifestyle 
factors will be collected at baseline, and followed up quarterly for changes, during the 
regular follow-up contacts. 
 
The subjects enrolled in the primary study will be followed up for episodes of RSV 
LRTI from 0 to 2 years of age. At 2nd birthday (on completion of primary study or as 
soon as possible thereafter), the surveillance for RSV LRTI will be stopped and the 
subjects will be re-consented for study extension during which they will be followed up 
for the occurrence of wheeze and asthma. Thus, this study also helps to assess how 
much of wheeze and asthma and its healthcare utilization from birth until the sixth 
birthday can be attributable to RSV clinical LRTI and RSV infection in the first two 
years of life. Any information pertaining to a gap period between completion of 
primary study and consent to the extension will be captured retrospectively by 
examination of health records, discussion with health care provider and parental 
interview. 
*Data about wheeze and asthma were also collected in the primary study (documented 
at an examination visit or extracted from all treatments that were recorded during the 
examination visits, see Section 9.8). 
 
This cohort provides us an opportunity and information to evaluate a potential 
association between RSV LRTI (exposure) early in life and the development of 
recurrent wheeze and asthma later in life (outcome). In other words, this study will 
assess to what extent this early life experience of RSV LRTI is accounting for the total 
burden of wheeze and asthma from birth until sixth birthday. Moreover, this study will 
also test the performance of asthma case definition. This study will be able to 
potentially demonstrate a measurement of potential public health impact and potential 

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incidence reduction if a successful maternal and/or pediatric vaccine introduced and 
exposure (RSV) eliminated/reduced. 
 
Section 4 
Case definition 
 
LRTI case definition and severity scale 
 
During the analysis of the study on the full dataset available for each case, all cases 
identified during the surveillance for LRTI will be definitively classified as either RTI, 
LRTI or severe LRTI according to the LRTI case definition and severity scale described 
in Table 4, and also according to the classification of WHO and the classification used by 
Nokes et al [Wright, 2010 Modjarrad, 2016; Nokes, 2004] (see below). 
 
Case definition of LRTI by WHO (2001). 
 
LRTI is diagnosed when a child <5 years present with cough and/or difficulty in 
breathing has the following symptom: 
 
In children < 2 months of age: 
 
• 
Fast breathing, (> 60 per minute in a child < 2 months of age),or 
• 
Severe chest indrawing, or 
• 
Stridor in a calm child, or 
• 
Wheezing, or 
• 
Apnea 
In children 2-59 months of age: 
 
• 
Fast breathing, (> 50 per minute in a child 2 to 11 months of age and; > 40 per 
minute in a child 12 to 59 months of age) or 
• 
Chest indrawing, or 
• 
Stridor in a calm child, or 
• 
Wheezing, or 
• 
Apnea 
Case definition of LRTI by WHO (2015) [Modjarrad, 2016] 
 
LRTI is diagnosed when a child <5 years present with cough and/or difficulty in 
breathing has the following symptoms: 
 
• 
Fast breathing, (> 60 per minute in a child < 2 months of age, > 50 per minute in a 
child 2 to 11 months of age and; > 40 per minute in a child 12 to 59 months of 
age), or 
• 
Oxygen saturation < 95% by pulse oximetry. 

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Severe LRTI is diagnosed when a child has LRTI and 1 or more of the following 
features of severe disease: 
 
• 
Oxygen saturation < 93% by pulse oximetry. 
• 
Lower chest wall in-drawing. 
Case definition of asthma and recurrent wheeze pertaining to the amendment: 
Table 5 presents the case definitions of asthma and recurrent wheeze. 
Table 5 
Case definitions of wheeze and asthma 
 
Definition 
Reference 
Episode of reported wheeze 
Parents report a whistling or stridor sound 
associated with labored breathing 
NA 
Episode of confirmed wheeze 
Healthcare provider confirmed wheeze (by 
chest auscultation with stethoscope) 
associated with labored breathing 
NA 
Recurrent wheeze 
Four or more episodes of wheeze in one 
calendar year. These may be parent reported 
wheeze or health care provider confirmed 
wheeze 
[Morgan, 2005] 
Medically attended wheeze 
An episode of health care provider confirmed 
wheeze 
NA 
Wheeze or asthma requiring 
admission 
An episode of health care provider confirmed 
wheeze requiring admission 
NA 
Prescription of medication for 
wheeze or asthma 
Oral steroids 
Intravenous steroids 
Inhaled steroids (ICS) 
Leukotriene modifiers or receptor antagonists 
Long-acting beta agonists (LABA) 
Short-acting beta agonists (SABA) 
Theophyline 
Combination inhalers that contain steroids and 
long-acting beta agonists 
Ipratropium (atrovent) 
Omalizumab 
NA 
Asthma case definition 1 
Asthma will be defined at the annual review 
based on the documented presence of one or 
more of the following characteristics in the 
previous year: 
(1) provider diagnosis of asthma 
(2) use of albuterol for coughing or wheezing 
episodes (prescribed by physician) 
(3) use of a daily controller medication 
(4) step-up plan including use of albuterol or 
short-term use of inhaled corticosteroids 
during illness 
(5) use of prednisone for asthma exacerbation 
[Jackson, 2008] 
Asthma case definition 2 
Asthma will be defined at the annual review 
based on parent interview and review of 
medical records with the presence of all of the 
following: 
(1) recurrent episodes of troublesome lung 
symptoms (wheeze or whistling sounds, 
[Bisgaard, 2011] 

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Definition 
Reference 
breathlessness, or recurrent troublesome 
cough severely affecting the well-being of the 
infant occurring with a frequency of 5 episodes 
within 6 months period or 4 weeks of 
consecutive symptoms); 
(2) symptoms typical of asthma (recently 
proposed to be termed multitrigger wheeze; 
e.g., exercise-induced symptoms, prolonged 
nocturnal cough, recurrent cough outside the 
common cold, and symptoms causing 
wakening at night); 
(3) intermittent rescue use of inhaled β2- 
agonist; 
(4) response to a 3-month course of inhaled 
corticosteroids of 400 μg/d and relapse when 
stopping treatment. Relapse was treated with a 
defined course of 6 months of 400 μg/d inhaled 
corticosteroids and subsequent relapses by 
further 12-month courses only to be prolonged 
after documented relapse 
 
Synopsis and section 5.1 
Number of subjects/centres 
 
Target enrollment for the primary study will be 2400 subjects to obtain approximately 
1920 fully evaluable subjects at primary study completion. Target enrollment for 
extension period will be maximum 2400 subjects (all subjects participating in the 
primary study, fulfilling all inclusion/exclusion criteria pertaining to the amendment 
related to wheeze and asthma and whose parent(s)/LAR(s) will give re-consent for the 
extension period). 
 
Section 5.2 
Inclusion criteria for enrollment in primary study (from birth up to the 
age of 2 years) 
Section 5.3 
Exclusion criteria for enrollment in primary study (from birth up to the 
age of 2 years) 
 
Section 5.4 
Inclusion criteria for extension period (from the age of approximately 2 
years up to the age of 6 years) 
 
• 
Subject whose parent(s)/LAR(s), in the opinion of the investigator, can and will 
comply with the requirements of the protocol (e.g., availability for quarterly 
contacts). 
• 
Written informed consent obtained from the parent(s)/LAR(s) of the subject. 
• 
Previous participation in the primary study (from birth up to the age of 2 years). 
Section 5.4 
Exclusion criteria for extension period (from the age of approximately 2 
years up to the age of 6 years) 
 
• 
Child in care. 

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Section 6.3 
General study aspects 
 
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the accompanying Study Procedures Manual (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. 
 
Collection and recording of data by the investigator. 
 
Section 6.4 
Outline of study procedures 
 
In the primary study subjects were to be followed-up from birth up to the age of 2 years 
for RSV LRTI. In order to determine the population attributable risk and population 
attributable risk percent of wheeze and asthma from birth to sixth birthday due to RSV 
clinical LRTI in the first two years of life, and to explore the association of RSV 
clinical LRTI in the first two years of life with other potential risk factors for wheeze 
and asthma the study will be extended and subjects will be followed-up up to the age of 
6 years.* 
 
*Note: The procedures related to primary study (surveillance of RSV LRTI) will not be 
extended into the extension period. The extension period will survey for occurrence of 
wheeze and asthma. Data about wheeze and asthma were also collected in the primary 
study (documented at an examination visit or extracted from all treatments that were 
recorded during the examination visits, see Section 9.8). 
 
During the extension subjects will be followed up through quarterly contacts. Parents 
will be encouraged to seek a clinical assessment of their child in between quarterly 
contacts and/or during quarterly contacts whenever their child develops wheezing 
and/or breathing difficulties. 
 
Table 7 presents the list of study procedures pertaining to the primary study (from birth 
up to the age of 2 years). 
Table 8 presents the list of study procedures pertaining to the extension (from the age 
of approximately 2 years up to the age of 6 years). 

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Table 7 
List of study procedures for the primary study (from birth up to the age 
of 2 years) 
 
Epoch-1 
Prospective data collection 
Visit/Contact 
Visit 1 
Visit 2 
Visit 3 
Surveillance 
contact * 
Examination visit ** 
Time points 
Pre-Day 0 Post-Day 
0 † 
As    
randomized 
 § 
Regular & a 
Unscheduled 
Informed Consent 
● 
Check inclusion/exclusion criteria 
applicable before birth 
● 
Subject number allocation and 
registration in SBIR-Screening 
● 
Collection of expected birth date 
● 
Collection of cord blood sample (up to 
approximately 10 mL) 
● 
Check inclusion/exclusion criteria 
applicable after birth and re-sign-off 
ICF 
● 
Collection of family medical history, 
demographic and lifestyle 
characteristics 
● 
Collection of data on child at birth and 
delivery (incl. medical care provided 
immediately after birth) 
● 
Registration in SBIR-enrollment 
● 
Distribution of diary cards to record 
symptoms and healthcare utilization 
(as needed) 
O 
O 
O 
Obtain blood sample at randomized 
time point (approximately 3.5 mL) from 
a sub-cohort of subjects 
● 
Ascertain RTI symptoms and potential 
difficulty in breathing and assessment 
of need for examination visit (off- 
site/site) 
● 
Recording of data on changes to 
baseline medical, demographic and 
lifestyle characteristics data E.g. 
Chronic diseases and changes to 
living conditions 
● 
(quarterly) 
Examination during (off-site/site) visit 
and collection of all disease symptoms 
(including RR and pulse oximetry) 
● 
Data collection on, disease course and 
healthcare utilization before and 
during the examination visit (off- 
site/site) *** # 
● 
Collection of nasal swab samples 
● 
Return of diary cards at completion or 
at case resolution  ‡ 
O 
Confirmation and expansion of data on 
healthcare utilization as recorded in 
the diary card occurring after the 
examination visit (off-site/site) *** # 
● 

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Epoch-1 
Prospective data collection 
Visit/Contact 
Visit 1 
Visit 2 
Visit 3 
Surveillance 
contact * 
Examination visit ** 
Time points 
Pre-Day 0 Post-Day 
0 † 
As    
randomized 
 § 
Regular & a 
Unscheduled 
Recording of SAEs related to study 
procedure throughout the study period 
● 
● 
● 
● 
Diary card transcription into eCRF 
● 
● 
Study conclusion after 2 years follow- 
up or end of study End of primary 
study after 2 years follow-up 
● 
● is used to indicate a study procedure that requires documentation in the individual eCRF. 
○ is used to indicate a study procedure that does not require documentation in the individual eCRF. 
SBIR = Randomization System on Internet; mL = milliliter; ICF = Informed Consent Form 
RTI = Respiratory Tract Infection; RR = Respiratory Rate 
eCRF = electronic Case Report Form; SAE = Serious Adverse Events 
*The surveillance contact consists of the following: 
Active surveillance: Follow-up contacts will be made by the investigator/study staff with the parent(s)/LAR(s) of the 
subjects at predefined intervals (to be confirmed based on the local settings) from Visit 2 up to study conclusion. 
Passive surveillance: Follow-up contacts made by the parent(s)/LAR(s) with the study investigator/study staff in case of 
development of RTI symptoms or increase in severity of existing symptoms after the previous reporting of the 
initial symptoms. 
** The examination visit (off-site/site) will be applicable only for subjects with a suspicion of LRTI. 
*** # Whenever required healthcare utilization data should be completed or confirmed with the healthcare provider 
involved in the management of the case. 
 § Selected subjects will be randomized to the time point at which a single blood sample needs to be collected; 2, 4, 6, 
12, 18 or 24 months. The sample can be collected between the intervals of  1 week. E.g. Month 2  1 week, Month 4 
 1 week. Randomization will be done using a second phase application of SBIR. 
& a Refer to APPENDIX C for the active and passive of contact schedule. 
 ‡ Diary card can be collected by mail or in person depending on local best practice. 
† Visit 2 can take place anytime within 5 working days after birth. 

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Table 8 
List of study procedures pertaining to the amendment related to wheeze 
and asthma (from the age of approximately 2 years up to the age of 6 years) 
 
Epoch-2 
Data collection 
Visit/Contact 
Extension enrollment visit 
Surveillance for wheeze and 
asthma 1 
Time points 
Approximately 2 years of 
age 
Quarterly 
Informed consent for extension 
● 
Check inclusion/exclusion criteria for extension 
● 
Collection of demographic data for extension 
● 
Collection of data on potential risk factors for 
wheeze and asthma 4 
● 
● 
Collection of data on wheeze and asthma 4, 5 
● 
● 
Classification of physician diagnosis of asthma 
● 
● 2 
Study conclusion for extension 
● 3 
● is used to indicate a study procedure that requires documentation in the individual eCRF. 
○ is used to indicate a study procedure that does not require documentation in the individual eCRF. 
1 Surveillance contacts will happen quarterly, from approximately 2 years of age up to the age of 6 years. 
2 This will be done annually, i.e. at children’s 3rd, 4th, 5th and 6th birthday. 
3 Study conclusion for the extension will be at the last quarterly surveillance contact, at children’s 6th 
birthday. 
4 If there is a gap between the primary study and the extension period, the retrospective data pertaining to 
wheeze and asthma will be collected for the gap period. 
5 The investigator will supplement information from parents with review of routine medical records/ 
consultation with routine health care provider. 
 
Section 6.5 
Detailed description of study procedures pertaining to the primary study 
(from birth up to the age of 2 years) 
Section 6.5.5 Collection of cord blood sample 
 
Cord blood samples collected will provide RSV-A and B antibody levels in the child, at 
birth. 
 
Section 6.5.11 
Blood sampling 
 
Blood samples collected will be used to assess RSV -A and B antibody levels in the 
subjects. 
 
Section 6.5.21 
Study conclusion End of primary study after 2 years follow-up 
 
Section 6.6 
Detailed description of study procedures for extension period (from the 
age of approximately 2 years up to the age of 6 years) 
 
6.6.1 Informed consent 
 
The signed/witnessed/thumb printed informed consent of the subject’s 
parent(s)/LAR(s) must be obtained before participation in the extension. Refer to 
Section 6.1 for the requirements on how to obtain informed consent. 

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6.6.2 Check inclusion and exclusion criteria 
 
Check all applicable inclusion and exclusion criteria for the extension as described in 
Sections 5.4 and 5.5. 
 
6.6.3 Collection of demographic data 
 
Record gender, geographic ancestry, ethnicity in the subject’s eCRF. 
 
6.6.4 Collection of data on potential risk factors for wheeze and asthma 
 
The parent(s)/LAR(s) will be interviewed to obtain information on potential risk factors 
for wheeze and asthma. The investigator will supplement information from parents 
with review of routine medical records /consultation with routine health care provider. 
 
If there is a gap between the primary study and the extension period, the retrospective 
data pertaining to potential risk factors for wheeze and asthma will be collected for the 
gap period. 
 
At the first contact of the extension the following variables will be collected: 
 
• 
Maternal/parental exposure variables of interest (will also be collected annually) 
 
maternal history of asthma hospitalization (yes/no); 
 
family history of atopy or food allergy or asthma (yes/no). 
• 
Children exposure variables of interest 
 
living or recurrent contact with pets (e.g. dogs, cats) (yes/no) (will also be 
collected quarterly); 
 
child history or diagnosis of atopy (yes/no) or allergy (yes/no) or eczema 
(yes/no) or atopic dermatitis (yes/no) or food allergy (yes/no) (will also be 
collected annually); 
 
siblings history or diagnosis of atopy (yes/no) or allergy (yes/no) or eczema 
(yes/no) or atopic dermatitis (yes/no) or food allergy (yes/no) or asthma 
(yes/no) (will also be collected annually); 
 
enrollment in school (yes/no) (will also be collected quarterly); 
 
left school (yes/no); 
 
baby or child exercise (yes/no or how many days of the week) (will also be 
collected quarterly). 

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6.6.5 Collection of data on wheeze and asthma 
 
The parent(s)/LAR(s) will be interviewed at the first contact of the extension and 
contacted quarterly to solicit morbidity associated with wheeze or asthma, with the 
questions since the last contact: Did your child have at least one episode of wheezing? 
Did your child take prescription medicines for wheeze or asthma? Has your child 
experienced troublesome symptoms at night of cough or wheezing or heavy breathing? 
The investigator will supplement information from parents with review of routine 
medical records /consultation with routine health care provider. Refer to the SPM for a 
more detailed set of questions. 
 
Data collection will also occur from medical charts retrospectively for those who have 
already completed 2 years of life prior to providing re-consent for the extension. 
 
6.6.6 Classification of physician diagnosis of asthma 
 
The investigator will on an annual basis assess whether a child meets the protocol 
defined case definition of asthma based on information of parents and review of 
routine medical records /consultation with routine health care provider. (Refer to 
Section 4 for definition of asthma). 
6.6.7 Study conclusion for the extension 
The investigator/study staff will: 
• 
review all the data collected to ensure accuracy and completeness. 
• 
complete the Study Conclusion screen in the eCRF. 
Section 6.7.2 Biological samples 
 
The following samples will be collected, as a part of the primary study: 
 
• 
Cord blood sample (up to approximately 10 mL) at birth from all the subjects. 
• 
Nasal swab samples within 72 hours from the first identification of a potential LRTI 
case by the investigator/study staff during an active or passive surveillance study 
contact. 
• 
Single blood sample (approximately 3.5 mL) from a sub-cohort of subjects, at the 
time point allocated through randomization (2, 4, 6, 12, 18 or 24 months). Children 
who are born with a gestational age of less than 36 weeks will be excluded from this 
sub-cohort. 
No additional samples will be collected during the extension period 
 
Section 6.7.3 Laboratory assays 
For cord blood and sub-cohort blood samples: 
• 
Serum neutralization assay to assess RSV-A and B antibody [Table 9]. 

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Table 9 
Antibody determination 
 
System 
Component 
Method 
Kit/ 
Manufacturer 
Unit 
Cut- 
off** 
Laboratory 
Serum 
Anti-RSV-A 
Neutralization 
In house 
TBDED60 
TBD8 
GSK Biologicals* and/or 
designated laboratory 
Serum 
Anti-RSV-B 
Neutralization 
In house 
TBDED60 
TBD6 
GSK Biologicals* and/or 
designated laboratory 
*GlaxoSmithKline Biologicals laboratory refers to the Global Vaccines Clinical Laboratories (GVCL) Clinical 
Laboratory Sciences (CLS) in Rixensart, Belgium; Wavre, Belgium; Laval, Canada. 
** Unit and cut-off for the RSV-A and/or RSV-B neutralization assay may be subject to change 
RSV = Respiratory Syncytial Virus; TBD = To be defined; RR = Respiratory Rate; ED = Effective Dose 
 
For nasal swab samples: 
 
• 
RT-qPCR assay for the detection of RSV and determination of RSV subtype (A/B). 
• 
xTAG™ RVP Fast assay for the detection of the following 17 viruses and subtypes 
in selected nasal swabs. 
 RSV 
 Influenza A, including subtypes H1 and H3 
 
Influenza A H1N1 2009 
 Influenza B 
 Parainfluenza virus type 1, 2, 3, and 4 
 Human Metapneumovirus 
 Enterovirus/Rhinovirus 
 Adenovirus 
 Bocavirus 
 Coronavirus - 229E, OC43, NL63, HKU1 
Synopsis and section 9.1.2 Secondary endpoints 
 
• 
Levels of RSV -A and B neutralizing antibodies in the cord blood samples collected 
at birth. 
• 
Levels of RSV-A and B neutralizing antibodies in the blood samples collected at 2, 
4, 6, 12, 18 and 24 months. 
Endpoints pertaining to the amendment related to wheeze and asthma as secondary 
endpoints: 
 
• 
Occurrence of medically attended wheeze. 
• 
Occurrence of wheeze or asthma requiring admission. 
• 
Occurrence of prescription of medication for wheeze or asthma. 
Synopsis and section 9.1.3 Tertiary endpoints 

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• 
Occurrence of RSV and other respiratory viruses as confirmed by xTAG™ RVP Fast 
assay: 
 
RSV 
 
Influenza A, including subtypes H1 and H3 
 
Influenza B 
 
Parainfluenza virus type 1, 2, 3, and 4 
 
Human Metapneumovirus 
 
Rhinovirus 
 
Adenovirus 
 
Bocavirus 
 
Coronavirus - 229E, OC43, NL63, HKU1 
• 
RSV viral load as determined by RSV RT-qPCR 
• 
Cord-blood sample collection variables including collection and storage times and 
temperatures. 
Endpoints pertaining to the amendment related to wheeze and asthma as tertiary 
endpoints: 
 
• 
Number of children with diagnosis of asthma (case definiton1) at age 2, 3, 4, 5, 
and 6 years of age. 
• 
Number of children with diagnosis of asthma (case definition 2) at age 2, 3, 4, 5, 
and 6 years of age. 
• 
Number of children with recurrent wheeze. 
Section 9.3.5 Total enrolled cohort pertaining to the amendment related to wheeze 
and asthma 
 
The total enrolled cohort for the amendment related to wheeze and asthma will include 
all subjects enrolled in the extension study. 
 
Section 9.4 
Derived and transformed data 
 
• 
All potential LRTI cases identified during the surveillance period will be classified 
as RTI, LRTI or severe LRTI according to the LRTI case definition and severity 
scale (refer section 4). The cases will also be classified according to the classification 
of WHO and by Nokes et al [Wright, 2010 Modjarrad, 2016; Nokes, 2004]. First 
time, the classification will be done at visit level, i.e. according to the data collected 
at the initial visit and, if applicable, at each additional examination visit. Finally, a 
classification at case level will be done considering the most severe classification 
from all visits. 
 
Section 9.6 
Analysis of co-primary objectives 

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• 
To assess the performance of the LRTI case definition and severity scale for 
RSV-associated cases. 
Incidences rates will be calculated as the number of RSV-associated LRTI/severe LRTI 
as classified by the LRTI case definition and severity scale and also as classified by the 
comparator case definitions (WHO and Nokes, et al [Wright, 2010 Modjarrad, 2016; 
Nokes, 2004]), over the number of children-years observations, overall and by subgroups. 
 
Descriptive statistics of the different types of healthcare utilization will be provided 
(proportions, duration, etc.) among RSV-associated LRTI/severe LRTI as classified by 
the LRTI case definition and severity scale and also as classified by the comparator case 
definitions (WHO and Nokes, et al [Wright, 2010 Modjarrad, 2016; Nokes, 2004]), 
overall and by subgroups. 
 
Section 9.7 
Analysis of secondary objectives 
 
Descriptive statistics of the different types of healthcare utilization will be provided 
(proportions, duration, etc.) among non-RSV-associated RTI with a suspicion of 
involvement of the lower respiratory tract, overall and by subgroups. 
 
• 
To evaluate the association between RSV-associated LRTI, RSV-associated 
severe LRTI and RSV neutralizing antibodies in the baseline cord blood samples 
collected from subjects, at birth. 
The impact of the level of RSV neutralizing antibodies in the baseline cord blood samples 
on the risk of having a RSV-associated LRTI and RSV-associated severe LRTI will be 
assessed through a statistical model. 
 
• 
To determine the prevalence of RSV A and B infection, at 2, 4, 6, 12, 18 and 24 
months in a randomly selected sub-cohort of subjects by assessing antibodies in 
serum. 
• 
To determine the population attributable risk of wheeze and asthma from birth to 
sixth birthday due to RSV clinical LRTI in the first two years of life. 
The population attributable risk together with 95% CI of medically attended wheeze, 
wheeze or asthma requiring admission, prescription of medications for wheeze or 
asthma will be calculated overall and by age strata (0-2 years, 2-4 years and 5-6 years) 
and by country, respectively. 
 
The population attributable risk is calculated by subtracting the incidence rate in the 
subjects who did not have RSV clinical LRTI in the first two years of life from the 
incidence rate in all subjects including both who had and who did not have RSV 
clinical LRTI in the first two years of life. 

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For example, the population attributable risk of medically attended wheeze will be 
calculated as 
 
Ip-Iu 
 
Where Iu is the incidence rate of medically attended wheeze in subjects who did not 
have RSV clinical LRTI in the first two years of life, and Ip is the incidence rate of 
medically attended wheeze in all subjects including both who had and who did not have 
RSV clinical LRTI in the first two years of life. 
 
• 
To determine the population attributable risk percent of wheeze and asthma from 
birth until sixth birthday due to RSV clinical LRTI in the first two years of life. 
The population attributable risk percent together with 95% CI of medically attended 
wheeze, wheeze or asthma requiring admission, and prescription of medications for 
wheeze and asthma will be calculated overall and by age strata (0-2 years, 2-4 years 
and 5-6 years), respectively. 
 
The population attributable risk percent is calculated by dividing the population 
attributable risk by the incidence rate in all the subjects including both who had and 
who did not have RSV clinical LRTI in the first two years of life. 
 
For example, the population attributable risk percent of medically attended wheeze will 
be calculated as 
 
(Ip-Iu)/Ip*100 
 
Where Iu is the incidence rate of medically attended wheeze in subjects who did not 
have RSV clinical LRTI in the first two years of life, and Ip is the incidence rate of 
medically attended wheeze in all subjects including both who had and who did not have 
RSV clinical LRTI in the first two years of life. 
 
The population attributable risk and population attributable risk percent will be 
stratified by country and other confounding factors as well such as, but not limited to 
family and siblings, history of asthma, atopy or food allergy, living or recurrent contact 
with pets, child history or diagnosis of allergy, atopy, eczema or atopic dermatitis, etc. 
The detail for calculating the CI for both population attributable risk and population 
attributable risk percent will be provided in the statistical analysis plan. 
 
Section 9.8 
Analysis of tertiary objectives 
 
• To explore the association of RSV and other respiratory viruses with the 
incidence of LRTI and/or severe LRTI (as determined by the LRTI case 
definition and severity scale) using xTAG™ RVP Fast assay. 
For each of the other respiratory viruses, incidence rates will be calculated as the number 
of LRTI/severe LRTI cases associate ed with the virus over the number of children-years 
observations. 

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• 
To explore the association of RSV viral load with the incidence of RSV-associated 
RTI, LRTI and/or severe LRTI (as determined by the LRTI case definition and 
severity scale). 
Descriptive analyses (mean, median, min, max) of viral load assessed by the RSV RT- 
qPCR of RSV RTI, RSV LRTI and severe LRTI cases will be tabulated. 
 
• 
To assess the natural decay of maternal antibody levels using a single follow-up 
blood sample collected from a randomly selected sub-cohort of subjects at 2, 4, 6, 
12, 18 and 24 months. 
The decay of maternal antibody levels over time will be analysed graphically and by a 
log-linear regression. A true, natural decay curve will be explored by stochastically 
reducing the sample to uninfected subjects only. The following steps will be taken to 
identify, confirmed and suspected infected subjects to eliminate these from the sample; 
 
• 
Subjects with an RSV positive sample nasal swab during the study before time of 
sampling will be eliminated. 
• 
To explore the association of RSV clinical LRTI in the first two years of life and 
other potential risk factors for wheeze and asthma. 
The incidence rate of medically attended wheeze, wheeze or asthma requiring 
admission, and prescription of medications for wheeze or asthma will be stratified by 
country. 
 
Besides, multivariate Poisson regression model including RSV clinical LRTI in the 
first two years of life (Yes/No) and other potential risk factors such as, but not limited 
to, family and siblings, history of asthma, atopy or food allergy, living or recurrent 
contact with pets, child history or diagnosis of allergy, atopy, eczema or atopic 
dermatitis, etc, will be explored, respectively. 
 
The number and percentage of children with diagnosis of asthma (case definition 1 
and 2) will be described for each age (2, 3, 4, 5 and 6 years); the number and 
percentage of children with recurrent wheeze from age 2-3, 3-4, 4-5 and 5-6 will be 
described overall and by country listed above in frequency tables. 
 
The risk of physician diagnosed asthma at the age of 6 years using case definition 1 
and case definition 2 and recurrent wheeze (occurring from 2nd to the 6th birthday) will 
be analyzed using multivariate logistic regression model including RSV clinical LRTI 
in the first two years of life (Yes/No) and other potential risk factors listed above, 
respectively. 
 
• 
To explore the performance of asthma case definitions. 
 
Statistical analysis of agreement will be performed to compare the two case definitions 
of asthma. A 2x2 contingency table similar as for one of the co-primary objective will 
be provided and the following measures of agreement (with 95% CI) will be calculated: 

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• 
Sensitivity: TP/ (TP+FN) 
• 
Specificity: TN/ (TN+FP) 
• 
Positive predictive value (PPV): TP/ (TP+FP) 
• 
Negative predictive value (NPV): TN/ (TN+FN) 
• 
Proportion of overall agreement, which is the proportion of cases similarly 
classified: (TP + TN)/ (TP+FP+FN+TN). 
• 
Cohen’s kappa coefficient. The magnitude of the kappa coefficient represents the 
proportion of agreement greater than that expected by chance. 
Data for endpoints will be pooled across primary and extension period as follows: 
 
• 
Medically attended wheeze, in the primary phase corresponds to episodes of 
wheeze documented at an examination visit initiated by monthly contacts with 
parents and in the extension phase by a history from parents solicited by contact 
every 3 months, which may be supplemented by review of routine medical records 
or contact with health care provider. 
• 
Wheeze or asthma requiring admission in the primary phase corresponds to 
episodes of wheeze documented at an examination visit that were associated with 
admission to hospital and in the extension phase by a history from parents, which 
may be supplemented by review of routine medical records or contact with health 
care provider. 
• 
Prescription of medications for wheeze or asthma in the primary phase will be 
extracted from all treatments that were recorded during the examination visits and 
in the extension phase by specific request for relevant medication from parents, 
which may be supplemented by review of routine medical records or contact with 
health care provider. 
• 
Diagnosis of asthma according to case definition 1 and 2will not be assessed 
during the primary phase and will be assessed for the first time at the first contact 
of the extension period and annually thereafter until study conclusion. 
• 
Diagnosis of recurrent wheeze as 4 or more episodes in one calendar year, will be 
assessed in the primary phase based on the episodes of wheeze documented at an 
examination visit initiated by monthly contacts with parents and in the extension 
phase by a history from parents solicited by contact every 3 months, which may be 
supplemented by review of routine medical records or contact with health care 
provider. 
Section 9.10.1 
Sequence of analyses 
 
An interim analysis will be performed after data lock at the end of recruitment (expected 
after 18 months) or in June 2015 whichever occurs first, on the data collected for the 
subjects recruited in the first year of the study (approximately 1600). This interim 
analysis will be performed to obtain preliminary indications of the results in very young 
infants. These preliminary results will be used for potential adjustment of the LRTI Case 
Definition and Severity Scale before final analysis, to assess the need to extend the 
primary study to allow all subjects to complete 2 years of follow-up and to provide data 

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for other relevant decision making, as soon as possible.* The results pertaining to this 
analysis will be descriptively reported in the interim statistical report. 
*Based on the preliminary results of the interim analyses it was decided that the 
incidence rate would be more robust if all subjects completed the primary study until 2 
years of age. 
 
Final analysis will be performed on all the data collected and cleaned in the study, at the 
end of the extension period which is expected to occur 7 years after study start. An 
integrated study report presenting the consolidated analysis for the entire study duration 
(primary and extension study period [as applicable]) will be written and made available 
to the investigators. 
 
Section 9.10.3 
Statistical considerations pertaining to the amendment 
 
Statistical analyses pertaining to the amendment will be performed on all the data 
collected and cleaned for the subjects who re-consented for the extension. For these 
analyses data from birth up to the age of 6 years will be used. 
 
There will be no interim analysis pertaining to the amendment. 
 
Section 12 
References 
 
Bisgaard H, et al. Childhood Asthma after Bacterial Colonization of the Airway in 
Neonates. NEJM 2007; 357:15. 
 
Bisgaard H, et al. Endotyping early childhood asthma by quantitative symptom 
assessment. J Allergy Clin Immunol. 2011; 127(5):1155-64.e2. 
 
Bønnelykke K, et al. Association between respiratory infections in early life and later 
asthma is independent of virus type. J Allergy Clin Immunol. 2015; 136(1):81-86.e4. 
 
Feldman AS, He Y, Moore ML, Hershenson MB, Hartert TV. Toward primary 
prevention of asthma. Reviewing the evidence for early-life respiratory viral infections 
asmodifiable risk factors to prevent childhood asthma. Am J Respir Crit Care Med. 
2015; 191(1):34-44. 
 
Jackson DJ, et al. Wheezing rhinovirus illnesses in early life predict asthma 
development in high-risk children. Am J Respir Crit Care Med. 2008; 178 (7):667-672. 
 
Jackson DJ, et al. Evidence for a causal relationship between allergic sensitization and 
rhinovirus wheezing in early life. Am J Respir Crit Care Med. 2012; 185(3):281-5. 
 
Lemanske RF Jr. The Childhood Origins of Asthma (COAST) study. Pediatr Allergy 
Immunol 2002; 13 (Suppl. 15): 38–43. 
 
Lemanske RF Jr, et al. Rhinovirus illnesses during infancy predict subsequent 
childhood wheezing. J Allergy Clin Immunol 2005;116:571–577. 

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Modjarrad K, Giersing B, Kaslow DC, Smith PG, Moorthy VS; 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. doi: 10.1016/j.vaccine.2015.05.093. Epub 
2015 Jun 20. 
 
Morgan WJ, et al. Outcome of asthma and wheezing in the first 6 years of life: follow- 
up through adolescence. Am J Respir Crit Care Med. 2005;172(10):1253-8. 
 
Wright PF, Cutts FT. Generic protocol to examine the incidence of lower respiratory 
infection due to respiratory syncytial virus in children less than five years of age. WHO, 
2010. 
 
Appendix A LABORATORY ASSAYS 
 
The Serum Neutralization assay is a functional assay that measures the ability of serum 
antibodies to neutralise the cytopathic effects of RSV (for example, strains A and B) on 
the host cell line, hence RSV replication. In the first step of the assay, a specific quantity 
of a replication capable RSV virus and a defined dilution of serum are mixed and 
incubated. Each serum dilution is tested in duplicates or triplicates. 
 
RT-qPCR assay 
 
Briefly, RSV A and RSV B ribonucleic acids (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 (cDNA) 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. 
 
Based on genetic and antigenic variations in the structural proteins, RSV is classified in 
two subgroups, A and B. In order to identify and quantify RSV-A and RSV-B nucleic 
acids in various respiratory specimens, such as nasal and throat swab samples, a single- 
step quantitative RT-qPCR assay has been developed. Two sets of primers’ pairs and 
probe have been designed in the N gene encoding the nucleocapsid protein: one targeting 
RSV-A and the other targeting RSV-B. 
 
Viral RNA from 200 µL of the clinical sample is extracted using the MagNA Pure LC 
Instrument and MagNA Pure LC Total Nucleic Acid Isolation Kit. Purified RNA is 
eluted in a final volume of 50 µL. RNA from the clinical sample is amplified and 
detected using the specific primers and probes for RSV-A and RSV-B RNA with the help 
of ABI PRISM 7900 HT Sequence Detection System 96-Well Block Module (Applied 
Biosystems). Viral load values are quantified and the sample is considered positive when 
the measured viral load is equal to or above the assay cut-off. Several controls are 
included at the extraction step to monitor the efficiency of the extraction and the potential 
contamination during the extraction run. In addition, RT-qPCR positive controls 
corresponding to a standard curve obtained by dilution of a mix of RSV-A and RSV-B 
synthetic RNA from 106 to 102 copies/RT-qPCR are added to the RT-qPCR step. Two 

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water controls are used for each RT-qPCR run (per 96-well plate) as RT-qPCR negative 
controls. These controls are used to monitor any potential contamination during the RT- 
qPCR run. 
 
Appendix B CLINICAL LABORATORIES 
 
Table 14 
GSK Biologicals’ laboratories 
 
Laboratory 
Address 
GSK Biologicals Global Vaccine Clinical 
Laboratory Clinical Laboratory Sciences, 
Rixensart 
Biospecimen Reception - B7/44 
Rue de l'Institut, 89 - B-1330 Rixensart - Belgium 
GSK Biologicals Global Vaccine Clinical 
Laboratory, North America- Laval 
Biospecimen Reception - Clinical Serology 
525 Cartier blvd West - Laval - Quebec - Canada - H7V 3S8 
GSK Biologicals Global Vaccine Clinical 
Laboratory Clinical Laboratory Sciences, 
Wavre-Nord Noir Epine 
Avenue Fleming, 20 - B-1300 Wavre - Belgium 
 
Table 15 
Outsourced laboratory 
 
Laboratory 
Address 
NÉOMED-LABS Inc. 
525, Cartier Ouest Laval, 
Quebec 
Canada H7V 3S8 
 
Appendix C ACTIVE SURVEILLANCE CONTACT SCHEDULE TO IDENTIFY 
ANY POTENTIAL LRTI CASE 

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GlaxoSmithKline Biologicals 
Vaccine Value & Health Science (VVHS) 
Protocol Amendment 3 
eTrack study number and Abbreviated Title 
200150 (EPI-RSV-005 BOD) 
Amendment number: 
Amendment 3 
Amendment date: 
15-DEC-2017 
Co-ordinating author: 
PPD 
, Lead Science Writer 
Rationale/background for changes: 
The protocol has been amended to reflect the following changes and provide the 
following clarifications / corrections. 
The Bisgaard and Jackson asthma case definitions were adapted so as to integrate asthma 
treatment advances while preserving the case definitions’ core intent. 
The International Study of Asthma and Allergies in Childhood (ISAAC) asthma case 
definitions, which facilitate a wider range of international results comparisons, were 
added. 
Throughout the document, text has been consolidated and clarified for consistency with 
these changes and to better facilitate uniform, harmonized implementation of the 
protocol. Beginning with Section 2.0, text pertaining to the primary study has been 
shaded in grey to differentiate it from text pertaining to the extension study. Some details 
regarding (a) recruitment into the primary study and (b) primary study visits and 
procedures have been moved from the body of the document to newly created 
Appendices. 
Amended text has been included in bold italics and deleted text in strikethrough in the 
following sections. The grey shading indicated above appears only in Sections 2.0 
through 12.0; it is not reproduced in the detailed summary of changes that follows. 

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PPD 
PPD 
, 
PPD 
, 
PPD 
PPD 
PPD 
PPD 
PPD 
PPD 
PPD 
PPD 
 
Contributing authors: 
 
The list has been re-organized to group all past and present contributing authors by role. 
The following additions to the list of contributing authors have been made: 
 
• 
, RSV Epidemiologist 
• 
Clinical Research & Development Lead 
• 
, Clinical and Epidemiology Project Lead 
• 
, Project Delivery Lead 
• 
Study Delivery Lead 
• 
, Lead EPI Statistician 
• 
, Study statistician 
• 
, Oversight Data Manager 
• 
, Study Data Manager, TCS for GSK Biologicals 
• 
, Study Data Manager, TCS for GSK Biologicals 
• 
, Clinical Read-Out Team Leader 
List of Abbreviations 
SAP 
Statistical Analysis Plan 
 
Glossary of Terms 
Active Surveillance 
A contact with the subject’s parent/LAR, initiated by the 
study physician or by a member of the study staff for the 
purpose of identifying an event of interest. 
 
Passive Surveillance 
A contact initiated by the subject’s parent/LAR, notifying 
the study physician / site staff of the occurrence of an 
event of interest. 
 
Section 1.1 
Background 
 
1.1.1 
RSV 
This study aims to assess the incidence and associated healthcare utilization of RSV- 
associated, suspected LRTI in a general population of infants from birth up to 2 years of 
age, and also to assess the accuracy of a newly developed LRTI case definition and 
severity scale compared to two existing scales developed by World Health Organization 
(WHO) and Nokes et al. The World Health Organization (WHO) has recently updated 
its RSV-associated LRTI case definition [Modjarrad, 2016]. The latter includes clinical 
features considered to be objective, easily standardized, generalizable across settings, 
and generally accepted markers of severe or very severe RSV disease. 
 
1.1.2 Asthma 
 
The LRTI case definition and severity scale has been developed as a consensus model 
derived from existing definitions in the literature, and existing guidelines by 

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GlaxoSmithKline (GSK) clinical staff, taking into account the advice of a panel of 
international RSV experts. Suspected cases of LRTI will be classified into RTI, LRTI or 
severe LRTI based on the data collected in the study, according to the newly developed 
LRTI case definition and severity scale. The presence of RSV in potential LRTI cases 
will be confirmed by polymerase chain reaction (PCR) on nasal swabs. Following the 
confirmation of RSV, the performance of LRTI case definition and severity scale will be 
determined based on the resulting incidence of LRTI and severe LRTI and their 
association with healthcare utilization. Full symptom data over the course of the disease 
for all suspected LRTI cases will be collected before positive identification of RSV by 
nasal swab testing. With this symptom data, the LRTI case definition and severity scale 
will be further explored to determine the clinical symptoms which better describe an 
LRTI and severe LRTI case and the LRTI case definition and severity scale will be 
updated if this improves its performance. 
 
Infant respiratory viral infection and childhood asthma are the most common acute 
and chronic diseases of childhood, respectively. Common clinical features and links 
between these diseases have long been recognized, with early-life RSV LRTIs being 
strongly associated with increased asthma risk. 
 
World Health Organization (WHO) has recently updated its RSV-associated LRTI case 
definition [Modjarrad, 2016]. The latter includes clinical features considered to be 
objective, easily standardized, generalizable across settings, and generally accepted 
markers of severe or very severe RSV disease. 
 
Although asthma is probably a heterogeneous disease or syndrome, three factors 
and/or events consistently emerge for their ability to significantly influence asthma 
inception in the first decade of life: immune response aberrations, which appear to be 
defined best by the concept of cytokine dysregulation; LRTIs, in particular RSV; and 
some form of gene–environment interaction that needs to occur at a critical time- 
period in the development of the immune system or the lung [Lemanske, 2002]. 
 
Population-level contribution of RSV LRTIs is best demonstrated by the population- 
attributable risk for asthma after these early-life LRTIs. Among infants, the 
prevalence cumulative incidence of LRTI is approximately 18 to 32% in the first year 
of life and approximately 9 to 17% in the second year of life. Among infants with 
LRTI, the prevalence of RSV can be as high as 80%, especially in the first 3 months of 
life. Thus, the phenotype of asthma after infant RSV LRTI accounts for up to 31% of 
early childhood asthma, with a population-attributable risk estimated at about 13% in 
several diverse populations [Feldman, 2015]. 
 
Numerous longitudinal studies have demonstrated this first important line of evidence 
that RSV LRTIs precede the development of asthma. Several birth cohort studies also 
demonstrate a dose–response relationship between infant respiratory viral infection 
severity and asthma risk, with increasing infant infection severity associated with 
greater childhood asthma risk and asthma severity [Feldman, 2015]. 
 
The Childhood Origins of Asthma (COAST) study was developed to determine and 
define the importance of these three factors on asthma pathogenesis and to test 
different asthma case classifications [Lemanske, 2002; Lemanske, 2005; Bisgaard, 

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2011; Jackson, 2008; Jackson, 2012; Bønnelykke, 2015]. These studies have used 
similar albeit slightly different case definitions on asthma diagnosis. The International 
Study of Asthma and Allergies in Childhood (ISAAC) takes a slightly different parent- 
based questionnaire approach toward assessing asthma prevalence in young children. 
 
These definitions are widely used in epidemiological literature of asthma etiology in 
children. The Bisgaard definition [Bisgaard, 2011] has multiple criteria that are 
assessed by the physician from records. Therefore the advantage of this definition is 
that the same objective criteria are applied to ascertain each case of asthma. However, 
its application may be challenging in some settings if routine medical records do not 
fully capture the necessary information in source. The Jackson definition [Jackson, 
2008] includes the criteria of health care provider (HCP) diagnosis of asthma and 
prescription of 2 agonists. This definition is therefore influenced by any differences in 
local practice of asthma diagnosis and management of wheeze. However, its advantage 
is that it captures the reality of diagnosis and treatment. This study anticipates that 
Bisgaard will be more specific and Jackson more sensitive. Hence, this study will assess 
the performance of these two case definitions since this will help planning for phase 3 
clinical trials of RSV vaccines.ISAAC uses simple, robust, primarily symptom-based 
questions that are administered solely to the parents. ISAAC’s strength is that its 
definitions are not affected by differences in local asthma treatment practices; 
however, its lack of clinical case confirmation may decrease its precision. The ISAAC 
questionnaire has been used to assess pediatric asthma prevalence in at least 42 
countries across the globe [Pearce, 2007]. 
Numerous longitudinal studies have demonstrated this first important line of evidence 
that RSV LRTIs precede the development of asthma. Several birth cohort studies also 
demonstrate a dose–response relationship between infant respiratory viral infection 
severity and asthma risk, with increasing infant infection severity associated with greater 
childhood asthma risk and asthma severity [Feldman, 2015]. 
 
Population-level contribution of RSV LRTIs is best demonstrated by the population- 
attributable risk for asthma after these early-life LRTIs. Among infants, the prevalence of 
LRTI is approximately 18 to 32% in the first year of life and approximately 9 to 17% in 
the second year of life. Among infants with LRTI, the prevalence of RSV can be as high 
as 80%, especially in the first 3 months of life. Thus, the phenotype of asthma after infant 
RSV LRTI accounts for up to 31% of early childhood asthma, with a population- 
attributable risk estimated at about 13% in several diverse populations [Feldman, 2015]. 
 
Section 1.2 and Synopsis Rationale for the Study: 
 
Paragraphs 1 and 2: 
 
This study aims to assess the incidence and associated healthcare utilization of RSV- 
associated, suspected LRTI in a general population of infants from birth up to 2 years of 
age, and also to assess the accuracy of a newly developed LRTI case definition and 
severity scale compared to two existing scales developed by the World Health 
Organization (WHO) [Modjarrad, 2016] and Nokes, 2008. 

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This study will also assess the extent to which RSV LRTI in early life (up to 2 years of 
age) accounts for the total burden of wheeze and asthma up to the sixth birthday, and 
test the performance of 3 asthma case definitions – those of Bisgaard, Jackson, and 
ISAAC. 
 
Paragraph 4: 
 
Considering asthma case definitions, this study anticipates that Bisgaard will be 
more specific and Jackson more sensitive. Although it is likely that the ISAAC 
symptom-based case definitions will be the most sensitive and least specific of all 
three definitions [Yang 2011], its incorporation will facilitate wider international 
results comparisons. Hence, this study will assess the performance of the different 
case definitions since this will help planning for phase 3 clinical trials of RSV 
vaccines. 
 
Paragraph 5: 
 
If, in future, a maternal and/or pediatric RSV vaccine is introduced, results of this 
study may be used to evaluate post-vaccination incidence reduction (in RSV LRTI 
and/or wheeze and asthma) and the vaccine’s potential public health impact. 
 
Objectives, Section 2.0 and Synopsis: 
 
Objectives for the primary study are now presented in Section 2.1; objectives for the 
extension study are now presented in Section 2.2. 
 
Cross references to definitions of endpoints have been updated. 
 
Study Design, Section 3.0 and Synopsis 
The detailed discussions of the Study Visit Schedule and of Procedures for LRTI 
assessment in this section have been moved to (new) Appendices D and E. 
 
Design (Section 3.0 and Synopsis) 
 
3.1 
Design Summary 
 
In the primary study subjects were to be followed-up from birth up to the age of 2 years 
for RSV LRTI, Episodes of wheeze and diagnoses of asthma were also documented. 
Refer to Figure 1.. 
 
In order to determine the population attributable risk and population attributable risk 
percent of wheeze and asthma from birth to sixth birthday due to RSV clinical LRTI in 
the first two years of life, and to explore the association of RSV clinical LRTI in the first 
two years of life with other potential risk factors for wheeze and asthma, the study will be 
extended and subjects will be followed-up from the age of 2 years up to 6 years to detect 
episodes of wheeze and diagnoses of asthma.* Refer to Figure 2.. 

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*Note: The procedures related to primary study surveillance of RSV LRTI will not be 
extended into the extension period. The extension period will survey for occurrence of 
wheeze and asthma. Data about wheeze and asthma were also collected in the primary 
study (documented at an examination visit or extracted from all treatments that were 
recorded during the examination visits, see Section 9.8.3). 
 
Epidemiological cohort studies have some limitations. It is possible that study dropouts 
might occur leading to differential lost to follow up and bias study. Moreover, it is 
possible that a selection bias might occur. Factors pertaining to enrollment of subjects 
into this prospective cohort study would not introduce selection bias. In order to 
introduce bias, selection has to be related to both exposure and outcome. But in this 
study, subjects are enrolled in prospective cohort before they experience the outcome of 
interest. 
 
Another potential limitation of this study is the occurrence of confounding especially 
with potential risk factors. A possible alternative would be to match within a cohort 
study. But this can reduce the efficiency of a cohort study even when there is no sample- 
size reduction and even when the matching variable is a confounder. Furthermore, albeit 
cohort matching prevents confounding by the matched variable, it is not considered an 
advantage of matched designs since in an unmatched study confounding by the covariates 
can be removed by analytical methods. Hence, in order to deal with the confounding 
factors stratification analysis will be used for each confounder. Multivariate logistic 
regression will also be used to adjust to confounders after selection from the univariate 
logistic regression. All possible confounding factors such as gender, geographic ancestry, 
pets, parental smoking and previous maternal or siblings history of asthma will be 
analyzed first in stratification and then in logistic regression (univariate and multivariate). 
 
Figure 1 shows the study diagram for the primary study (from birth up to the age of 2 
years for detection of RSV LRTI). 
 
Figure 2 
describes the extension (from the age of approximately 2 years up to the 
age of 6 years for the detection of episodes of wheeze and diagnosis of asthma). 
 
In Figure 2, the title has been changed as follows: 
 
Study design diagram for the extension (from the age of approximately 2 years up to the 
age of 6 years 6th birthday) for the detection of episodes of wheeze and diagnosis of 
asthma 
 
Annual asthma assessments 
 
The following text has been revised: 
 
• 
Parent(s)/legally acceptable representative(s) (LARs) of the subject will be contacted 
during the pregnancy in order to be informed about the study and to request consent 
for their child’s participation in the primary study. 
 
The parent(s)/LAR(s) will be requested to provide consent during pregnancy, 
after at least 20 weeks gestation, to enrol their child into the study, at birth. 

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 
The child will be checked for eligibility criteria applicable before birth. 
 
The remaining eligibility criteria applicable after birth will be assessed as soon 
as possible, and the child’s participation in the study will be confirmed through 
an updated and resigned informed consent form (ICF) (including any other 
potentially relevant identifiers as applicable by local requirements) , not later 
than 5 working days after the birth of the subject. 
At the end of primary study (from birth up to the age of 2 years), parent(s)/LARs) 
will be asked for re-consent for their child’s participation in the extension (from 
approximately 2 years of age up to 6 years of age), pertaining to the amendment 
related to wheeze and asthma. 
• 
Study population: A cohort of approximately 2400 infants will be included in the 
study at birth and followed-up up to 2 years of age. Maximum A maximum of 2400 
children will be included in the extension and followed up to 6 years of age. 
• 
Type of study: Self-contained. 
• 
Data collection: Electronic case report form (eCRF). 
• 
Biological samples (Primary Study only): 
 Serum derived from up to approximately 10 milliliters (mL) of cord blood 
samples Cord Blood collected from all the subjects participating in the 
studysubjects, at birth. 
 Nasal swabs collected from subjects with potential LRTI symptoms i.e. RTI 
symptoms with any signs of difficulty in breathing. 
 Serum derived from a single blood sample of approximately 3.5 mL Serum 
collected from a sub-cohort of subjects. This sub-cohort consists of the first 2000 
enrolled subjects, from which excluding those born at a gestational age of less 
than 36 weekswill be excluded from this blood sampling. Sampling time points 
for this sub-cohort will be randomly allocated as specified in Table 1. 
 No biological samples will be collected during the extension (from 
approximately 2 years of age up to 6 years of age). 
• 
Duration of the study: The entire duration of Approximately 2 years for each 
participant enrolled in the primary study will be and an additional (approximately) 
3 yearsto 4 years for each participant enrolled in the extension study. 
 
Assuming no delays in recruitment, two-thirds of the subjects (approximately 
1600) will be recruited in Year 1 of the study and will be followed-up up to 2 
years of age, resulting in a total primary study duration of 3 years. The 
remaining subjects (approximately 800) will be recruited in the first half of Year 
2 of the study and will be followed up till the end of Year 3. The follow-up 
period for subjects recruited in Year 2 will thus be 1.5 to 2 years.* Refer to 
Figure 1 for more details. 
 
In case of any delays in recruitment for the first two-thirds of the subjects in the 
study, the study duration will be extended until all these subjects have 
completed follow-up up to 2 years of age. 

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 
Based on the preliminary results of the interim analyses including any delays 
incurred in the recruitment at that time, a decision will be taken whether to 
complete the study as currently described in this protocol, or to extend study 
completion to allow all subjects to complete 2 years of follow-up.* 
 
*Note: Based on the preliminary results of the interim analyses it was decided 
that the incidence rate would be more robust if all subjects completed the 
primary study until 2 years of age. 
The duration of the extension period will be approximately 4 years. Subjects will be 
followed-up from approximately 2 years of age up to 6 years of age. 
 
Epoch 1: Prospective data collection starting at birth up to 2 years of age on 
episodes of RSV LRTI.* 
 
Epoch 2: Prospective data collection starting at the age of approximately 2 
years and up to 6 years of age on episodes of wheeze and asthma. 
*  Data about wheeze and asthma were also collected in the primary study 
(documented at an examination visit or extracted from all treatments that were 
recorded during the examination visits, see Section 9.8.3). 
 Epoch 1 (Primary Study): Begins at birth (Visit 1) and ends at the age of 
approximately 2 years (Visit or contact at 2 years). 
 Epoch 2 (Extension Study): Begins with the first contact for the 
extension study (at approximately age 2 years; ends with the contact at 
approximately the sixth birthday Table 2 presents the study groups and 
epochs foreseen in the study. 
Surveillance Plan: 
 
• 
Surveillance for RSV Lower Respiratory Tract Infection (RSV LRTI), wheeze and 
asthma during the Primary Study period.* 
• 
Surveillance for wheeze and asthma during the extension study period. 
* Note that discussion of additional primary study visit details has been moved to (new) 
Appendix D. Discussion of details regarding Surveillance for RSV Lower Respiratory 
Tract Infection (RSV LRTI), wheeze and asthma during the primary study period have 
been moved to (new) Appendix E. 
 
Safety Follow-up: 
 
• 
Study procedure related Serious Adverse Events (SAEs) to be reported throughout 
the study. 
 
Design Discussion 
 
Discussion of Study Design 
 
This The multi-country design of both the primary and extension studies will provide 
multinational estimates of the incidence of RSV-associated LRTI during the first two 

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years of life and assess the amount of wheeze and asthma that may be attributable to 
those early RSV-LRTI infections. 
 
3.2.1 Primary Study 
The Primary study is being conducted to will determine the incidence and associated 
utilization of RSV-associated LRTIs in infants from birth up to the age of 2 years, and 
also to assess the performance of a new LRTI case definition and severity scale. 
Subjects will be identified for participation in the study during the pregnancy after at least 
20 weeks gestation and before the start of the delivery. This will be done to ensure that 
the parent(s)/LAR(s) have sufficient time to consider and provide informed consent 
before the subject is born and to obtain a baseline blood cord sample from each subject, 
at birth. Using this sample, the level of natural protection conferred by the mother to the 
child at birth in the form of maternal antibodies will be assessed and prospectively related 
to subsequent risk of RSV-associated LRTI. 
 
In order to identify all cases of LRTI that occur on a community level, the cohort of 
infants recruited at birth will be followed-up by active and passive surveillance for 
respiratory symptoms and potential LRTI, up to maximum 2 years of age. For the passive 
surveillance, parent(s)/LAR(s) of the subjects will be instructed to report new RTI 
symptoms of cough or a runny or blocked nose as soon as possible to the 
investigator/study staff. Proper passive surveillance is important in order to identify 
potential cases as early as possible. The active surveillance is mostly aimed at reinforcing 
the passive surveillance as the chance of picking up a (developing) case at the exact time 
of the active surveillance contact is limited. Active surveillance, at a frequency dependent 
of the RSV seasonality, involves regular contact of the investigator/study staff with the 
parent(s)/LAR(s) of the subjects to report any new sign of RTI symptoms (cough, runny 
nose, blocked nose) as soon as possible themselves. In between scheduled active 
surveillance contacts, the study staff can employ activities to solicit passive surveillance 
according to local practices, e.g. reminder emails or text messages up to regular 
community centre visits. 
After identification of a potential case of LRTI based on all reported symptoms, an 
examination visit will be scheduled as early as possible in the disease progression (within 
72 hours after initial identification of a potential LRTI case by the investigator/study staff 
during a follow-up contact, based on reported symptoms). During this visit, data 
(including RR and SaO2) will be collected on these cases through an initial assessment 
by the study team during examination visit (off-site/site) and through a diary card. Nasal 
swabs will be taken by the investigator/study staff during the examination visit (off- 
site/site), and will be used to positively identify cases of RSV infection. 
During the examination visit (off-site/site), an initial assessment of the presence of LRTI 
according to the LRTI case definition for surveillance will be made in order to assess 
the need for a potential subsequent examination visit if the case is found not to be an 
LRTI. 
RSV-associated healthcare resource utilization for RTI with a suspicion of difficulty 
breathing will be collected. Parent(s)/LAR(s) will be asked to report any care availed 
(e.g. self-care with over-the-counter [OTC] medication, GP visits, ER visits, hospital 
visits, etc.) via the diary card. Where possible, the study team will confirm and expand 

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relevant healthcare utilization with the healthcare provider involved in the management 
of the case. Healthcare resource utilization is expected to vary between countries, regions 
and/or sites due to the local variations in policy and healthcare. 
 
The association of other respiratory viruses with RSV-associated LRTI and/or severe 
LRTI, and the impact of potential RSV risk factors on the incidence and severity of RSV- 
associated LRTI will also be explored. In order to assess and adjust for other potential 
confounders in the various analyses, data on the subjects’ demography and lifestyle 
factors will be collected at baseline, and followed up quarterly for changes, during the 
regular follow-up contacts. 
 
The study has been designed to target a multi-national population by including multiple 
countries across the globe. Including infants from multiple parts of the world into this 
single study will provide an overall estimate of the incidence of RSV-associated LRTI, 
and will indicate potential variations between countries and regions. Data on known and 
suspected risk factors of RSV and/or LRTI will be collected to perform exploratory 
analyses of the association between risk factors and disease. 
 
Recruitment into the study will be controlled as much as possible to occur at a stable rate 
using SBIR, so as to achieve a population that is distributed evenly according to their age 
at first exposure to an RSV season. In practice, some subjects will be recruited just at the 
beginning of a season and be exposed immediately for several months, whereas others 
will be recruited just at the end of a season and thus be at least 6 months old before the 
next season starts. In order to assess the impact of fluctuations in the occurrence of RSV 
between consecutive seasons, the recruitment period will at least be one-and-a half years 
so that the recruitment after the first year yields a population of subjects with a similar 
age at exposure to an RSV season as the subjects recruited in the same time period, 1 year 
earlier. 
 
The first 2000 subjects enrolled in the study will be randomized at recruitment to a time 
point at which a single blood sample will be collected from these subjects if they are still 
participating in the study at that time. This can be either at 2, 4, 6, 12, 18 or 24 months 
old. The serum of these samples will be tested for RSV A/B neutralizing antibodies. 
Adjusted for the baseline level of maternal antibodies, this will provide point prevalence 
estimates over time that will indicate the rate of any RSV infection in the study 
population, including the cases that did not develop into an LRTI. In addition, especially 
the samples at earlier time points will indicate the duration of persistence of maternal 
antibodies. 
 
3.2.2 Extension Study 
At 2nd birthday (on completion of primary study or as soon as possible thereafter), the 
surveillance for RSV LRTI will be stoppedand the Consenting, eligible subjects from 
participating study centers will be re-consented for enrolled in the study extension and 
followed up for the occurrence of wheeze and asthma.* Thus, this study also helps to 
assess how much This will permit an assessment of the proportion of wheeze and 
asthma from birth until the sixth birthday can that may be attributable to RSV clinical 
LRTI and RSV infection in the first two years of life. Any information pertaining to a 
gap period between completion of primary study and consent to the extension will be 

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captured retrospectively by examination of health records, discussion with health care 
provider and parental interview. 
*Data about wheeze and asthma were also collected in the primary study (documented 
at an examination visit or extracted from all treatments that were recorded during the 
examination visits, see Section 9.8.3). 
It This cohort provides us an opportunity and information to evaluate a potential 
association between RSV LRTI (exposure) early in life and the development of recurrent 
wheeze and asthma later in life (outcome). In other words, this study will assess to what 
extent this early life experience of RSV LRTI is accounting for the total burden of 
wheeze and asthma from birth until sixth birthday. Moreover, this study will also test the 
performance of asthma case definitions. This study will be able to potentially 
demonstrate a measurement of potential public health impact and potential incidence 
reduction if a successful maternal and/or pediatric vaccine introduced and exposure 
(RSV) eliminated/reducedthe different asthma case definitions (Table 5), 
 
Section 4, Case Definitions 
 
Case definitions for the primary study are now presented in Section 4.1. 
 
Case definitions for the Extension Study are now presented in Section 4.2, and have been 
adjusted as follows: 
 
Table 5 presents the case definitions of wheeze and asthma. The Bisgaard and Jackson 
case definitions have been updated so as to better account for advances in asthma 
treatment options while still preserving the case definitions’ core intent. 
Table 5 
Case definitions of wheeze and asthma 
 
Definition 
Reference 
Episode of reported wheeze 
Parents report a whistling or stridor sound associated 
with labored breathing 
NA 
Episode of confirmed wheeze 
Healthcare provider confirmed wheeze (by chest 
auscultation with stethoscope) associated with 
labored breathing 
NA 
Recurrent wheeze 
This will be defined as four or more episodes of wheeze 
in one calendar year. These may be parent reported 
wheeze or health care provider confirmed wheeze 
[Morgan, 2005] 
Medically attended wheeze 
An episode of health care provider confirmed wheeze 
NA 
Wheeze or asthma requiring 
hospital admission 
An episode of health care provider confirmed wheeze 
requiring hospital admission 
NA 
Prescription of medication for 
wheeze or asthma 
(entire row moved to Section 
6.6) 
Oral steroids 
Intravenous Systemic (intramuscular or intravenous) 
steroids 
Inhaled steroids (ICS) 
Combination inhalers containing steroids and long- 
acting beta agonists 
Long-acting beta agonists (LABA) 
Short-acting beta agonists (SABA) 
Leukotriene modifiers or receptor antagonists 
Theophyline 
Combination inhalers that contain steroids and long- 
NA 

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Definition 
Reference 
acting beta agonists 
Ipratropium 
Anti-IgE therapy (e.g.,Omalizumab) 
Asthma case definition 1 
Asthma will be defined at the annual review based on the 
documented presence of one or more of the following 
characteristics in the previous year: 
(1) provider diagnosis of asthma 
(2) Use of a short acting beta agonist (e.g., albuterol) 
for coughing or wheezing episodes (prescribed by a 
physician healthcare provider 
(3) use of a daily controller medication 
(4) step-up plan including use of a short acting beta 
agonist (e.g., albuterol) or short-term use of inhaled 
corticosteroids during illness 
(5) use of prednisone oral and/or systemic steroids for 
asthma exacerbation 
Based on 
[Jackson, 2008] 
Asthma case definition 2 
Asthma will be defined at the annual review based on 
parent interview and review of medical records with the 
presence of all of the following: 
(1) recurrent episodes of troublesome lung symptoms 
(wheeze or whistling sounds, breathlessness, or recurrent 
troublesome cough severely affecting the well-being of the 
infant occurring with a frequency of 5 episodes within 6 
months period or 4 weeks of consecutive symptoms); 
(2) symptoms typical of asthma (recently proposed to be 
termed multitrigger wheeze; e.g., exercise-induced 
symptoms, prolonged nocturnal cough, recurrent cough 
outside the common cold, and symptoms causing 
wakening at night); 
(3) intermittent rescue use of inhaled β2-agonist; 
(4) response to a 3-month course of inhaled 
corticosteroids of 400 μg/d and relapse when 
stopping treatment. Relapse was treated with a 
defined course of 6 months of 400 μg/d inhaled 
corticosteroids and subsequent relapses by further 
12-month courses only to be prolonged after 
documented relapse(4) symptoms controlled by daily 
inhaled corticosteroids 
Based on 
[Bisgaard, 2011] 
Asthma case definition 3 
In the past 12 months: four or more episodes of 
wheeze AND either one or more nights of sleep 
disturbance from wheeze per week, or wheeze that 
was severe enough to limit the child’s speech to only 
one or two words at a time between breaths 
Based on 
[Wong 2013] 
 
Section 5, Study Population: 
 
Target enrollment for the primary study will be 2400 subjects to obtain approximately 
1920 fully evaluable subjects at primary study completion. Target enrollment for 
extension period will be a maximum of 2400 subjects. (All subjects participating in the 
primary study fulfilling all inclusion/exclusion criteria pertaining to the amendment 
related to wheeze and asthma and whose parent(s)/LAR(s) will give re-consent for the 
extension period and who fulfill all relevant inclusion/exclusion criteria may be followed 
in the extension.) 

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The primary study includes a sub-cohort for blood sampling. Refer to Table 6. 
 
The overview of the recruitment plan has been moved to Appendix C. 
 
Subsections for the primary study and the extension study have been created: Section 
5.3.1 and 5.3.2, Inclusion Criteria and Sections 5.4.1 and 5.4.2, Exclusion Criteria: 
 
In Section 5.3.1, the following adjustment has been made: 
 
• 
Written informed consent (or witnessed thumb printed consent in case of an 
illiterate subject) (including consent to obtain a cord blood sample at birth) obtained 
from the parent(s)/LAR(s) of the subject 
In Section 5.3.2, the following adjustments have been made: 
 
• 
Subject is enrolled at a study site that is participating in the extension period 
follow-up. 
• 
Written informed consent (or witnessed thumb printed consent in case of an 
illiterate subject) obtained from the parent(s)/LAR(s) of the subject. 
 
Section 6.4, Outline of Study Procedures 
 
Subsections for the primary study and the extension study have been created: Section 
6.4.1, Primary Study and 6.4.2, Extension study. 
Changes to 6.4.1 are as follows: 
 
In the primary study subjects were to be followed-up from birth up to the age of 2 years 
for RSV LRTI. In order to determine the population attributable risk and population 
attributable risk percent of wheeze and asthma from birth to sixth birthday due to RSV 
clinical LRTI in the first two years of life, and to explore the association of RSV clinical 
LRTI in the first two years of life with other potential risk factors for wheeze and asthma 
the study will be extended and subjects will be followed-up up to the age of 6 years.* 
 
*Note: The procedures related to primary study (surveillance of RSV LRTI) will not be 
extended into the extension period. The extension period will survey for occurrence of 
wheeze and asthma. Data about wheeze and asthma were also collected in the primary 
study (documented at an examination visit or extracted from all treatments that were 
recorded during the examination visits, see Section 9.8.3). 
 
During the extension subjects will be followed up through quarterly contacts. Parents will 
be encouraged to seek a clinical assessment of their child in between quarterly contacts 
and/or during quarterly contacts whenever their child develops wheezing and/or breathing 
difficulties. 
 
In Table 7, footnote symbols have been adjusted and a cross reference has been added: 
 
Refer to Section 6.5 for additional details. 

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Changes to 6.4.2 are as follows: 
 
Extension Study (approximately 2 years of age up to the 6th birthday) 
Table 8 presents the list of procedures for the extension study. 
Note that although extension study enrolment ideally occurs at the time of the subjects’ 
second birthdays, enrolment into, and first contact for, the extension study may take 
place at any time between the end of the primary study and the subject’s 6th birthday. 
After the first extension study contact, subjects will be contacted around the time of 
each subject’s birthday and (approximately) quarterly during the intervals between (a) 
first contact and next birthday; (b) subsequent birthdays. 
Site staff may contact subjects more frequently than indicated in Table 8 if consistent 
with the language of the local ICF and considered necessary by the study physician. 
Parents will be encouraged to seek a clinical assessment of their child in between 
quarterly contacts and/or during quarterly contacts whenever their child develops 
wheezing and/or breathing difficulties. 
 
Refer to Section 6.6 and the SPM for additional details. 

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Table 8 
List of extension study procedures pertaining to the amendment related to wheeze and asthma (from the age of 
approximately 2 years up to the age of 6 years 6th birthday) 
 
Epoch 2 
Data collection 
Visit/Contact 
First Contact a 
Extension enrolment visit 
Quarterly Contact b,c 
Surveillance for wheeze 
and asthma 
Annual Contact c, d 
Time points 
Approximately 2 years of 
age 
Extension study enrolment 
Approximately 2 years of age 
Around the 3rd, 4th, 5th, and 6th birthdays 
(+ 2 months) 
Perform/document results of these procedures 
Informed consent for extension 
● 
Check inclusion/exclusion criteria for extension 
● 
Collection of Collect demographic data for extension 
● 
Collection of Collect data on potential symptoms and risk 
factors for wheeze and asthma 4 
● 
● 
(applies to Version 1.0 of 
the quarterly contact 
script) 
●d 
Collection Record episodes of wheeze and, asthma, and 
troublesome lungs 
● 
● 
●d 
Classification of physician diagnosis of asthmaCollect 
data about medication used to treat asthma, wheeze, 
or troublesome lung symptoms 
● 
● 
●d 
Review / assess information about asthma diagnoses 
and medication use based on medical record abstraction 
and subject information over approximately the past 12 
months or longer 
● e 
● e 
Interim analysis after 4th birthday; Final analysis after 
6th birthday 
● 
Investigator sign-off on eCRF before analysis 
●f 
Study conclusion for extension 
●g 
… and enter data into these eCRF modules 
• 
First Contact 
• 
Annual 
• 
Quarterly 
• 
Quarterly 
• 
Annual 

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● is used to indicate indicates a study procedure that requires documentation in the individual eCRF. 
○ is used to indicate a study procedure that does not require documentation in the individual eCRF. 
1 Surveillance cont]acts will happen quarterly, from approximately 2 years of age up to the age of 6 years. 
2 This will be done annually, i.e. at children’s 3rd, 4th, 5th and 6th birthday. 
3 Study conclusion for the extension will be at the last quarterly surveillance contact, at children’s 6th birthday. 
4 If there is a gap between the primary study and the extension period, the retrospective data pertaining to wheeze and asthma will be collected for the gap period. 
a At the time of first contact, if delayed, all missed annual assessments of asthma will be completed retrospectively by the Investigator. 
b At approximately 3, 6 and 9 months (+/- 1.5 months), between consecutive birthdays. There should be at least one month between each Quarterly Contact 
c Both Quarterly parent/LAR interview AND Annual investigator review/assessment data to be collected and reported. 
d To accurately complete investigator-targeted asthma questions, up-to-date information about all asthma, wheeze, and troublesome lung episodes as well as a review of 
any and all potential asthma medications that were taken by the subject will be needed for the accurate completion of the investigator assessment. Refer to Section 6.6.4.2. 
e The investigator will supplement information from parents with review of routine medical records/ consultation with routine health care provider(s), as appropriate. 
f After completion of 4th birthday annual contact (for interim analysis), and at study conclusion 
g Study conclusion for the extension will be at the last contact, at child’s 6th birthday. 
Refer to Section 6.6 and the SPM for additional details. 

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Section 6.5, Detailed Description of Study Procedures – Primary Study Period 
 
• 
In case of anticipated twins (or multipletother multiple births), an ICF needs to be 
signed for each expected child before the start of delivery. 
• 
In case of unexpected twins (or multiplets,other multiple births), only the children 
for whom an ICF has been signed before birth can be enrolled. This should occur as 
per the birth order. 
• 
In case of anticipated twins (or multiplets other multiple births), a subject number 
will be assigned sequentially to each child for whom the consent has been obtained, 
as per the birth order, where the first born will be associated with the lowest subject 
number, the second born with the successive subject number, etc. 
 
Section 6.6, Detailed Description of Extension Study Procedures 
Section 6.6.3: 
Record gender, geographic ancestry, and ethnicity in the subject’s eCRF. 
 
Section 6.6.4: Collection of data on potential Potential risk factors for / occurrences of 
wheeze and asthma 
 
6.6.4.1 Data collected from the parent(s)/LAR 
 
The parent(s)/LAR(s) will be interviewed to obtain information on potential risk factors 
for wheeze and asthma. The investigator will supplement information from parents with 
review of routine medical records /consultation with routine health care provider. 
 
If there is a gap between the primary study and the extension period, the retrospective 
data pertaining to potential risk factors for wheeze and asthma will be collected for the 
gap period. 
 
At the first contact of the extension the following variables will Data collected by 
interviewing the parent(s)/LAR(s) 
• 
Maternal/parental exposure variables of interest (will also be collected annually) 
 
maternal history of asthma hospitalization (yes/no); 
 
family history of atopy or food allergy or asthma (yes/no). 
• 
Children exposure variables of interest 
 
living or recurrent contact with pets (e.g. dogs, cats) (yes/no) (will also be 
collected quarterly); 
 
child history or diagnosis of atopy (yes/no) or allergy (yes/no) or eczema 
(yes/no) or atopic dermatitis (yes/no) or food allergy (yes/no) (will also be 
collected annually); 

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 
siblings history or diagnosis of atopy (yes/no) or allergy (yes/no) or eczema 
(yes/no) or atopic dermatitis (yes/no) or food allergy (yes/no) or asthma (yes/no) 
(will also be collected annually); 
 
enrollment in school (yes/no) (will also be collected quarterly); 
 
left school (yes/no); 
 
baby or child exercise (yes/no or how many days of the week) (will also be 
collected quarterly). 
 
Collection of data on wheeze and asthma 
 
The parent(s) / LAR(s) will be interviewed at the first contact of the extension and 
contacted quarterly to solicit morbidity associated with wheeze or asthma, with the 
questions since the last contact: Did your child have at least one episode of wheezing? 
Did your child take prescription medicines for wheeze or asthma? Has your child 
experienced troublesome symptoms at night of cough or wheezing or heavy breathing? 
The investigator will supplement information from parents with review of routine 
medical records /consultation with routine health care provider. Refer to the SPM for a 
more detailed set of questions. 
 
Data collection will also occur from medical charts retrospectively for those who have 
already completed 2 years of life prior to providing re-consent for the extension. 
 
At each of these contacts, the data collected may include the following types of 
information. Refer to the SPM for additional details 
 
Genetic History 
 
• 
Family history of asthma 
• 
Family history of allergies 
Child/subject variables of interest 
 
 
Past or current allergies 
 
Exposure to environmental/household or other risk factors for asthma 
 
Child’s activity levels 
 
Potential signs/symptoms of asthma 
 
Episodes of wheeze, asthma, or troublesome lung symptoms since the end of the 
primary study and their associated care 
 
Medications taken to prevent or treat asthma, wheeze or troublesome lung 
problems symptoms 
 
Section 6.6.4.2: Investigator review and assessment 

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Investigators will review each subject’s data to assess whether a child meets the subject 
previously met the protocol defined case definition(s) of asthma at the 2d, 3d, 4th, 5th and 
6th birthdays. This First Contact assessment will be based on: 
• 
Review of information gathered at the first extension study contact with the subject’s 
parent(s) / LAR(s) about past wheeze, asthma, and troublesome lung symptoms 
issues, and the medications used to treat them. 
• 
Review of information about any applicable primary study episodes of wheeze and 
troublesome lung symptoms, and history of asthma medications use. 
• 
Review of the subject’s routine medical records (where these exist and are 
available), as needed to verify/clarify study informationof parents and 
• 
Consultation with the subject’s health care provider(s), as needed to verify/clarify 
study information. 
 
Note that all information about all asthma, wheeze, and troublesome lung episodes as 
well as a review of any and all potential asthma medications that were taken by the 
subject will be needed for the accurate completion of the investigator assessment. (Refer 
to Section 4 for definition case definitions of asthma). 
 
To this end, quarterly contact information about asthma, wheeze, and troublesome 
lung episodes as well as the medications used to treat them should all be brought up-to- 
date at the time of each annual contact. 
 
Refer to the SPM for additional details. 
 
Section 6.6.5: Medications for Wheeze or Asthma 
 
Table 9 presents a list of medications for wheeze or asthma that should be identified 
during parent/LAR interviews and investigator review / assessment (Section 6.6.4), and 
recorded in the eCRF. These medications are usually prescribed by a health care 
provider. 
 
Table 9 Medication(s) for wheeze or asthma (Amended 15-Dec-2017) 
 
 
Section 6.6.6: Recording of SAEs related to study procedures 
 
Refer to Section 7.2 and Section 7.3. There is no biological sample collection during 
the extension study. 
Oral steroids 
Systemic (intramuscular or intravenous) steroids 
Inhaled steroids (ICS) 
Combination inhalers containing steroids and long-acting beta agonists 
Long-acting beta agonists (LABA) 
Short-acting beta agonists (SABA) 
Leukotriene modifiers or receptor antagonists 
Theophyline 
Anti-IgE therapy (e.g.,Omalizumab) 

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Section 6.6.7: Study conclusion for the extension 
 
The investigator/study staff will: 
• 
review Review all the data collected to ensure accuracy and completeness. 
• 
complete Complete the Study Conclusion screen in the eCRF. 
Section 8, Subject Completion and Withdrawal 
 
A subject who is available for the concluding contact foreseen in the protocol for the 
primary study is considered to have completed the primary study. 
 
A subject who is available for the concluding contact foreseen in the protocol for the 
extension study is considered to have completed the extension study. 
 
Subjects who are withdrawn from the study because of AEs or SAEs study procedure 
related to study participation SAEs must be clearly distinguished from subjects who are 
withdrawn for other reasons. The investigator Investigators will follow subjects who are 
withdrawn from the study as the result of an a study procedure related SAE until 
resolution of the event (see Section 7.4.1.2). 
 
Investigators will make an attempt to contact those subjects who do not return for 
scheduled visits or follow-up. E.g. Three attempted telephone contacts and/or a certified 
letter to the last known address, those subjects who do not return for scheduled visits or 
follow-up. 
 
Subjects who are withdrawn from the study because of SAEs must be clearly 
distinguished from subjects who are withdrawn for other reasons. Investigators will 
follow subjects who are withdrawn from the study as result of an SAE until resolution of 
the event (see Section 7.4.1.2). 
 
**Details concerning the definition of “lost to follow up” are presented in the SPM. 
 
Section 9.0 Statistical Methods 
 
Endpoints for the primary study are now presented in Section 9.1. Endpoints for the 
Extension study are now presented in Section 9.2 
 
Section 9.1: Endpoints pertaining to the amendment related to wheeze and asthma as 
secondary endpoints: 
 
• 
Occurrence of medically attended wheeze. 
• 
Occurrence of wheeze or asthma requiring admission. 
• 
Use of prescription medications for wheeze or asthma. 
Section 9.2: Endpoints pertaining to the amendment related to for Extension Study 
Primary: none 

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Secondary: 
 
• 
Use of prescription medication(s) for wheeze or asthma. 
Tertiary 
• 
Number of children with diagnosis of asthma (case definition 1) at age 2, 3, 4, 5, and 
6 years of age 
• 
Number of children with diagnosis of asthma (case definition 2) at age 2, 3, 4, 5 and 
6 years of age. 
• 
Number of children with asthma (case definition 3) at 3, 4, 5 and 6 years of age. 
• 
Number of children with recurrent wheeze. 
Study Cohorts 
 
Analysis cohorts for the primary study are now presented in Section 9.4.2 Analysis 
cohorts for the extension study are now presented in Section 9.4.3. 
 
Section 9.2.4.1: Total enrolled cohort at Year 2 
 
The total enrolled cohort will include all subjects enrolled in the primary study. 
 
Section 9.2.4.2: Per Protocol Set (PPS) cohort at Year 2 
 
The ATP PPS cohort will include all subjects enrolled in the primary study meeting all 
eligibility criteria up to the time of their censoring, either at study completion of epoch 1 
or prematurely as drop-out (e.g. withdrawn consent, lost-to-follow-up, lack of 
compliance). Additional details are provided in the Statistical Analysis Plan (SAP).. 
 
• 
Lost-to-follow-up is defined as no contact by the subject’s parent(s)/LAR(s) over the 
period of 3 planned contacts and/or 2 months and after a final attempt has been made 
by mail. Once this has been reached, the subject is censored at the time of last 
contact. 
• 
Lack of subject’s compliance is defined as 2 consecutive missed cases by not 
reporting through passive surveillance or by not cooperating to perform an 
examination visit in the given timeframe. 
Section 9.2.4.3: ATP Per Protocol Set (PPS) sub-cohort at Year 2 
 
• 
The ATP PPS sub-cohort at Year 2 will include subjects in the PPS cohort at Year 
2 for whom a blood sample result will be available (at Month 2, 4, 6, 12, 18 or 24). 
Analyses will be done on the ATP sub-cohort from the total cohort defined in section 
9.4.2 as well as from the ATP cohort defined in section 9.4.2.2. 
 
Section 9.4.3: Analysis Cohorts for Extension Study 
 
Section 9.4.3.1: Total enrolled cohort pertaining to the amendment related to wheeze 
and asthma for extension 

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The total enrolled cohort will include all subjects enrolled in the extension study. 
 
Section 9.4.3.2: PPS cohort for extension 
 
The PPS cohort for the Extension study will include all subjects meeting all eligibility 
criteria up to the amendment related time of their censoring, either at study completion 
or prematurely as drop-out (e.g. withdrawn consent or lost-to- wheeze and asthma 
follow-up). 
 
The total enrolled cohort for the amendment related to wheeze and asthma will include 
all subjects enrolled in the extension study. 
 
Section 9.5: Derived and transformed data 
 
Data transformations and derived variables will be described in the SAP. However, 
they may include the following: 
Section 9.5.1: General considerations for statistical analyses 
 
The primary analyses will at least be performed on the ATP PPS cohort or sub-cohort. If 
more than 5% of the subjects are eliminated from the total enrolled cohort, then all 
analyses will may also be performed on the total enrolled cohort in addition to the ATP 
PPS cohort or sub-cohort. 
 
When mentioned below in the upcoming analyses sections, analysis by subgroups 
willmay include: 
 
Analysis of demographics 
 
The distribution of subjects enrolled among the study sites will may be tabulated at least 
overall, by hemisphere, country, region, center and/or by regionother relevant grouping. 
The demographic and lifestyle characteristics collected for the enrolled subjects will may 
be summarized at least overall, by hemisphere and by, country, region, center, and/or 
other relevant grouping. 
 
• 
Frequency tables will be generated as appropriate, for categorical variable variables 
such as center. 
• 
Mean, median, standard error will be provided as appropriate, for continuous data 
such as age. 
 
Analysis of Objectives for the primary study now appears in Section 9.7; Analysis of 
Objectives for the extension study now appears in Section 9.8. 
 
Section 9.7 Analysis of co Objectives for the Primary Study (birth to 2 years of age): 
Section 9.7.3 Tertiary Objectives: 
• 
To determine the population attributable risk of wheeze and asthma from birth to 
sixth birthday due to RSV clinical LRTI in the first two years of life. 

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The population attributable risk together with 95% CI of medically attended wheeze, 
wheeze or asthma requiring admission, prescription of medications for wheeze or asthma 
will be calculated overall and by age strata (0-2 years, 2-4 years and 5-6 years)and by 
country, respectively. 
 
The population attributable risk is calculated by subtracting the incidence rate in the 
subjects who did not have RSV clinical LRTI in the first two years of life from the 
incidence rate in all subjects including both who had and who did not have RSV clinical 
LRTI in the first two years of life. 
 
For example, the population attributable risk of medically attended wheeze will be 
calculated as 
 
• 
To determine the population attributable risk percent of wheeze and asthma from 
birth until sixth birthday due to RSV clinical LRTI in the first two years of life. 
The population attributable risk percent together with 95% CI of medically attended 
wheeze, wheeze or asthma requiring admission, and prescription of medications for 
wheeze and asthma will be calculated overall and by age strata (0-2 years, 2-4 years and 
5-6 years), respectively. 
 
The population attributable risk percent is calculated by dividing the population 
attributable risk by the incidence rate in all the subjects including both who had and who 
did not have RSV clinical LRTI in the first two years of life. 
 
For example, the population attributable risk percent of medically attended wheeze will 
be calculated as 
 
The detail for calculating the CI for both population attributable risk and population 
attributable risk percent will be provided in the statistical analysis plan. 
 
Section 9.8 Analysis of Objectives for the Extension study 
Primary objectives: none 
Secondary objectives: 
 
Data for secondary endpoints may be pooled across the primary and extension periods. 
Additional details are provided in the SAP. 
 
Section 9.8.2.1: 
The incidence rate of medically attended wheeze, wheeze or asthma requiring hospital 
admission, and prescription of medications for wheeze or asthma may be calculated 
and stratified by country. 
 
The population attributable risk may be calculated by subtracting the incidence rate in the 
subjects who did not have RSV clinical LRTI in the first two years of life from the 
incidence rate in all subjects including both who had and who did not have RSV clinical 
LRTI in the first two years of life. 

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Details will be provided in the SAP. An example follows. 
 
The population attributable risk of medically attended wheeze may be calculated as: 
 
Ip-Iu 
 
Where Iu is the incidence rate of medically attended wheeze in subjects who did not have 
RSV clinical LRTI in the first two years of life, and Ip is the incidence rate of medically 
attended wheeze in all subjects including both who had and who did not have RSV 
clinical LRTI in the first two years of life. The above population attributable risk 
formula may be further adapted to best accommodate the data and their required 
analytic assumptions (e.g., a modified formula may be used for population attributable 
risk calculations involving recurrent outcomes). 
 
Section 9.8.2.2: To determine the population attributable risk percent of wheeze and 
asthma from birth until sixth birthday due to RSV clinical LRTI in the first two years of 
life. 
 
The population attributable risk percent together with 95% CI of wheeze, medically 
attended wheeze, recurrent wheeze, wheeze or asthma requiring admission, and 
prescription of medications for wheeze and asthma may be calculated overall and by age 
strata (0-2 years, 2-4 years and 5-6 years), respectively. 
 
The population attributable risk percent may be calculated by dividing the population 
attributable risk by the incidence rate in all the subjects including both who had and who 
did not have RSV clinical LRTI in the first two years of life. 
 
For example, the population attributable risk percent of medically attended wheeze may 
be calculated as: 
 
(Ip-Iu)/Ip*100 
 
Where Iu is the incidence rate of medically attended wheeze in subjects who did not have 
RSV clinical LRTI in the first two years of life, and Ip is the incidence rate of medically 
attended wheeze in all subjects including both who had and who did not have RSV 
clinical LRTI in the first two years of life. As with the population attributable risk, the 
above formula may be adapted, as appropriate, to best suit the data. 
 
The detail for calculating the CI for both population attributable risks and population 
attributable risk percent will be provided in the SAP. 
 
Section 9.8.3: Tertiary objectives 
 
Section 9.8.3.1: To explore the association of RSV clinical LRTI in the first two years of 
life and other potential risk factors for wheeze and asthma 

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The incidence rate of Endpoints such as medically attended wheeze, recurrent wheeze 
or asthma requiring admission, and prescription of medications for wheeze or asthma 
will be requiring hospital admission, and prescription of medications for wheeze or 
asthma may be calculated as recurrent events and stratified by country. 
 
Besides, multivariate Occurrence/recurrence rates will be calculated overall and by 
subgroups for each of the outcomes, as relevant. Multivariate Poisson regression model 
including RSV clinical LRTI in the first two years of life (Yes/No) and other potential 
risk factors such as, but not limited to, family and siblings history of asthma, atopy or 
food allergy, living and/or recurrent allergies, contact with pets, child history or 
diagnosisof allergy, atopy eczema or atopic dermatitis, etc., will be explored, 
respectively. 
 
Section 9.8.3.2: To explore the performance of asthma case definitions. 
 
The number and percentage of children with diagnosis of asthma (case definitions 1, 2, 
and 3) will be described for each applicable age(2, 3, 4, 5 and 6 years); the number and 
percentage of children with recurrent wheeze from at each applicable age 2-3, 3-4, 4-5 
and 5-6 will be described overall and by country in frequency tables. 
 
The risk of physician diagnosed asthma at the age of 6 years using case definitions 1and 
case definition, 2 and recurrent wheeze 3 (occurring from 2nd to the 6th birthday) will be 
analyzed using multivariate logistic regression model including RSV clinical LRTI in the 
first two years of life (Yes/No) and other potential risk factors listed above, respectively. 
 
Statistical analysis of agreement will be performed to compare the two case definitions of 
asthma. A 2x2 contingency table similar as for one of the co-primary objective will be 
provided and the following measures of agreement (with 95% CI) will be 
calculated:asthma case definitions 1, 2, and 3 to each other. 
 
• 
Sensitivity: TP/ (TP+FN) 
• 
Specificity: TN/ (TN+FP) 
• 
Positive predictive value (PPV): TP/ (TP+FP) 
• 
Negative predictive value (NPV): TN/ (TN+FN) 
• 
Proportion of overall agreement, which is the proportion of cases similarly classified: 
(TP + TN)/ (TP+FP+FN+TN). 
Cohen’s kappa (or other appropriate) coefficient may be used for the comparisons. The 
magnitude of the kappa coefficient represents the proportion of agreement greater than 
that expected by chance. 

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Data for endpoints will be pooled across primary and extension period as follows: 
 
• 
Medically attended wheeze, in the primary phase corresponds to episodes of wheeze 
documented at an examination visit initiated by monthly contacts with parents and in 
the extension phase by a history from parents solicited by contact every 3 months, 
which may be supplemented by review of routine medical records or contact with 
health care provider. 
• 
Wheeze or asthma requiring admission in the primary phase corresponds to episodes 
of wheeze documented at an examination visit that were associated with admission 
to hospital and in the extension phase by a history from parents, which may be 
supplemented by review of routine medical records or contact with health care 
provider. 
• 
Prescription of medications for wheeze or asthma in the primary phase will be 
extracted from all treatments that were recorded during the examination visits and in 
the extension phase by specific request for relevant medication from parents, which 
may be supplemented by review of routine medical records or contact with health 
care provider. 
• 
Diagnosis of asthma according to case definition 1 and 2 will not be assessed during 
the primary phase and will be assessed for the first time at the first contact of the 
extension period and annually thereafter until study conclusion. 
• 
Diagnosis of recurrent wheeze as 4 or more episodes in one calendar year, will be 
assessed in the primary phase based on the episodes of wheeze documented at an 
examination visit initiated by monthly contacts with parents and in the extension 
phase by a history from parents solicited by contact every 3 months, which may be 
supplemented by review of routine medical records or contact with health care 
provider. 
 
Section 9.9: Interpretation of analyses 
 
Analyses All analyses will be descriptive with the aim to characterise overall 
occurrences, patterns and potential differences between groups in the endpoints related to 
the objectives. No hypothesis testing will be performed. 
 
Section 9.10: Conduct of analyses 
 
Analytic plans may be modified as appropriate to accommodate final sample sizes and 
data distributions. 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. 
 
Section 9.10.1: Sequence of analyses 
 
…… These preliminary results will be used for potential adjustment of the LRTI Case 
Definition and Severity Scale before final analysis, to assess the need to extend the 
primary study to allow all subjects to complete 2 years of follow-up and to provide data 
for other relevant decision making, as soon as possible.* The results pertaining to this 
analysis will be descriptively reported in the an interim statistical report. 

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Section 9.10.2: Statistical considerations for interim analyses the primary study 
 
Section 9.10.3: Statistical considerations for the extension study 
 
All Statistical analyses pertaining to the extension study will be performed on all the data 
collected and cleaned for the subjects who re-consented for the extension. For these 
analyses data from birth up to the age of 6 years will be used. 
 
An interim analysis for the study extension will be conducted near the midway point of 
study extension data collection, after all subjects have reached four years of age (and 
completed their annual contact, or passed the window for that contact). The interim 
analysis will be purely descriptive, no adjustment of the type I error is foreseen. 
 
Final extension study analysis will be conducted after all subjects have reached six 
years of age (and completed their annual contact, or passed the window for that 
contact). 
 
References (Synopsis and Section 12) 
 
Pearce N, Aït-Khaled N, Beasley R, et al. Worldwide trends in the prevalence of 
asthma symptoms: phase III of the International Study of Asthma and Allergies in 
Childhood (ISAAC). Thorax 2007;62:758-766. 
 
Wong G, Brunekreef B, Ellwood P, et al. Cooking fuels and prevalence of asthma: a 
global analysis of phase three of the International Study of Asthma and Allergies in 
Childhood (ISAAC). Lancet Respir Med. 2013; 1: 386–94. 
 
Yang CL, To T, Foty RG, Stieb DM, Dell SD. Verifying a questionnaire diagnosis of 
asthma in children using health claims data. BMC Pulmonary Medicine. 2011;11:52. 
doi:10.1186/1471-2466-11-52. 
 
APPENDIX C 
OVERVIEW OF RECRUITMENT PLAN (Primary Study) 
 
The text now presented in Appendix C has been moved (from Section 4.0) but it has not 
been altered. 
 
APPENDIX D 
Additional Information Regarding Primary Study Visits 
 
The text now presented in Appendix D has been moved (from Section 3.0) but it has not 
been altered. 
 
APPENDIX E 
Additional Information Regarding LRTI Surveillance, 
including Active Surveillance Contact Schedule (Primary Study) 
 
The text now presented in Appendix E has been moved (from Section 3.0) and minor 
alterations have been made. The alterations are presented below. 

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ACTIVE SURVEILLANCE CONTACT SCHEDULE to identify any potential 
LRTI case 
 
Active surveillance is aimed at confirming that a case is/was not missed due to lack of 
reporting by parent(s)/LAR(s) and to remind parent(s)/LAR(s) to report cases of RTI 
symptoms as soon as possible themselves. Although active surveillance is an important 
aspect to ensure that all cases are identified timely, the number of active surveillance 
contacts should not be too high. Too many active surveillance contacts could put an 
unnecessary demand on the parent(s)/LAR(s) of the subjects and has been known to 
negatively impact long term compliance. In order to reduce the number of active 
surveillance contacts to an acceptable and valuable level, the following measures should 
be applied. 
Active surveillance is allowed to occur through various media (e.g. text messaging, email 
and, telephone, and in-person) based on local possibilities 
 
DISCONTINUATION OF ACTIVE SURVEILLANCE 
 
Active surveillance should be suspended after there has been no contact for more than 3 
planned contacts and/or no contact for more than 2 months and a final attempt has been 
made by mail or a live visit. If the parent(s)/LAR(s) of the subject contact the 
investigator/study staff at a later point in time through passive surveillance, the case 
should be followed up, data should be collected at intermittent period and active 
surveillance could be reinitiated. These subjects will however no longer be included in 
the ATP cohort, therefore, all efforts should be made to avoid this. 

 
  
 
 
 
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Protocol Amendment 3 Sponsor Signatory Approval 
 
eTrack study number and 
Abbreviated Title 
 
Date of Amendment 
Detailed Title 
 
 
 
 
 
 
Sponsor signatory (Amended 
15-DEC-2017) 
200150 (EPI-RSV-005 BOD) 
 
 
Amendment 3 Final: 15 December 2017 
 
A prospective, epidemiological, interventional, multi- 
country based, cohort study to assess the disease 
burden of respiratory syncytial virus (RSV) 
associated, suspected lower respiratory tract 
infections (LRTis) in newborns, from birth up to 2 
years of age and population attributable risk percent 
of RSV LRTI on the development of wheeze and 
asthma from birth up to 6 years of age. 
 
Amanda Leach 
Clinical and Epidemiology R&D Project Leader 
RSV Program GSK Biologicals 
PPD 
'--------- 
 
 
Signature 
 
 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
For internal use only 
 
 
 
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