A Prospective Epidemiological Study of Pregnancy Outcomes and of Events of Interest in Pregnant Women, Neonates and Infants (PEPNI)
Phase: NA
Conditions: Respiratory Syncytial Virus Infections
Sponsor: GlaxoSmithKline

 
 
 
 
Protocol Amendment 4 
 
Study ID:  207636 
 
A prospective epidemiological study of women between 24-27 weeks of pregnancy to 
describe pregnancy outcomes and events of interest in the mother and neonate, as well as 
determine incidence in infants of RSV LRTI and RSV hospitalization 
 
 
Date of Document: 29-May-2020 
 
 

CONFIDENTIAL 
207636 (EPI-RSV-008 BOD) 
Protocol Amendment 4 Final 
29-MAY-2020 
1 
 
Study Protocol 
Sponsor: 
GlaxoSmithKline Biologicals SA 
Rue de l’institut 89, 
1330 Rixensart, Belgium 
eTrack study number and 
Abbreviated Title 
207636 (EPI-RSV-008 BOD) 
Date of protocol 
Final Version 1: 11 July 2017 
Date of Amendment 
Amendment 1 Final: 12 February 2018 
 
Amendment 2 Final: 03 July 2018  
 
Amendment 3 Final: 18 February 2019 
 
Amendment 4 Final: 29 May 2020 
Title 
A prospective epidemiological study of pregnancy 
outcomes and of events of interest in pregnant women, 
neonates and infants (PEPNI)  
Detailed Title 
A prospective epidemiological study of women 
between 24-27 weeks of pregnancy to describe 
pregnancy outcomes and events of interest in the 
mother and neonate, as well as determine incidence in 
infants of RSV LRTI and RSV hospitalization.  
Coordinating author 
 
Contributing authors 
• 
, Clinical & Epidemiological 
Project Lead 
• 
, Lead Epidemiologist 
• 
, Expert Biostatistician, 
 
 Lead Biostatistician  
• 
, 
, Study Delivery Leads 
• 
, Clinical Read-Out Team 
Leader 
• 
, Clinical Laboratory 
Sciences Study Manager, Business & Decision 
Life Sciences Contractor for GSK Biologicals 
• 
, Safety Physician 
• 
, Oversight Data Manager 
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Protocol Amendment 4 Final 
29-MAY-2020 
2 
eTrack study number and 
Abbreviated Title 
207636 (EPI-RSV-008 BOD) 
Detailed Title 
A prospective epidemiological study of women 
between 24-27 weeks of pregnancy to describe 
pregnancy outcomes and events of interest in the 
mother and neonate, as well as determine incidence in 
infants of RSV LRTI and RSV hospitalization. 
Authors who contributed 
to previous versions of the 
protocol: 
• 
 
 Clinical & Epidemiological Project Leads 
• 
, 
Epidemiologists 
• 
, 
, Study 
Delivery Leads 
• 
, Clinical Research and 
Development Lead 
• 
, Clinical Research and Development 
Lead 
• 
, Lead Epi Statistician 
• 
, Study statistician 
• 
 (Aixial for GSK Biologicals), 
Clinical Trial Supply manager 
• 
, Clinical Trial Supply manager 
• 
, Safety Physician 
• 
, Clinical Read-Out Team Leader  
• 
 (Business & Decision Life 
Sciences for GSK Biologicals), Clinical 
Laboratory Sciences Study Manager 
• 
, Safety Physician  
• 
, Oversight Data Manager 
• 
, Study Data Manager (Tata 
Consultancy Services for GSK Biologicals) 
• 
, Regulatory Affairs 
Representative 
GSK Biologicals’ Protocol DS v15.0 
©2017-2020 GSK group of companies or its licensor. 
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CONFIDENTIAL 
207636 (EPI-RSV-008 BOD) 
Protocol Amendment 4 Final 
29-MAY-2020 
3 
Protocol Amendment 4 Sponsor Signatory Approval 
eTrack study number and 
Abbreviated Title 
207636 (EPI-RSV-008 BOD) 
Date of Amendment 
Amendment 4 Final: 29 May 2020 
Detailed Title 
A prospective epidemiological study of women 
between 24-27 weeks of pregnancy to describe 
pregnancy outcomes and events of interest in the 
mother and neonate, as well as determine incidence in 
infants of RSV LRTI and RSV hospitalization.  
Sponsor signatory 
Ouzama Henry, Clinical & Epidemiological Project 
Lead 
 
 
Signature 
 
 
 
Date 
 
 
 
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CONFIDENTIAL 
207636 (EPI-RSV-008 BOD) 
Protocol Amendment 4 Final 
29-MAY-2020 
4 
Protocol Amendment 4 Rationale  
Amendment number: 
Amendment 4 
Rationale/background for changes:  
This amendment outlines measures that may be applicable during special 
circumstances (e.g., COVID-19 pandemic). The primary purpose of the amendment is 
to protect the subject’s welfare, and as far as possible ensure the potential benefit to the 
subject and promote data integrity.  Several additional modifications and clarifications 
have also been made.  
Changes are outlined below. 
• 
Globally:  
− 
Intervals between study visits/contacts/observations: the window for the first 
infant subject visit has been extended from 0-10 to 0-21 days to provide site 
personnel with additional time to obtain and document post-delivery/birth 
informed consent (where this is required). 
− 
References to Gestational Age Range at maternal Visits 2, 3 and 4 have been 
removed as their inclusion was only intended as a guide and was not intended 
to further restrict allowed intervals between study visits. 
• 
Synopsis, Section 3.3, Tertiary Objectives, and Section 11.1.3, Tertiary Endpoints, 
have been updated to indicate that the incidence of LRTIs/ Severe LRTIs (using 
alternative case definitions) will also be evaluated.   
• 
Synopsis and Section 11.1.3, Tertiary Endpoints, has been updated to clarify that 
further exploratory characterization of immune responses to RSV and/or other 
respiratory tract infections or infections of relevance to pregnant women and their 
newborns (based on maternal serum and cord blood) includes, for example, levels 
of RSV-B neutralizing antibodies. 
• 
The List of Abbreviations has been updated to include a reference to COVID-19. 
• 
Section 2.3, Overall Benefit: Risk Conclusion has been updated. 
• 
Section 4, Figure 1: A note has been added to indicate that COVID-19 cases 
identified within the surveillance framework of the study will be captured to the 
eCRF. 
• 
Section 5.4, Table 4, Alternative LRTI/Severe LRTI Case Definitions, has been 
added. All subsequent Table numbers therefore increase by one. 
• 
Section 8.2.1, Study procedures during special circumstances, has been added. 
• 
Section 8.3, Table 5 and Table 6, List of study procedures for maternal subjects, 
and List of study procedures for neonates/infants, have been clarified to indicate 
that COVID-19 cases are considered clinically significant events and will be 
recorded as such in the eCRF.  
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• 
Sections 8.5.8, 8.6.2, 8.6.7 have been modified to reference the collection of 
COVID-19 case information. 
• 
Section 8.6.5.2 has been modified to clarify that RTI surveillance in infants cannot 
begin before additional consent for the infant’s participation (where required) has 
been supplied. 
• 
Section 8.7, Reporting COVID-19 cases, has been added. 
• 
Section 11.3 has been modified to introduce definitions for the Enrolled set, and to 
clarify definitions for the Exposed, and Per Protocol sets for analysis. 
• 
Section 11.6, 11.7, and 11.8 have been modified for consistency with the changes 
in Section 11.3.  
• 
Section 11.11.1, Statistical considerations for interim analysis, has been modified 
to indicate that an interim analysis for RSV LRTIs may be performed if deemed 
necessary. 
• 
Section 14 has been updated to include a reference to the WHO Guidance for 
surveillance of COVID-19. 
• 
Additional editorial clarifications have been made and typographic errors have 
been corrected. 
• 
A detailed summary of changes (including deletions) appears in APPENDIX E. 
 
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6 
Protocol Amendment 4 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) 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 and/or the subject’s legally acceptable representative.  
• 
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 
207636 (EPI-RSV-008 BOD) 
Date of Amendment 
Amendment 4 Final: 29 May 2020 
Detailed Title 
A prospective epidemiological study of women 
between 24-27 weeks of pregnancy to describe 
pregnancy outcomes and events of interest in the 
mother and neonate, as well as determine incidence 
in infants of RSV LRTI and RSV hospitalization.  
Investigator name 
 
 
 
Signature 
 
 
 
Date 
 
 
 
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Sponsor Information 
1. Sponsor 
GlaxoSmithKline Biologicals 
Rue de l’institut 89,1330 Rixensart, Belgium 
2. Sponsor Medical Expert for the Study 
Refer to the local study contact information document. 
3. Sponsor Study Monitor 
Refer to the local study contact information document. 
4. Study Contact for Reporting of a Serious Adverse Event (SAE) 
GSK Biologicals Central Back-up Study Contact for Reporting SAEs: refer to protocol 
Section 9.4. 
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SYNOPSIS  
Detailed Title A prospective epidemiological study of women between 24-27 weeks 
of pregnancy to describe pregnancy outcomes and events of interest in 
the mother and neonate, as well as determine incidence in infants of 
RSV LRTI and RSV hospitalization.  
Objectives  
(Amended 
29-MAY-
2020) 
Primary 
In healthy pregnant women with uncomplicated pregnancies: 
• 
To determine the frequencies of pregnancy outcomes. 
• 
To determine the frequencies of pregnancy related events of 
interest from enrollment (Visit 1) through 42 days after delivery 
(Visit 6).   
(Although pregnancy related events of interest occur within the first 
42 days after delivery they may only be detected later, and are to be 
reported throughout the study.) 
In all neonates live-born to women enrolled in the study: 
• 
To determine the frequencies of neonatal events of interest.  
 
Neonatal events of interest occur within the first 28 days after birth 
but may only be detected later, and are to be reported throughout the 
study. 
 
Secondary 
In healthy pregnant women with uncomplicated pregnancies  
• 
To determine frequencies of pregnancy related events of interest 
according to GAIA levels of diagnostic certainty (where these are 
specified) from enrollment (Visit 1) through 42 days after 
delivery (Visit 6).  (Although pregnancy related events of interest 
occur within the first 42 days after delivery they may only be 
detected later, and are to be reported throughout the study.) 
• 
To describe the distribution of RSV-A antibody titers in maternal 
blood at delivery.  
In all neonates live-born to women enrolled in the study: 
• 
To determine frequencies of neonatal events of interest according 
to GAIA levels of diagnostic certainty (where these are specified). 
Neonatal events of interest occur within the first 28 days after 
birth (but may only be detected later and are to be reported 
throughout the study). 
• 
To describe the distribution of RSV-A antibody titers in cord 
blood at delivery.   
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In all neonates/infants live-born to women enrolled in the study, from 
birth through 1 year of age: 
• 
To determine the incidence of all, of severe, and of very severe 
RSV-lower respiratory tract illnesses (LRTIs).  
• 
To determine the incidence of RSV hospitalization.  
 
Tertiary 
• 
To describe co-infections of RSV-LRTI with other respiratory 
viruses in infants.  
• 
To estimate the association of RSV-LRTI in neonates/infants and 
the level of RSV neutralizing antibodies in cord blood.  
• 
To determine the incidence of LRTIs/ Severe LRTIs (using 
alternative case definitions) 
• 
To determine risk factors for pregnancy-related and neonatal 
events of interest  
• 
If deemed necessary, to further characterize the immune 
responses to RSV and other infections in maternal subjects and 
infants (based on maternal serum and cord blood).  
Rationale for 
the study and 
study design 
Maternal immunization aims to prevent diseases in neonates and 
infants via transplacental antibody transfer from the mother to the 
fetus following vaccination of the pregnant woman. Several marketed 
vaccines are already recommended for and routinely administered to 
pregnant women, including influenza, tetanus, and Tdap vaccines 
(CDC 2013a, CDC 2013b). There are also a number of maternal 
vaccines in development that aim to protect neonates and infants from 
pathogens in addition to respiratory syncytial virus (RSV). 
GlaxoSmithKline (GSK) is developing an investigational vaccine for 
use in pregnant women against RSV disease. Of note this vaccine is 
developed solely for immunization in pregnancy. 
Maternal immunization is implemented worldwide and has the 
potential to make a major contribution to reducing RSV lower 
respiratory tract illnesses (LRTI) and the burden of other diseases in 
infants globally. Therefore, it is imperative that clinical trials are 
conducted across different countries in different settings. GSK is 
proactively addressing potential challenges of conducting clinical 
trials in pregnant women in low- and middle income countries 
(LMIC). 
Before conducting clinical trials it is important to understand the 
frequency of pregnancy outcomes and the maternal and neonatal 
events of interest (i.e. clinically significant events that may be 
considered adverse events if they occur after vaccination) in each 
setting where clinical trials may be conducted for better interpretation 
of safety data. Also, to ensure safety of the participating women, and 
to characterize the safety profile of the product, adverse events (AEs) 
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in pregnancy should be appropriately detected and managed. This 
study addresses gaps in understanding of anticipated rates of 
pregnancy outcomes as well as events of interest in pregnant women 
and neonates. Furthermore, this study will be conducted at potential 
sites for future maternal immunization trials and will help assure the 
capacity of sites to detect and manage clinically significant events of 
interest in pregnant women and their neonates.  
Secondarily, the study will establish surveillance mechanisms for 
RSV associated illnesses in the neonate/infant (through the first 12 
months of life. Whilst there is good documentation of the global 
burden of RSV disease, incidence of RSV-LRTI according to the 
World Health Organization (WHO) 2015 case definitions [Modjarrad, 
2016] is limited in the literature, particularly in many LMIC settings. 
Hence, this study will also estimate the incidence of infant RSV-LRTI 
using WHO case definitions across geographically distinct locations to 
support incidence rate assumptions for planning of future efficacy 
trials.  
To achieve these goals, GSK will be guided by the WHO 
recommendations on antenatal care for a positive pregnancy 
experience [WHO, 2016] and the Global Alignment of Immunization 
Safety Assessment in pregnancy (GAIA) case definitions [Bonhoeffer, 
2016; Bauwens, 2016; Kochhar, 2017]. Standardization of 
surveillance methodology and case definitions (applicable to maternal 
immunization AEs) may support comparison of data across different 
countries [Jones, 2016]. 
This multi-country study will enroll pregnant women ≥ 240/7 weeks 
and ≤ 276/7 weeks gestational age (GA).  Study procedures in this 
protocol are defined to ensure that maternal and neonatal events of 
interest are captured. They are not intended to replace procedures 
performed by local healthcare providers as part of standard care. 
Prenatal screening and care will be provided by local healthcare 
providers (in accordance with local standards). 
Study design 
• 
Type of design: Prospective, epidemiological, interventional 
(without administration of medicinal products as described in a 
research protocol), multi-country, cohort study. 
• 
Study population: The study will be conducted in multiple 
countries, in pregnant women and their infants.  
• 
Type of study: self-contained. 
• 
Data collection: Electronic Case Report Form (eCRF). 
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Synopsis Table 1 Sampling schedule for maternal subjects   
 
 
Visit 
Sample 
Parameter(s) evaluated 
1 
2 
3 
4 
Delivery 
Maternal 
Blood 
Hematology/  
biochemistry1, 4 
x 
 
x3 
 
 
Antibody titer (RSV-A)  
 
 
 
 
≤ 72 hours after 
delivery5 
Cord Blood 
Antibody titer (RSV-A)  
 
 
 
 
x 
Urine 
Protein, glucose, RBC, WBC 2, 4 
x 
x 
x 
x 
 
1 To be performed preferentially by local healthcare providers, as per local practice. To be performed by the 
investigator/study staff ONLY if not done by the local healthcare provider within 2 weeks before the study visit. 
2 The investigator/site staff will perform a urine dipstick test using supplies provided by GSK.  
3 Hemoglobin only    
4 If results are abnormal, subjects will be referred per local standard of care. 
5 This sample may be collected from start of labor (e.g. when the mother arrives at the hospital to deliver and an 
intravenous line is inserted) through 72 hours after delivery.     
Sampling 
schedule for 
neonates/ 
infants 
Surveillance for RSV LRTI will be conducted in infants through 
the 12 month study period. During this 1-year post-birth 
surveillance period, for each RTI with suspicion of difficulty in 
breathing, or wheezing, or with parental concern, a nasal swab 
will be collected at a visit to assess potential RSV associated 
RTIs/LRTIs 
Primary 
Completion 
Date (PCD)  
42 days post-delivery/birth (i.e. Visit 6 for the mother and Visit 
2-NB for the infant) or last visit of Epoch 2. 
End of Study 
(EoS) 
Last testing results released of samples collected up to Visit 4-NB 
(assays related to primary and secondary endpoints) 
Duration of the 
study 
Approximately 4.5 to 6 months for participating pregnant women; 
approximately 1 year for participating infants. 
• 
Epoch 001: Screening 
• 
Epoch 002: Primary starting at Visit 1 and ending 42 days post-
delivery/birth (Visit 6 for the mothers and Visit 2-NB for the 
infants).* 
• 
Epoch 003: Follow-up of infants starting 43 days post-
delivery/birth and ending at Visit 4-NB (1 year post-birth). 
*Any safety and disease surveillance data collected after Visit 2-NB 
will be collected in Epoch 003. 
Synopsis Table 2 
Study groups and epochs foreseen in the study   
Study Groups 
Number of 
subjects enrolled 
Age (Min/Max) 
Epochs 
Epoch 001  
Epoch 002 
Epoch 003  
Maternal subjects 
Up to  2300  
18 years - 45 
years  
x  
x  
 
Infants  
Up to  2300  
NA  
 
x 
x  
Approximately 200 to 300 subjects per country. To achieve the enrollment targets noted above, the number of 
pregnant women SCREENED in each country may exceed the country-specific enrolment target. 
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• 
Surveillance for pregnancy outcomes and pregnancy-
related events of interest that occur from Visit 1 up to 42 
days after delivery (Visit 6). 
• 
Surveillance for neonatal events of interest that occur from 
birth up to 28 days of age  
• 
Surveillance for RSV LRTI and RSV hospitalization in 
infants: from birth up to 1 year of age 
Number of subjects 
• 
Approximately 2300 pregnant women. Neonates of 
enrolled pregnant women who consent to the infant’s 
continued study participation will also be enrolled. 
Endpoints 
 (Amended 29-
MAY-2020) 
Primary 
• 
Pregnancy outcomes.  Of note, fetal death/stillbirth has 
multiple subcategories. For example, fetal death/stillbirth 
with no congenital anomalies is an outcome with two 
subcategories that include: 1) antepartum stillbirth; 2) 
intrapartum stillbirth. For each outcome, the investigator 
should select the applicable sub-category. 
− 
Live birth with no congenital anomalies,  
− 
Live birth with congenital anomalies,  
− 
Fetal death/stillbirth (loss at or after 22 weeks of 
gestation) with no congenital anomalies: 
o 
Antepartum stillbirth  
o 
Intrapartum stillbirth  
− 
Fetal death/still birth (loss at or after 22 weeks of 
gestation) with congenital anomalies: 
o 
Antepartum stillbirth 
o 
Intrapartum stillbirth  
− 
Elective/therapeutic termination with no congenital 
anomalies,  
− 
Elective/therapeutic termination with congenital 
anomalies. 
• 
Pregnancy related events of interest from Visit 1 through 
Visit 6. Although pregnancy related events of interest 
occur within the first 42 days after delivery they may only 
be detected later, and are to be reported throughout the 
study. They are listed below. Of note, some events of 
interest fall under a single category but have multiple 
subcategories. For example, hypertensive disorders of 
pregnancy is an event with three subcategories that 
include: 1) gestational hypertension; 2) pre-eclampsia; and 
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3) pre-eclampsia with severe features (including 
eclampsia). For each event, the investigator should 
identify the event and select the applicable sub-category. 
− 
Maternal death 
− 
Hypertensive disorders of pregnancy:  
o 
Gestational hypertension,  
o 
Pre-eclampsia,  
o 
Pre-eclampsia with severe features (including 
eclampsia)  
− 
Antenatal bleeding:  
o 
Morbidly adherent placenta 
o 
Placental abruption 
o 
Cesarean Scar Pregnancy 
o 
Uterine rupture 
− 
Postpartum hemorrhage 
− 
Fetal growth restriction 
− 
Dysfunctional labor 
o 
first stage of labor 
o 
second stage of labor 
− 
Gestational diabetes mellitus,  
− 
Non reassuring fetal status 
− 
Pathways to preterm birth:  
o 
Premature preterm rupture of membranes,  
o 
Preterm labor,  
o 
Provider-initiated preterm birth. 
− 
Chorioamnionitis 
− 
Oligohydramnios 
− 
Polyhydramnios 
− 
Gestational Liver Disease: 
o 
Intrahepatic Cholestasis of Pregnancy (ICP)  
o 
Acute Fatty Liver of Pregnancy  
− 
Maternal Sepsis 
− 
Any other pregnancy related event considered by the 
investigator to be of concern (specify) 
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• 
Neonatal events of interest from birth through 28 days of 
age. Neonatal events of interest occur within the first 28 
days after birth, but may only be detected later and are to 
be reported throughout the study. They include: 
− 
Small for gestational age, 
− 
Low birth weight including very low birth weight, 
− 
Neonatal encephalopathy, 
− 
Congenital microcephaly,  
o 
Postnatally diagnosed 
o 
Prenatally diagnosed 
− 
Congenital anomalies, 
o 
Major external structural defects 
o 
Internal structural defects 
o 
Functional defects 
− 
Neonatal death, 
o 
Neonatal death in a preterm live birth (gestational 
age>=28 to < 37 weeks) 
o 
Neonatal death in a term live birth 
− 
Neonatal infections, 
o 
Blood stream infections 
o 
Meningitis 
o 
Respiratory infection 
− 
Respiratory distress in the neonate, 
− 
Preterm birth, 
− 
Failure to thrive, 
− 
Large for gestational age, 
− 
Macrosomia, 
− 
Any other neonatal event considered by the 
investigator to be of concern (specify, e.g. 
neurodevelopment delay)  
 
Secondary  
• 
Pregnancy related events of interest from Visit 1 through 
Visit 6 (as defined in primary endpoints) for each GAIA 
level of diagnostic certainty (where applicable and 
feasible) 
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• 
Neonatal events of interest from birth through 28 days of 
age (as defined in primary endpoints) for each GAIA level 
of diagnostic certainty (where applicable and feasible)  
Of note, some events of interest fall under a single category 
but have multiple subcategories. For each event, the 
investigator should identify the event and select the applicable 
sub-category and the GAIA level of diagnostic certainty. 
• 
RSV-A neutralizing antibody titers in maternal blood at 
delivery. 
• 
RSV-A neutralizing antibody titers in cord blood at 
delivery.  
• 
Episode(s) of RSV-LRTI from birth up to 1 year of age.  
• 
Episode(s) of RSV hospitalization from birth up to 1 year 
of age.  
 
Tertiary  
• 
Co-infections of RSV-LRTI with other respiratory viruses 
in infants, confirmed by PCR of nasal swabs in infants 
from birth up to 1 year of age: 
− 
Influenza A virus (Flu A) 
− 
Influenza B virus (Flu B) 
− 
Human Influenza A virus subtype H1 (Flu A-H1)  
− 
Human Influenza A virus subtype H3 (Flu A-H3) 
− 
Human Influenza A virus subtype H1pdm09 (Flu A-
H1pdm09) 
− 
Human adenovirus (AdV) 
− 
Human metapneumovirus (MPV) 
− 
Human enterovirus (HEV) 
− 
Human parainfluenza virus 1 (PIV1) 
− 
Human parainfluenza virus 2 (PIV2) 
− 
Human parainfluenza virus 3 (PIV3) 
− 
Human parainfluenza virus 4 (PIV4) 
− 
Human bocavirus 1/2/3/4 (HBoV) 
− 
Human rhinovirus A/B/C (HRV) 
− 
Human coronavirus 229E (229E) 
− 
Human coronavirus NL63 (NL63)  
− 
Human coronavirus OC43 (OC43) 
• 
Episodes of LRTIs/Severe LRTIs up to one year of age - 
using alternative case definitions  
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• 
Potential risk factors for pregnancy related and neonatal 
events of interest.  
• 
Any further exploratory characterization of immune 
responses to RSV and/or other respiratory tract infections 
or infections of relevance to pregnant women and their 
newborns (based on maternal serum and cord blood). (For 
example, levels of RSV-B neutralizing antibodies). 
References 
Bauwens J, Bonhoeffer J, Chen RT, editors. Harmonising 
Immunisation Safety Assessment in Pregnancy. Vaccine. 
2016. 34 (49): 5991 – 6110. 
Bonhoeffer J, Kochhar S, Hirschfeld S, et al. Global alignment 
of immunization safety assessment in pregnancy - The GAIA 
project. Vaccine. 2016;34(49):5993-5997. doi: 
10.1016/j.vaccine.2016.07.006.  
Centers for Disease Control and Prevention (CDC). Updated 
recommendations for use of tetanus toxoid, reduced diphtheria 
toxoid, and acellular pertussis vaccine (Tdap) in pregnant 
women. Advisory Committee on Immunization Practices 
(ACIP) - 2012.  MMWR. 2013a ; 62 (7) :131 -135. 
Centers for Disease Control and Prevention (CDC). Influenza 
Vaccination Coerage Among Pregnant Women — United 
States, 2012–13 Influenza Season. MMWR.  2013b; 62 (38): 
787–792. 
Jones CE, Munoz FM, Kochhar S et al. Guidance for the 
collection of case report form variables to assess safety in 
clinical trials of vaccines in pregnancy. Vaccine. 2016; 
34(49):6007-6014. 
Kochhar S, Bauwens J, Bonhoeffer J, editors. Harmonising 
Immunization Safety Assessment in Pregnancy – Part II. 
Vaccine. 2017. 35 (48): 6469-6582. 
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.  
 
World Health Organization (WHO). WHO recommendations 
on antenatal care for a positive pregnancy experience. 
Published in 2016. 
http://www.who.int/reproductivehealth/publications/maternal_
perinatal_health/anc-positive-pregnancy-experience/en. Last 
accessed on 09 February 2017. 
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TABLE OF CONTENTS 
PAGE 
SPONSOR INFORMATION ............................................................................................ 8 
SYNOPSIS ...................................................................................................................... 9 
LIST OF ABBREVIATIONS (AMENDED 29-MAY-2020) ............................................... 26 
GLOSSARY OF TERMS ............................................................................................... 28 
1. 
INTRODUCTION .................................................................................................... 32 
1.1. 
Background and rationale for the study ....................................................... 32 
1.2. 
Rationale for the study population ............................................................... 33 
1.3. 
Rationale for the surveillance of pregnancy related events of 
interest ........................................................................................................ 33 
1.4. 
Rationale for the use of Global Alignment of Immunization safety 
Assessment in pregnancy (GAIA) case definitions ...................................... 34 
1.5. 
Rationale for the active and passive surveillance for RSV 
associated respiratory tract illnesses (RTI) with suspicion of 
difficulty in breathing/wheezing or with parental concern in 
neonates/ infants ........................................................................................ 34 
2. 
BENEFIT: RISK ASSESSMENT ............................................................................. 35 
2.1. 
Risk Assessment ........................................................................................ 35 
2.2. 
Benefit Assessment .................................................................................... 35 
2.3. 
Overall Benefit:Risk Conclusion (Amended 29-MAY-2020) ......................... 35 
3. 
OBJECTIVES ......................................................................................................... 36 
3.1. 
Primary objectives ...................................................................................... 36 
3.2. 
Secondary objectives .................................................................................. 36 
3.3. 
Tertiary objectives (Amended 29-MAY--2020) ............................................ 37 
4. 
STUDY DESIGN OVERVIEW (AMENDED 29-MAY-2020) ..................................... 38 
5. 
CASE DEFINITIONS .............................................................................................. 40 
5.1. 
Pregnancy related events of interest ........................................................... 40 
5.2. 
Neonatal events of interest ......................................................................... 40 
5.3. 
Respiratory tract illness (RTI) / Lower respiratory tract illness (LRTI) .......... 40 
5.4. 
RSV infection (Amended 29-MAY-2020) ..................................................... 40 
6. 
STUDY POPULATION ........................................................................................... 42 
6.1. 
Number of subjects/ centers (Amended 29-MAY-2020) .............................. 42 
6.2. 
Inclusion criteria for enrollment ................................................................... 43 
6.2.1. 
Maternal subjects: ........................................................................ 43 
6.2.2. 
Infants (Amended 29-MAY-2020): ............................................... 44 
6.3. 
Exclusion criteria for enrollment .................................................................. 44 
6.3.1. 
Maternal subjects: ........................................................................ 44 
6.3.2. 
Infants: ......................................................................................... 45 
7. 
CONDUCT OF THE STUDY .................................................................................. 45 
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7.1. 
Regulatory and ethical considerations, including the informed 
consent process.......................................................................................... 45 
8. 
DETAILED STUDY PROCEDURES ....................................................................... 46 
8.1. 
Subject identification ................................................................................... 46 
8.2. 
General study aspects ................................................................................ 46 
8.2.1. 
Study procedures during special circumstances (Amended 
29-MAY-2020) ............................................................................. 47 
8.3. 
Outline of study procedures (Amended 29-MAY-2020) ............................... 48 
8.4. 
Intervals between study visits (Amended 29-MAY-2020) ............................ 54 
8.5. 
Description of study procedures for maternal subjects ................................ 54 
8.5.1. 
Eligibility Review and Confirmation .............................................. 54 
8.5.2. 
History for maternal subjects ........................................................ 55 
8.5.3. 
Examinations of maternal subjects............................................... 56 
8.5.4. 
Maternal Diary Card ..................................................................... 56 
8.5.5. 
Biological Specimens / Laboratory Data for maternal 
subjects ....................................................................................... 56 
8.5.6. 
Labor / Delivery............................................................................ 57 
8.5.7. 
Medications, vaccinations, and supplements administered 
to maternal subjects as per standard of care ............................... 57 
8.5.8. 
Outcomes and Events of Interest in maternal subjects 
(Amended 29-MAY-2020) ............................................................ 57 
8.5.9. 
Additional Antenatal / medical evaluations external to 
study visits / procedures .............................................................. 58 
8.6. 
Description of study procedures for Neonates / Infants (Amended 
29-MAY-2020) ............................................................................................ 58 
8.6.1. 
Eligibility Review and Confirmation for Neonates ......................... 58 
8.6.2. 
History and Examinations for Neonates / Infants 
(Amended 29-MAY-2020) ............................................................ 59 
8.6.3. 
Infant Diary Cards ........................................................................ 59 
8.6.4. 
Surveillance for Neonatal events of interest ................................. 60 
8.6.5. 
Surveillance for potential Lower Respiratory Tract Illness 
(LRTI) .......................................................................................... 60 
8.6.5.1. 
Definitions .................................................................. 60 
8.6.5.2. 
Overview (Amended 29-MAY-2020) ........................... 61 
8.6.5.3. 
Active surveillance ...................................................... 63 
8.6.5.4. 
Passive surveillance ................................................... 63 
8.6.6. 
Decision to conduct a Visit to assess a potential LRTI ................. 63 
8.6.7. 
Visit to assess a potential LRTI .................................................... 64 
8.6.7.1. 
Overview (Amended 29-MAY-2020) ........................... 64 
8.6.7.2. 
Clinical evaluation (Amended 29-MAY-2020) ............. 64 
8.6.7.3. 
Nasal swab ................................................................. 65 
8.6.7.4. 
Missed assessment visit ............................................. 65 
8.6.8. 
Follow-up after an assessment visit to evaluate a potential 
LRTI ............................................................................................. 65 
8.6.9. 
RSV Hospitalization ..................................................................... 66 
8.7. 
Reporting Covid-19 Cases – Maternal and Infant subjects 
(Amended 29-MAY-2020) ........................................................................... 66 
8.8. 
SAEs related to study participation ............................................................. 66 
8.9. 
Study Conclusion ........................................................................................ 67 
8.10. 
Screening failures ....................................................................................... 67 
8.11. 
Biological sample handling and analysis ..................................................... 67 
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8.11.1. 
Use of specified study materials .................................................. 68 
8.11.2. 
Biological samples ....................................................................... 69 
8.11.3. 
Laboratory assays ....................................................................... 69 
8.11.3.1. Antibody determination (Amended 29-MAY-
2020) .......................................................................... 69 
8.11.3.2. Molecular biology ....................................................... 70 
8.11.3.3. Hematology, biochemistry and urinalysis .................... 70 
8.11.3.4. Additional tests ........................................................... 71 
8.11.4. 
Biological samples evaluation ...................................................... 72 
8.11.4.1. Immunological read-outs ............................................ 72 
8.11.4.2. Molecular biology ....................................................... 72 
8.11.4.3. Hematology/blood chemistry ...................................... 73 
9. 
SERIOUS ADVERSE EVENTS RELATED TO STUDY PARTICIPATION .............. 73 
9.1. 
Definition..................................................................................................... 73 
9.2. 
Event Identification ..................................................................................... 74 
9.3. 
Subject cards .............................................................................................. 74 
9.4. 
GSK Contact information, GSK Reporting Timeframes, and 
Regulatory reporting requirements .............................................................. 75 
9.5. 
Information to be reported ........................................................................... 75 
9.6. 
SAE Report Completion and transmission to GSK ...................................... 76 
9.6.1. 
Back-up system in case the electronic reporting system 
does not work .............................................................................. 76 
9.6.2. 
Updating of SAE information after removal of write access 
to the subject’s eCRF................................................................... 76 
9.7. 
Follow-up of SAEs related to study participation (Amended 29-MAY-
2020) .......................................................................................................... 77 
9.7.1. 
Follow-up during the study ........................................................... 77 
9.7.2. 
Follow-up after the subject is discharged from the study 
(Amended 29-MAY-2020) ............................................................ 77 
10. SUBJECT COMPLETION AND WITHDRAWAL ..................................................... 77 
10.1. 
Subject completion ..................................................................................... 77 
10.2. 
Subject withdrawal ...................................................................................... 77 
11. STATISTICAL METHODS ...................................................................................... 79 
11.1. 
Endpoints.................................................................................................... 79 
11.1.1. 
Primary endpoints ........................................................................ 79 
11.1.1.1. Pregnancy outcomes. ................................................. 79 
11.1.1.2. Pregnancy related events of interest from Visit 
1 through Visit 6. ........................................................ 79 
11.1.1.3. Neonatal events of interest from birth through 
28 days of age ............................................................ 81 
11.1.2. 
Secondary endpoints ................................................................... 82 
11.1.3. 
Tertiary endpoints (Amended 29-MAY-2020) ............................... 82 
11.2. 
Determination of sample size ...................................................................... 83 
11.3. 
Cohorts for Analyses (Amended 29-MAY-2020) ......................................... 84 
11.3.1. 
Exposed Sets (ES) ...................................................................... 84 
11.3.1.1. Pregnant women (mothers) ........................................ 84 
11.3.1.2. Neonates/Infants ........................................................ 84 
11.3.2. 
Enrolled sets ................................................................................ 84 
11.3.2.1. Pregnant women (mothers) ........................................ 84 
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11.3.2.2. Neonates/Infants ........................................................ 84 
11.3.3. 
Per Protocol Sets (PPS) (Amended 29-MAY-2020) ..................... 84 
11.3.3.1. Pregnant women (mothers) ........................................ 84 
11.3.3.2. Neonates/Infants ........................................................ 84 
11.4. 
Derived and transformed data ..................................................................... 85 
11.4.1. 
Handling of missing values/censoring/discontinuations ................ 85 
11.5. 
Analysis of demographic and baseline characteristics ................................ 85 
11.6. 
Analysis of primary objectives (Amended 29 May 2020) ............................. 85 
11.7. 
Analysis of secondary objectives (Amended 29-MAY-2020) ....................... 86 
11.8. 
Analysis of tertiary objectives (Amended 29-MAY-2020) ............................. 87 
11.9. 
Interpretation of analyses ............................................................................ 88 
11.10. Analysis of safety ........................................................................................ 88 
11.11. Conduct of analyses ................................................................................... 89 
11.11.1. Statistical considerations for interim analyses (Amended 
29-MAY-2020) ............................................................................. 89 
12. ADMINISTRATIVE MATTERS ............................................................................... 90 
12.1. 
Electronic Case Report Form instructions ................................................... 90 
12.2. 
Study monitoring by GSK Biologicals .......................................................... 90 
12.3. 
Study and site closure................................................................................. 91 
12.4. 
Record retention ......................................................................................... 91 
12.5. 
Quality assurance ....................................................................................... 92 
12.6. 
Posting of information on publicly available registers and publication 
policy .......................................................................................................... 92 
12.7. 
Provision of study results to investigators ................................................... 92 
12.8. 
Data Sharing ............................................................................................... 92 
13. COUNTRY SPECIFIC REQUIREMENTS ............................................................... 92 
14. REFERENCES (AMENDED 29-MAY-2020) ........................................................... 93 
 
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LIST OF TABLES 
PAGE 
Table 1 
Sampling schedule for maternal subjects ............................................... 39 
Table 2 
Study groups and epochs foreseen in the study ..................................... 40 
Table 3 
RTI/LRTI case definitions for data analysis ............................................ 41 
Table 4 
Alternative LRTI / Severe LRTI Case Definitions (Amended 29-
MAY-2020) ............................................................................................. 42 
Table 5 
List of study procedures for maternal subjects (Amended 29-
MAY-2020) ............................................................................................. 48 
Table 6 
List of study procedures for neonates/ infants (Amended 29-
MAY-2020) ............................................................................................. 52 
Table 7 
Intervals between study visits/contacts/observations* (Amended 
29-MAY-2020) ........................................................................................ 54 
Table 8 
Biological samples ................................................................................. 69 
Table 9 
Humoral immunity (Antibody determination) (Amended 29-MAY-
2020) ...................................................................................................... 69 
Table 10 
Molecular biology ................................................................................... 70 
Table 11 
Hematology, biochemistry, urine tests .................................................... 71 
Table 12 
Immunological read-outs ........................................................................ 72 
Table 13 
Molecular biology for nasal swab specimen analysis .............................. 72 
Table 14 
Hematology/blood chemistry tests .......................................................... 73 
Table 15 
Contact information for reporting SAEs related to study 
participation to GSK ............................................................................... 75 
Table 16 
Timeframes for submitting SAEs related to study participation to 
GSK ....................................................................................................... 75 
Table 17 
Precision (exact 95% confidence interval) on the percentage of 
subjects with maternal, fetal and neonatal events of interest for 
sample size of 270, 180 and 100 subjects .............................................. 83 
Table 18 
GSK Biologicals’ laboratories ................................................................. 96 
Table 19 
Outsourced laboratories ......................................................................... 96 
Table 20 
Fetal death / Stillbirth ........................................................................... 100 
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Table 21 
Maternal Death .................................................................................... 103 
Table 22 
Hypertensive disorders of pregnancy (Gestational hypertension, 
Pre-eclampsia, Pre-eclampsia with severe features including 
eclampsia) ............................................................................................ 104 
Table 23 
Antenatal Bleeding ............................................................................... 106 
Table 24 
Postpartum hemorrhage ....................................................................... 108 
Table 25 
Fetal growth restriction ......................................................................... 108 
Table 26 
Dysfunctional labor ............................................................................... 109 
Table 27 
Gestational diabetes mellitus (pregnancy induced 
hyperglycemia) ..................................................................................... 110 
Table 28 
Non-reassuring fetal status .................................................................. 111 
Table 29 
Pathways to preterm birth .................................................................... 112 
Table 30 
Standard Definitions for Maternal Events of interest not defined 
as events in GAIA ................................................................................ 114 
Table 31 
Small for Gestational Age ..................................................................... 116 
Table 32 
Low Birth Weight (LBW) ....................................................................... 117 
Table 33 
Neonatal encephalopathy ..................................................................... 118 
Table 34 
Congenital Microcephaly ...................................................................... 119 
Table 35 
Major Congenital anomalies ................................................................. 122 
Table 36 
Neonatal Death .................................................................................... 125 
Table 37 
Neonatal Infections .............................................................................. 127 
Table 38 
Respiratory Distress in the Neonate ..................................................... 130 
Table 39 
Preterm Birth ........................................................................................ 131 
Table 40 
Failure to Thrive ................................................................................... 132 
Table 41 
Standard Definitions for Neonatal Events of interestnot defined 
as events in GAIA ................................................................................ 133 
 
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LIST OF FIGURES 
PAGE 
Figure 1 
Study design (Amended 29-MAY-2020) ................................................. 38 
Figure 2 
Active and Passive Surveillance Decision Tree ...................................... 62 
 
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LIST OF APPENDICES 
PAGE 
APPENDIX A LABORATORY ASSAYS ....................................................................... 95 
APPENDIX B CLINICAL LABORATORIES .................................................................. 96 
APPENDIX C GAIA GESTATIONAL AGE ASSESSMENT FORM ................................ 97 
APPENDIX D DEFINITIONS OF MATERNAL, FETAL AND NEONATAL 
EVENTS OF INTEREST AS PER GAIA ................................................. 99 
APPENDIX E AMENDMENTS AND ADMINISTRATIVE CHANGES TO THE 
PROTOCOL ......................................................................................... 134 
 
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LIST OF ABBREVIATIONS (Amended 29-MAY-2020) 
AE 
Adverse Event 
BMI 
Body mass index 
CI 
Confidence Interval 
CLS 
Clinical Laboratory Sciences 
COVID-19 
Corona Virus Disease 2019 
eCRF 
electronic Case Report Form 
EoS 
End of Study 
FU 
Follow-Up 
GAIA 
Global Alignment of Immunization Safety Assessment in 
pregnancy 
GCP 
Good Clinical Practice 
GMC 
Geometric Mean Concentration 
GMT 
Geometric Mean Titer 
GSK 
GlaxoSmithKline 
HIV 
Human Immunodeficiency Virus 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
LAR 
Legally Acceptable Representative 
LLOQ 
Lower Limit of Quantification 
LMP 
Last Menstrual Period 
LRTI 
Lower Respiratory Tract Illness 
LSLV 
Last Subject Last Visit 
NB 
Newborn 
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PCD 
Primary Completion Date 
PCR 
Polymerase Chain Reaction 
RBC 
Red Blood Cell 
RR 
Respiratory Rate 
RSV 
Respiratory Syncytial Virus 
RTI 
Respiratory Tract Illness 
SAE 
Serious Adverse Event 
SPM 
Study Procedures Manual 
SpO2 
Blood oxygen saturation as measured by pulse oximetry 
WBC 
White Blood Cell 
WHO 
World Health Organization 
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GLOSSARY OF TERMS 
Adverse event: 
Any untoward medical occurrence in a subject, 
temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal 
product, or temporally associated with a study procedure. 
An adverse event (AE) can therefore be any unfavourable 
and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of a medicinal product. 
For marketed medicinal products, this also includes 
failure to produce expected benefits (i.e., lack of 
efficacy), abuse or misuse. 
Body Mass Index 
A key index for relating weight to height. Calculated as 
follows: Weight (kg) / (Height (m))2 
Child 
A young human being below the legal age of majority 
(generally < 18 years of age). 
Child in care: 
A child who has been placed under the control or 
protection of an agency, organisation, 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. 
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).  
Eligible: 
Qualified for enrollment into the study based upon strict 
adherence to inclusion/exclusion criteria. 
Enrollment 
Pregnant woman who meet all eligibility criteria at the 
Screening visit and return to the study site for Visit 1 are 
considered enrolled.  Live born neonates who meet all 
eligibility criteria and complete Visit 1-NB are considered 
enrolled. 
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Epidemiological study: 
An observational or interventional study without 
administration of medicinal product(s) as described in a 
research protocol. 
End of Study (Synonym of 
End of Trial) 
For studies with collection of Human Biological Samples 
or imaging data, EoS is defined as the date of the last 
testing/reading released of the Human Biological Samples 
or imaging data, related to primary and secondary 
endpoints. EoS must be achieved no later than 8 months 
after LSLV 
Epoch: 
An epoch is a set of consecutive timepoints or a single 
timepoint from a single protocol. Epochs are defined to 
support a main purpose which either to draw conclusions 
on subject participation or to draw a complete conclusion 
to define or precise the targeted label of the product. 
Supporting means that data collected at the timepoints 
included in an epoch must be sufficient to fulfill the 
purpose of the epoch. 
Typical examples of epochs are screening, 
immunogenicity follow-up, safety follow-up, ESFU, 
follow-up.  
eTrack: 
GSK Biologicals’ tracking tool for clinical/ 
epidemiological trials. 
Evaluable: 
Meeting all eligibility criteria, complying with the 
procedures defined in the protocol, and, therefore, 
included in the per-protocol analysis (see Section 11.3 for 
details on criteria for evaluability). 
GAIA 
Global Alignment of Immunization Safety Assessment in 
pregnancy. A project that aims to improve the quality of 
outcome data from clinical vaccine trials in pregnant 
women with a specific focus on the needs and 
requirements for safety monitoring in low to middle 
income countries.  
Gestational age: 
A measure of the age of a pregnancy where the origin is 
the first day of the woman's last normal menstrual period, 
or the corresponding age as estimated by other methods. 
Gestational age will be described in weeks of pregnancy 
completed + number of days completed of the following 
week. For example: 28 0/7 means completed 28 weeks of 
pregnancy + 0 days of the 29th week and 28 6/7 means 
completed 28 weeks of pregnancy + 6 days of the 29th 
week. 
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Infant 
A child younger than 1 year of age  
Interventional Human 
Subject Research: 
Studies in which participants are administered medical 
care, medicinal products and/or medical/scientific 
procedures as described in a research protocol. 
Legally acceptable 
representative (LAR) 
An individual or juridical or other body authorized under 
applicable law to consent, on behalf of a prospective 
subject, to the subject's participation in the trial.  (The 
terms legal representative or legally authorized 
representative are used in some settings.) 
Level 2 ultrasound (or 
fetal morphology 
ultrasound) 
Comprehensive, detailed evaluation of fetal anatomy and 
development that is usually performed at approximately 
20 weeks of gestational age. In addition to standard 
ultrasound parameters such as fetal heart activity and 
gestational age estimation, a Level 2 ultrasound usually 
includes assessment of amniotic fluid levels; assessment 
of the condition of the placenta, cervix, and uterus; and 
detection of fetal anomalies. May also be referred to as a 
fetal anomaly scan or fetal morphology assessment.  
Local healthcare provider 
A healthcare provider who provides subjects with medical 
care per local standards. This individual may or may not 
be a member of the study staff.  
Neonate (or Newborn) 
An infant ≤ 28 days old. 
Neonatal events of interest 
Clinically significant events that occur from birth through 
28 days of age and may be considered adverse events if 
they occur after vaccination.  They are listed in Section 
11.1 and described in detail in APPENDIX D 
Parental concern 
The parent(s) / Legally Acceptable Representative(s) or 
their designates are concerned about the infant’s 
respiratory tract illness, or general health in the context of 
the respiratory tract illness, and intend to seek medical 
care 
Pregnancy related events 
of interest 
Clinically significant events that occur up to 42 days after 
delivery and may be considered adverse events if they 
occur after vaccination.  They are listed in Section 11.1 
and described in detail in APPENDIX D 
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Primary completion date: 
The date that the final subject was examined or received 
an intervention for the purpose of final collection of data 
for all primary outcomes, whether the clinical trial/ 
pharmaco-epidemiological study was concluded 
according to the pre-specified protocol or was terminated. 
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. 
Protocol amendment: 
The International Council for Harmonisation (ICH) 
defines a protocol amendment as: ‘A written description 
of a change(s) to or formal clarification of a protocol.’ 
GSK Biologicals further details this to include a change 
to an approved protocol that affects the safety of subjects, 
scope of the investigation, study design, or scientific 
integrity of the study. 
Research protocol: 
A document that describes the objective(s), design, 
methodology, statistical considerations, and organisation 
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. 
Serious Adverse Event 
(SAE) related to study 
participation  
Any untoward medical occurrence related to study 
participation (e.g., protocol mandated procedures, 
invasive tests) that: 
• 
Results in death, 
• 
Is life-threatening, 
• 
Requires hospitalization or prolongation of an 
existing hospitalization, 
• 
Results in disability /incapacity (i.e., a substantial 
disruption of a person’s ability to conduct normal life 
functions) 
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. 
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1. 
INTRODUCTION  
1.1. 
Background and rationale for the study    
Maternal immunization aims to prevent diseases in neonates and infants via 
transplacental antibody transfer from the mother to the fetus following vaccination of the 
pregnant woman. Several marketed vaccines are already recommended for and routinely 
administered to pregnant women, including influenza, tetanus and Tdap vaccines [CDC, 
2013a, CDC, 2013b]. There are also a number of maternal vaccines in development that 
aim to protect neonates and infants from pathogens in addition to, respiratory syncytial 
virus (RSV). GlaxoSmithKline (GSK) is developing an investigational vaccine for use in 
pregnant women, against RSV disease. Of note this vaccine is developed solely for 
immunization in pregnancy.  
Maternal immunization is implemented worldwide and has the potential to make a major 
contribution to reducing RSV lower respiratory tract illnesses (LRTI) and the burden of 
other diseases in infants globally. Therefore, it is imperative that clinical trials are 
conducted across different countries in different settings. GSK is proactively addressing 
potential challenges of conducting clinical trials in pregnant women in low- and middle 
income countries (LMIC). 
Before conducting clinical trials it is important to understand the frequency of pregnancy 
outcomes and the maternal and neonatal events of interest (i.e. clinically significant 
events that may be considered adverse events if they occur after vaccination) in each 
setting where clinical trials may be conducted for better interpretation of safety data. 
Also, to ensure safety of the participating women, and to characterize the safety profile of 
the product, adverse events (AEs) in pregnancy should be appropriately detected and 
managed. This study addresses gaps in understanding of anticipated rates of pregnancy 
outcomes as well as events of interest in pregnant women and neonates. Furthermore, this 
study will be conducted at potential sites for future maternal immunization trials and will 
help assure the capacity of sites to detect and manage clinically significant events of 
interest in pregnant women and their neonates.  
Secondarily, the study will establish surveillance mechanisms for RSV associated 
illnesses in the neonate/infant (through the first 12 months of life. Whilst there is good 
documentation of the global burden of RSV disease, incidence of RSV-LRTI according 
to the World Health Organization (WHO) 2015 case definitions [Modjarrad, 2016] is 
limited in the literature, particularly in many LMIC settings. Hence, this study will also 
estimate the incidence of infant RSV-LRTI using WHO case definitions across 
geographically distinct locations to support incidence rate assumptions for planning of 
future efficacy trials.  
To achieve these goals, GSK will be guided by the WHO recommendations on antenatal 
care for a positive pregnancy experience [WHO, 2016] and the Global Alignment of 
Immunization Safety Assessment in pregnancy (GAIA) case definitions [Bonhoeffer, 
2016; Bauwens, 2016; Kochhar, 2017]. Standardization of surveillance methodology and 
case definitions (applicable to maternal immunization AEs) may support comparison of 
data across different countries [Jones, 2016]. 
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1.2. 
Rationale for the study population   
The intention of this epidemiological study is to obtain an estimate of the background rate 
of adverse pregnancy outcomes and events that may be seen in future vaccine trial 
populations and, separately, to assess whether sites are suitable for Phase II/III vaccine 
trials. The study aims to enroll healthy women with normal uncomplicated pregnancies 
so that event rates for pregnancy and neonatal events  of interest are applicable to the 
intended population for future vaccine trials. Regardless of enrollment location, healthy 
pregnant women aged 18 to 45 years with normal, uncomplicated, singleton pregnancies, 
who have had a level 2 (fetal morphology) ultrasound without any significant findings 
will be eligible for possible study participation. Inclusion / exclusion criteria have been 
structured in a way that resembles those of Phase II/III criteria to ensure good 
comparability between the current study population and that of anticipated future vaccine 
trials. 
Pregnant women 240/7 up to and including 276/7 weeks of gestation will be enrolled, to 
ensure that they are followed as of the time of potential vaccination in a clinical trial.  
Women who do not meet the enrollment criteria will be referred for appropriate local 
standard of care.   
1.3. 
Rationale for the surveillance of pregnancy related events of 
interest   
There are particular challenges in conducting clinical trials in pregnant women, among 
them limited data on background rates of pregnancy outcomes as well as what may be 
observed in clinical trials as maternal and neonatal adverse events. A large number of 
countries aim to strengthen their ability to provide comprehensive antenatal care for all 
and to enable a positive pregnancy experience. The WHO 2016 recommendations on 
antenatal care for a positive pregnancy experience [WHO, 2016] give guidance on the 
frequency of clinic visits, examination procedures and screening tests.  
To achieve these goals, GSK will be guided by the WHO recommendations on antenatal 
care for a positive pregnancy experience [WHO, 2016] and the Global Alignment of 
Immunization Safety Assessment in pregnancy (GAIA) case definitions [Bonhoeffer, 
2016; Bauwens, 2016; Kochhar, 2017]. Standardization of surveillance methodology and 
case definitions (applicable to maternal immunization AEs) may support comparison of 
data across different countries [Jones, 2016]. 
The number and timing of study visits was informed by WHO recommendations on 
antenatal care [WHO, 2016]. However, local standards of care differ from country-to 
country. Women should follow the local standard of care. Study data will be collected, in 
part, from records of the data obtained during the locally recommended antenatal care 
visits. 
In this study, best efforts will be made to work with local healthcare providers to collect 
the key data on maternal, fetal, neonatal and infant health from routine health records to 
avoid duplication and an undue burden on the trial subjects.  
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1.4. 
Rationale for the use of Global Alignment of Immunization 
safety Assessment in pregnancy (GAIA) case definitions   
GAIA, a Brighton collaboration project, aims to develop standardized case definitions 
and criteria for diagnostic certainty of maternal outcomes and events of interest and 
neonatal events of interest in the context of immunization trials [Bauwens, 2016; 
Bonhoeffer, 2016; Kochhar, 2017].  
GAIA was established in response to a WHO request to work on a globally aligned 
approach to monitor safety of maternal immunization clinical trials. The application of 
these case definitions (APPENDIX D) aims to improve the quality of data generated and 
to support safety assessment. The goal is to pilot these case definitions prior to the 
initiation of large maternal immunization trials. To achieve this, the level of diagnostic 
certainty (APPENDIX D) will be collected for all of the events of interest for which 
GAIA criteria have been developed.  
1.5. 
Rationale for the active and passive surveillance for RSV 
associated respiratory tract illnesses (RTI) with suspicion of 
difficulty in breathing/wheezing or with parental concern in 
neonates/ infants    
RSV infects 50-70% of infants in their first year of life, and practically all children have 
experienced RSV infection and / or illness by their third birthday [Hall, 2009]. In 
industrialized countries, approximately 2% of infants under one year of age are 
hospitalized as a consequence of RSV-induced lower respiratory tract illnesses (LRTI) 
each year. Infants younger than six months have the highest risk of developing severe 
RSV-induced LRTI. Approximately half of all pediatric LRTI occur in the first six 
months of life, and LRTI is the leading cause of hospitalization in this age group [Boyce, 
2000; Deshpande, 2003; Hall, 2009; Holman, 2004; Iwane, 2004; Nair, 2010; Vicente, 
2003].  
The implementation of surveillance will also assist in establishing robust infrastructure 
and processes for RSV-LRTI and RSV hospitalization detection in future vaccine trials.  
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2. 
BENEFIT: RISK ASSESSMENT 
The following section outlines the risk assessment and mitigation strategy for this study 
protocol:  
2.1. 
Risk Assessment   
Important Potential/Identified Risk 
Data/Rationale for Risk 
Mitigation Strategy 
Study Procedures 
Blood sample collection- While giving 
blood the subject may feel faint, or 
locally experience mild pain, bruising, 
irritation or redness. 
Spontaneous data 
Sample collection will only be performed by 
appropriately trained study personnel. 
All subjects will remain under observation, 
post venipuncture, through completion of the 
applicable study visit. 
Subjects will be notified of this risk in the 
informed consent form. 
Nasal swab collection from infant 
subjects may cause discomfort 
Spontaneous data 
Sample collection will only be performed by 
appropriately trained personnel. 
Subjects’ parent(s)/LAR(s) will be notified of 
this risk in the informed consent form. 
2.2. 
Benefit Assessment 
Study participation may have limited or no benefit for the study subjects themselves.   
Study procedures aim to ensure surveillance for maternal outcomes and events of interest 
and neonatal events of interest. The attention to surveillance may enhance the ability to 
detect these safety events and to refer subjects for management according to local 
standard of care. The protocol also includes procedures that may enhance surveillance for 
RSV, and possibly other lower respiratory tract illnesses, in neonates and infants. Thus, 
the procedures described in this protocol may enhance the ability to detect these events or 
illnesses and to refer subjects for management according to local standard of care.   
Data collected during the study may enhance understanding of the frequency of maternal 
events of interest in women with low risk pregnancies, neonatal events of interest, and 
RSV-associated lower respiratory tract illnesses in neonates and infants.   
Surveillance methods explored and data collected during this study may inform future 
care and prevention efforts and will be used to design robust monitoring systems for 
future clinical trials of maternal immunization. 
2.3. 
Overall Benefit:Risk Conclusion (Amended 29-MAY-2020) 
This is an epidemiologic study that describes the prevalence of pregnancy outcomes 
and maternal/neonatal events of interest. The study does not include the administration 
of any investigational vaccine. It is not expected that the participation of pregnant 
women and their babies in the study would create any further risk to study participants. 
The study includes the establishment of a surveillance system for lower respiratory 
tract infections (LRTI) which may facilitate detection of respiratory tract infections, 
including COVID-19 cases, that might be diagnosed in children enrolled in the study. 
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Potential risks to subjects participating in this study are limited to those associated with 
the collection of biological specimens. Taking into account the measures to minimize 
these potential risks for subjects participating in this study, the potential or identified 
risks are justified by the potential benefits of enhanced surveillance for the subjects, and 
by the knowledge gained about the frequency of events of interest. 
3. 
OBJECTIVES    
3.1. 
Primary objectives   
In healthy pregnant women with uncomplicated pregnancies: 
• 
To determine the frequencies of pregnancy outcomes. 
• 
To determine the frequencies of pregnancy related events of interest from enrollment 
(Visit 1) through 42 days after delivery (Visit 6).  (Although pregnancy related 
events of interest occur within the first 42 days after delivery they may only be 
detected later, and are to be reported throughout the study.) 
In all neonates live-born to women enrolled in the study: 
• 
To determine the frequencies of neonatal events of interest.  
Neonatal events of interest occur within the first 28 days after birth, but may only be 
detected later and are to be reported throughout the study.  
Refer to Section 11.1.1 for the definition of the primary endpoints. 
3.2. 
Secondary objectives   
In healthy pregnant women with uncomplicated pregnancies at enrollment: 
• 
To determine frequencies of pregnancy related events of interest according to GAIA 
levels of diagnostic certainty (where these are specified) (APPENDIX D) from 
enrollment (Visit 1) through 42 days after delivery (Visit 6).  (Although pregnancy 
related events of interest occur within the first 42 days after delivery they may only 
be detected later, and are to be reported throughout the study.) 
• 
To describe the distribution of RSV-A antibody titers in maternal blood at delivery.  
In all neonates live-born to women enrolled in the study: 
• 
To determine frequencies of neonatal events of interest according to GAIA levels of 
diagnostic certainty (where these are specified). (APPENDIX D). Neonatal events of 
interest occur within the first 28 days after birth, but may only be detected later and 
are to be reported throughout the study. 
• 
To describe the distribution of RSV-A antibody titers in cord blood at delivery. 
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In all neonates/infants live-born to women enrolled in the study, from birth through 1 
year of age: 
• 
To determine the incidence of all, of severe, and of very severe RSV-lower 
respiratory tract illnesses (LRTIs).  
• 
To determine the incidence of RSV hospitalization.  
• 
Refer to Section 11.1.2 for the definition of the secondary endpoints. 
Refer to the GLOSSARY OF TERMS for the definition of enrollment. 
3.3. 
Tertiary objectives (Amended 29-MAY--2020) 
• 
To describe co-infections of RSV-LRTI with other respiratory viruses in infants.  
• 
To estimate the association of RSV-LRTI in neonates/infants and the level of RSV 
neutralizing antibodies in cord blood.  
• 
To determine the incidence of LRTIs/Severe LRTIs (using alternative case 
definitions)  
• 
To determine risk factors for pregnancy-related and neonatal events of interest. 
• 
If deemed necessary, to further characterize the immune responses to RSV and other 
infections in maternal subjects and infants (based on maternal serum and cord 
blood).  
Refer to Section 11.1.3 for the definition of the tertiary endpoints. 
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4. 
STUDY DESIGN OVERVIEW (AMENDED 29-MAY-2020)   
Figure 1 
Study design (Amended 29-MAY-2020)  
 
D = day; M = month; V = visit; W = week; Y = year. NB = newborn; GA = Gestational age; BS = blood sample; US = 
urine sample for dipstick testing; IMM = immune response; HB = hematology/biochemistry; RBC = red blood 
cell(s); WBC = white blood cell(s); RSV = respiratory syncytial virus; RTI = respiratory tract illness; LRTI = lower 
respiratory tract illness;  
Refer to Section 11.11 for additional information about the analyses indicated above. 
1 If delivery occurs prematurely, skip to Visit 5 (“at delivery”). 
2 At Delivery, RSV-A antibody titers for all women  
3 At V3, only hemoglobin testing. 
4 Allowed interval for blood sample collection begins with start of labor (e.g. when the mother arrives at the hospital to 
deliver and an intravenous line is inserted) and ends 72 hours after delivery. 
5 RSV-A antibodies in cord blood  
6Neonatal events of interest occur (by definition) between 0 and 28 days after birth.  They will be reported once site 
staff become aware of them (whether this occurs during the first 28 days after birth, or at a later time). 
NOTE: Covid-19 cases identified within the surveillance framework of the study in maternal and infant subjects 
will also be recorded.  
Protocol waivers or exemptions are not allowed unless necessary for the management of 
immediate safety concerns. Therefore, adherence to the study design requirements, 
including those specified in the outline of study procedures (Section 8.3), are essential 
and required for study conduct.  
V2 (D28)1
Screening
GA: 24 0/7
- 27 6/7w
V5 
Delivery
V6
Day 42
BS:
• H/B
US :
• Glucose
• Proteins
• RBC
• WBC
Up to (approximately) 2,300 maternal subjects (≥ Week 24 of gestation) 
Maternal subjects
BS:
• H 3
US:
• Glucose
• Proteins
• RBC
• WBC
V3 (D56) 1
BS 4
• Imm 2
Cord blood 5
• Imm
Epoch 002
Mother: V1 through V6
Child: V1-NB through V2-NB
V4 (D84) 1
Analysis 1
Neonates/Infants
V1-NB
Birth
V2-NB
Day 42
V4-NB
Year 1
Final Analysis 
Epoch 003
Child: V3-NB
Neonatal events of interest 6
LRTI Surveillance in Neonates / Infants
Pregnancy outcomes, maternal/fetal events of interest 
Study Procedure Related Serious Adverse Event Follow-up
US:
• Glucose
• Proteins
• RBC
• WBC
US :
• Glucose
• Proteins
• RBC
• WBC
V1 (D1)
GA: 24 0/7 -
27 6/7w
Epoch 001
Screening
Mother only
Informed 
consent
Inclusion, 
Exclusion 
Criteria
V3-NB
Month 6
Interim 
Analysis
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• 
Type of design: Prospective, epidemiological, interventional (without administration 
of medicinal products as described in a research protocol), multi-country, cohort 
study. 
• 
Study population: The study will be conducted in multiple countries, in pregnant 
women and their infants.  
• 
Type of study: self-contained. 
• 
Data collection: Electronic Case Report Form (eCRF). 
Table 1 
Sampling schedule for maternal subjects   
 
 
Visit 
Sample 
Parameter(s) evaluated 
1 
2 
3 
4 
Delivery 
Maternal Blood 
Hematology/  
biochemistry1, 4 
x 
 
x3 
 
 
Antibody titer (RSV-A)  
 
 
 
 
≤ 72 hours after 
delivery5 
Cord Blood 
Antibody titer (RSV-A)  
 
 
 
 
x 
Urine 
Protein, glucose, RBC, WBC 2, 4 
x 
x 
x 
x 
 
1 To be performed preferentially by local healthcare providers, as per local practice. To be performed by the 
investigator/study staff ONLY if not done by the local healthcare provider within 2 weeks before the study visit. 
2 The investigator/site staff will perform a urine dipstick test using supplies provided by GSK.  
3 Hemoglobin only 
4 If results are abnormal, subjects will be referred per local standard of care. 
5 This sample may be collected from start of labor (e.g. when the mother arrives at the hospital to deliver and an 
intravenous line is inserted) through 72 hours after delivery.     
• 
Sampling schedule for neonates/infants: Surveillance for RSV LRTI will be 
conducted in infants through the 12 month study period. During this 1-year post-birth 
surveillance period, for each RTI with suspicion of difficulty in breathing, or 
wheezing, or with parental concern, a nasal swab will be collected at a visit to assess 
potential RSV associated RTIs/LRTIs. 
• 
Primary Completion Date (PCD): 42 days post-delivery/birth (i.e. Visit 6 for 
maternal subjects and Visit 2-NB for infant subjects) or last visit of Epoch 002. 
• 
End of Study (EoS): Last testing results released of samples collected up to Visit 4-
NB (assays related to primary and secondary endpoints). 
• 
Duration of the study: Approximately 4.5 to 6 months for maternal subjects; 
approximately 1 year for infant subjects. 
− 
Epoch 001: Screening  
− 
Epoch 002: Primary starting at Visit 1 and ending 42 days post-delivery/birth 
(Visit 6 for maternal subjects and Visit 2-NB for infant subjects).* 
− 
Epoch 003: Follow-up of infants starting 43 days post-delivery/birth and ending 
at Visit 4-NB (1 year post-birth). 
*Any safety and disease surveillance data collected after Visit 2-NB will be collected in 
Epoch 003.  
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Table 2 
Study groups and epochs foreseen in the study   
Study Groups 
Number of 
subjects enrolled 
Age (Min/Max) 
Epochs 
Epoch 001  
Epoch 002  
Epoch 003  
Maternal subjects  
Up to  2300  
18 years - 45 
years 
x  
x  
 
Infants  
Up to  2300  
NA  
 
x  
x  
Approximately 200 to 300 per country. To achieve the enrollment targets noted above, the number of pregnant women 
SCREENED in each country may exceed the country-specific enrolment goal. 
• 
Surveillance for pregnancy outcomes and pregnancy-related events of 
interest(Section 8.5.8) that occur from Visit 1 up to 42 days after delivery (Visit 6).  
• 
Surveillance for neonatal events of interest(Section 8.6.3) that occur from birth up to 
28 days of age.  
• 
Surveillance for RSV LRTI and RSV hospitalization (refer to Section 8.6.8) in 
infants, from birth up to 1 year of age. 
5. 
CASE DEFINITIONS 
5.1. 
Pregnancy related events of interest    
Pregnancy related events of interest are briefly defined in the GLOSSARY OF TERMS, 
listed in Section 11.1 and described in detail in APPENDIX D.  
5.2. 
Neonatal events of interest    
Neonatal events of interest are briefly defined in the GLOSSARY OF TERMS, listed in 
Section 11.1 and described in detail in APPENDIX D.  
5.3. 
Respiratory tract illness (RTI) / Lower respiratory tract 
illness (LRTI) 
During data analysis, cases of respiratory tract illness (RTI) identified from birth up to 1 
year of age will be classified according to the case definitions in Table 3. 
5.4. 
RSV infection (Amended 29-MAY-2020) 
Nasal swabs will be analyzed by the sponsor for the presence of RSV A/B. A positive test 
result constitutes a case of RSV infection.  Refer to Section 8.6.7.3. 
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Table 3 
RTI/LRTI case definitions for data analysis     
RSV-RTI 
Runny nose, OR Blocked nose, OR Cough 
AND 
Confirmed RSV infection 4 
RSV-LRTI 
History of cough OR difficulty in breathing 1 
AND  
SpO2 < 95% 2, OR RR increase 3 
AND  
Confirmed RSV infection 4 
RSV-severe LRTI 
Meeting the case definition of RSV-LRTI 
AND 
SpO2 < 93%, OR lower chest wall in-drawing 
RSV-very severe LRTI 
Meeting the case definition of RSV-LRTI  
AND  
SpO2 < 90%, OR inability to feed OR failure to respond / unconscious 
RSV hospitalization 
Confirmed RSV infection 5 
AND 
Hospitalized for acute medical condition 6 
All-cause RTI 
Runny nose, OR Blocked nose, OR Cough 
All-cause LRTI 
History of cough OR difficulty in breathing 1  
AND  
SpO2 < 95% 2, OR RR increase 3 
Definitions based on [Modjarrad, 2016] 
RTI = respiratory tract illness; LRTI = lower respiratory tract illness; RR = respiratory rate; SpO2 = blood oxygen 
saturation by pulse oximetry. 
1 Based on history reported by parents/LARs and includes difficulty in breathing (e.g. showing signs of wheezing or 
stridor, tachypnoea, flaring [of nostrils], chest in-drawing, apnoea). 
2 For blood oxygen saturation (SpO2), the lowest value monitored will be used. In high altitudes (>2500m), SpO2 <92% 
for LRTI, <90% for severe LRTI, <87% for very severe LRTI.     
3 RR increase defined as: 
> 60/minute (< 2 months of age) 
> 50/minute (2 to < 12 months of age) 
> 40/minute (12 to 24 months of age) 
4 RSV infection confirmed on nasal swab positive for RSV A or B by quantitative reverse transcription polymerase chain 
reaction (qRT-PCR). 
5 RSV sampling and testing is described in Sections 8.6.7, 8.6.8 and 8.6.9.  
6 Hospitalization is defined as admission for observation or treatment based on the judgement of a health care provider  
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Table 4 
Alternative LRTI / Severe LRTI Case Definitions (Amended 29-MAY-
2020) 
RSV 
confirmed 
Documented physical examination 
(PE) findings indicating lower 
respiratory tract involvement (at least 
one symptom) 
Objective measures of clinical severity (at 
least one symptom) 
LRTI 
Confirmed 
RSV infection 
Rhonchi1 
Increased respiratory rate (bpm) 
Rales1 
≥ 60 for < 2 mo 
Crackles 
≥ 50 for 2-6 mo 
Wheeze 
Hypoxemia: 
 
SpO2  <95% at ≤1800 meters 
 
SpO2  <92% at > 1800 meters 
 
New onset apnea 
 
Nasal flaring 
 
Retractions2 
 
Grunting 
 
 
Severe 
LRTI 
Confirmed 
RSV infection 
Rhonchi1 
Hypoxemia 
Rales1 
SpO2  <93% at ≤1800 meters 
Crackles 
SpO2 <90% at > 1800 meters 
Wheeze 
Acute hypoxic or ventilatory failure3 
 
Dehydration due to respiratory distress 
requiring IV hydration4 
 
Failure to respond or unconscious 
1Term not listed in the eCRF page in this study.  
2 Intercostal recession or chest wall indrawing are considered synonymous with and will be used as 
alternatives to the term “retractions,” which is not listed in the eCRF page for this study.  
3 Acute hypoxic or ventilatory failure is not listed in the eCRF page for this study.  Instead, the presence of 
either respiratory support excluding mechanical ventilation OR requirement for mechanical ventilation or 
both will be used.  
4 Dehydration due to respiratory distress requiring IV hydration is not listed in the eCRF page for this study. 
Skin turgor > 2 seconds or administration of IV fluid therapy will be used instead.  
6. 
STUDY POPULATION 
6.1. 
Number of subjects/ centers (Amended 29-MAY-2020) 
The study will be conducted at multiple centers in multiple countries.  The total enrolled 
study population will consist of up to (approximately) 2,300 pregnant women and their 
neonates.  
In each participating country, approximately 200 to 300 pregnant women ≥240/7 and 
≤276/7 weeks of gestation will be enrolled.  Neonates of enrolled pregnant women who 
consent to their child’s study participation will also be enrolled. 
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6.2. 
Inclusion criteria for enrollment 
Deviations from inclusion criteria are not allowed because they can potentially jeopardise 
the scientific integrity and regulatory acceptability of the study or subject safety. 
Therefore, adherence to the criteria as specified in the protocol is essential. 
All subjects must satisfy ALL the following criteria at study entry: 
6.2.1. 
Maternal subjects:    
• 
Healthy pregnant women 18-45 years of age who are ≥ 24 0/7 weeks GA at 
screening and ≤ 27 6/7 weeks GA at Visit 1, as established by ultrasound 
examination and/or last menstrual period (LMP) date* 
* The level of diagnostic certainty of the gestational age should be established by using 
the GAIA gestational age assessment form (provided in APPENDIX C). 
• 
Women with pre-pregnancy body mass index (BMI) ≥18.5 and ≤ 39.9 kg/m2. 
• 
Women whose pregnancy is considered low risk, based on medical history, obstetric 
history, and clinical findings during the current pregnancy. 
• 
Women who had no significant findings (such as abnormal fetal morphology, 
amniotic fluid levels, placenta, or umbilical cord) observed during a Level 2 
ultrasound (fetal morphology assessment).  
• 
HIV uninfected women who have been tested within the past year and have 
documented HIV negative test results. 
• 
Individuals who give written or witnessed/thumb printed informed consent after the 
study has been explained according to local regulatory requirements.  
− 
The informed consent given at screening should either include consent for both 
the mother’s participation and participation of the infant after the infant’s birth 
(if consistent with local regulations/guidelines), or consent for the mother’s 
participation and expressed willingness to consider permitting the infant to take 
part after the infant has been born (if local regulations/guidelines require 
parent(s) to provide an additional informed consent after the infant’s birth).  
− 
Both mother and father should consent if local regulations/guidelines require it. 
• 
Individuals who consent to have cord blood collected at delivery for the purpose of 
the study;  
• 
Individuals who plan to reside in the study area for at least one year after delivery. 
• 
Individuals who are in good health as determined by the outcome of medical history, 
physical examination and clinical judgment of the investigator; 
• 
Individuals who, in the opinion of the investigator can and will comprehend and 
comply with all study procedures (e.g., return for study follow-up visits, be 
contactable and available on a regular basis for surveillance). 
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6.2.2. 
Infants (Amended 29-MAY-2020):    
• 
Infants who were in utero at the time maternal (and paternal, if required) informed 
consent was given, and who are live-born.  
• 
If local law requires it: Written or witnessed/thumb printed informed consent for 
study participation of the infant obtained from parent(s)/LAR(s) within 21 days of 
birth.  
6.3. 
Exclusion criteria for enrollment 
Deviations from exclusion criteria are not allowed because they can potentially 
jeopardise the scientific integrity and regulatory acceptability of the study or subject 
safety. Therefore, adherence to the criteria as specified in the protocol is essential. 
The following criteria should be checked at the screening visit and at Visit 1. If ANY 
exclusion criterion applies, the subject must not be included in the study: 
6.3.1. 
Maternal subjects: 
• 
Individuals determined to have one of the following conditions associated with 
increased risk for a serious obstetrical complication (specify any/all that apply in the 
eCRF)  
− 
Gestational hypertension; 
− 
Gestational diabetes uncontrolled by diet and exercise;  
− 
Pre-eclampsia or eclampsia; 
− 
Multiple pregnancy; 
− 
Intrauterine growth restriction;  
− 
Placenta previa;  
− 
Polyhydramnios; 
− 
Oligohydramnios. 
• 
Individuals determined to have (during the current pregnancy) one of the following 
infections or conditions associated with risk of adverse outcome (specify any/all that 
apply in the eCRF): 
− 
Known or suspected: 
o 
Syphilis infection,  
o 
Parvovirus B19,  
o 
Rubella infection,  
o 
primary genital herpes simplex infection,  
o 
primary cytomegalovirus infection,  
o 
varicella infection,  
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o 
Zika infection, 
o 
Active tuberculosis infection, 
− 
Incompetent cervix or cerclage 
• 
Individuals who have any underlying condition or infection that would predispose 
them to increased risk for a serious obstetrical complication that is not mentioned 
above. 
• 
Individuals who have behavioral or cognitive impairment or psychiatric disease that, 
in the opinion of the investigator, could interfere with the subject's ability to 
participate in the study. 
• 
Individuals who have known or suspected impairment of the immune system, an 
active autoimmune disorder that is not well-controlled, or who are receiving 
systemic immunosuppressive therapy. 
• 
Individuals participating in any concurrent clinical trial during the current pregnancy.  
• 
Individuals pregnant with a fetus with a confirmed or suspected major congenital 
anomaly at the time of enrollment. 
6.3.2. 
Infants: 
• 
Child in care  
Please refer to the GLOSSARY OF TERMS for the definition of child in care. 
7. 
CONDUCT OF THE STUDY 
7.1. 
Regulatory and ethical considerations, including the 
informed consent process 
The study will be conducted in accordance with the ICH Guideline for Good Clinical 
Practice (GCP), all applicable subject privacy requirements and the guiding principles of 
the Declaration of Helsinki. 
The study has been designed and will be conducted in accordance with the ICH 
Harmonised Tripartite Guideline for clinical investigation of medicinal products in the 
pediatric 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/ subject’s parent(s)/LAR(s) informed consent, as appropriate. 
• 
Investigator reporting requirements as stated in the protocol.  
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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 informed consent must be obtained 
from each subject and/or each subject’s parent(s)/LAR(s) or the impartial witnesses 
appropriate, prior to participation in the study.  
GSK Biologicals will prepare a model Informed Consent Form (ICF) which will embody 
the applicable ICH GCP, 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 
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. 
8. 
DETAILED STUDY PROCEDURES 
8.1. 
Subject identification 
Subject numbers for pregnant women (mothers) who consent to participate in the study 
will be assigned at screening.  Subject numbers for their (yet to be born) neonates will be 
assigned at Visit 1.  Subject numbers will be assigned sequentially according to the range 
of numbers allocated to each study centre.  Subject numbers of mother –infant pairs will 
be clearly linked. 
8.2. 
General study aspects 
Critical study conduct information not mandated to be present in this protocol is provided 
in the Study Procedures Manual (SPM). As such, the SPM should be viewed as a 
companion document that should be read carefully to fully understand the study protocol. 
The SPM provides the investigator and the site personnel with detailed operational 
information that is essential for correct study execution and does not impact the safety of 
the subjects. 
Study visits and procedures in this protocol are defined to ensure that maternal and 
neonatal events of interest, as well as RSV-associated LRTIs and RSV hospitalization in 
infants, are captured. Prenatal screening and care will be provided by local healthcare 
providers (in accordance with local standards). 
Study visits are not intended to replace local standard of care antenatal visits. If local 
standard of care recommends additional visits/medical evaluations during pregnancy, 
women participating in this study should comply with their regular antenatal care visit 
schedules, per local recommendations. 
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Study procedures are not intended to replace procedures performed by local healthcare 
providers as part of standard care.  
8.2.1. 
Study procedures during special circumstances (Amended 29-
MAY-2020) 
During special circumstances (e.g., the COVID-19 pandemic), the specific guidance 
from local public health and other competent authorities regarding the protection of 
individuals’ welfare must be applied.  
For the duration of such special circumstances, the following measures may be 
implemented for enrolled subjects if deemed feasible by the investigator. 
• 
If it is not possible to conduct a protocol-specified, scheduled or event-driven (e.g., 
LRTI assessment) visit as described in Section 8.3, the visit may be replaced with a 
contact conducted by telephone, videotelephony or telemedicine. SMS and email 
are not allowed.  
• 
Biological samples may be collected at a different location* other than the study 
site, or at the subject’s home. Biological samples should not be collected if they 
cannot be obtained within the visit interval (Section 8.4), processed in a timely 
manner or appropriately stored until the intended use.  
− 
Nasal swabs should only be collected using centrally provided supplies. 
− 
Cord Blood for assessment of immune response may be collected locally but 
must be retrieved, processed and stored  in accordance with the Investigator 
Laboratory Manual.  
− 
Additional blood samples for assessment of immune response should only be 
collected using centrally provided supplies. 
• 
Diary cards may be transmitted from and to the site by electronic mail, and / or 
conventional mail. 
Impact on the per protocol sets for analysis will be determined on a case by case basis. 
Any impact of the above mentioned measures on the study results will be described in 
the clinical study report. 
* It is the investigator’s responsibility to identify an alternate location. The investigator 
should ensure that this alternate location meets ICH GCP requirements, such as 
adequate facilities to perform study procedures, appropriate training of the staff and 
documented delegation of responsibilities in this location. This alternate location 
should be covered by proper insurance for the conduct of study on participants by 
investigator and staff at a site other than the designated study site. Refer to EMA 
Guidance on the Management of Clinical Trials during the COVID-19 (Coronavirus) 
pandemic (version 2, 27 March, 2020) for more details. 
 
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8.3. 
Outline of study procedures (Amended 29-MAY-2020)   
Potential study participants (pregnant women) are to be screened at ≥ 24 0/7 weeks gestational age.  Pregnant women for whom eligibility 
has been confirmed are to complete Visit 1 not later than at 27 6/7 weeks gestational age..  
Table 5 
List of study procedures for maternal subjects (Amended 29-MAY-2020)     
Gestational age 
24 0/7  –  
 27 6/7 
24 0/7 –   
27 6/7 
 
 
 
 
 
 
Epoch 
Epoch 001   
Epoch 002 
Type of contact 
Screening 
Visit 1  
Visit 2 2   Visit 3  2  
Visit 4  2 
Visit 5  
Visit 6 3 ,4 
Additional 
antenatal/medical 
evaluations  5  
Timepoints 
 
Day 1 
Day 28 
Day 56 
Day 84 
At 
Delivery 
Post-Delivery 
Day 42 
 
Eligibility Review and Confirmation 
 
 
 
 
 
 
 
 
Informed consent 1  
● 
 
 
 
 
 
 
 
Check inclusion/exclusion criteria 
● 
O  
 
 
 
 
 
 
Assign subject study number (mother)  
● 
 
 
 
 
 
 
 
Assign subject study number (child)  
 
O 
 
 
 
 
 
 
Ensure that site study physicians (both obstetrician(s) and 
pediatrician(s)) are informed  
 
O  
 
 
 
O   
 
 
Medical History / Examinations 
 
 
 
 
 
 
 
 
Distribute Maternal Subject Card  
 
O  
 
 
 
 
 
 
Distribute maternal diary card 
 
O 
O 
O 
O  
O   
 
 
Review and collect maternal diary card  
 
 
O 
O 
O 
O  
O 
 
Transcribe applicable diary card data to the eCRF  
 
 
● 
● 
● 
● 
● 
 
Record demographic data 
●  
 
 
 
 
 
 
 
Record lifestyle characteristics 
 
● 
 
  
 
 
 
 
Record outcome of Level 2 ultrasound (fetal morphology 
scan)   9  
● 
 
 
 
 
 
 
 
Record outcome(s) of subsequent ultrasounds if clinically 
significant 5  
 
O 5  
O 5 
O 5 
O 5 
O 5 
 
● 5 
Review and collect medical history 
O 
● 
 
 
 
 
 
 
Review and collect obstetric history from past pregnancies  
●  
 
 
 
 
 
 
 
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Gestational age 
24 0/7  –  
 27 6/7 
24 0/7 –   
27 6/7 
 
 
 
 
 
 
Epoch 
Epoch 001   
Epoch 002 
Type of contact 
Screening 
Visit 1  
Visit 2 2   Visit 3  2  
Visit 4  2 
Visit 5  
Visit 6 3 ,4 
Additional 
antenatal/medical 
evaluations  5  
Timepoints 
 
Day 1 
Day 28 
Day 56 
Day 84 
At 
Delivery 
Post-Delivery 
Day 42 
 
Review and collect obstetric history from current pregnancy, 
including: gestational age, expected date of delivery and 
method of EDD estimation including pre-pregnancy weight  
●  
 
 
 
 
 
 
 
Travel history to, or living in, countries/regions with Zika 
virus transmission (during the current pregnancy)  
O  
● 
O  
O  
O  
O  
 
●  
Where authorized by the local Ethics Committee, inquire 
whether mother would have agreed to take part in the study 
if an investigational vaccine were given  
 
● 
 
 
 
 
 
 
Record outcome of HIV test 10  
●  
 
 
 
 
 
 
 
Record results of General and Obstetric examination 11  
●  
● 
●  
●  
●  
 
●  
● 14  
Check and record prescription medications, vaccinations, 
folate and/or iron (independently or included in a 
multivitamin) 13   
●  
●  
●  
● 
● 
● 
● 
●  
Biological Specimens / Laboratory Test Results 
 
 
 
 
 
 
 
 
Collect blood sample for antibody assessment by sponsor 
(5 ml) 
 
 
 
 
 
● 
 
 
Collect cord blood for antibody assessment by sponsor 
(5 to 10 ml) 
 
 
 
 
 
● 
 
 
Record results of local hematology/ biochemical analysis 
(Visit 15.5 ml; Visit 32 ml – hemoglobin only) 6  
 
●  
 
● 
 
 
 
● 14 
Record results of urine dipstick to check for presence of 
proteins, glucose, RBC, WBC 8  
 
●  
● 
● 
● 
 
 
● 14 
Record results of oral glucose challenge / tolerance test(s) if 
performed by local healthcare provider and available 7  
● 
O 5 
O 5 
O  5 
O 5 
 
 
● 5 
Record results of any clinically significant abnormal 
laboratory tests (including positive urine culture) if 
performed by local healthcare provider and available 5  
 
O 5 
O 5 
O 5 
O 5 
O 5 
O 5 
● 5 
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Gestational age 
24 0/7  –  
 27 6/7 
24 0/7 –   
27 6/7 
 
 
 
 
 
 
Epoch 
Epoch 001   
Epoch 002 
Type of contact 
Screening 
Visit 1  
Visit 2 2   Visit 3  2  
Visit 4  2 
Visit 5  
Visit 6 3 ,4 
Additional 
antenatal/medical 
evaluations  5  
Timepoints 
 
Day 1 
Day 28 
Day 56 
Day 84 
At 
Delivery 
Post-Delivery 
Day 42 
 
Labor / Delivery 
 
 
 
 
 
 
 
 
Collect and record labor and delivery information 12  
 
 
 
 
 
● 
 
 
Outcomes and Events of Interest 
 
 
 
 
 
 
 
 
Record Pregnancy/Delivery outcome(s)  
 
 
 
 
 
● 
 
 
Record pregnancy-related events of interest. Record 
other clinically significant events or diagnoses15 
 
●  
●   
● 
● 
● 
● 
● 
Record all hospitalizations (except hospitalization for 
delivery), and all extensions of hospitalizations (including 
extension of hospitalization for delivery) 5  
 
●  
●  
●  
●   
●   
●  
●  
Serious Adverse Events 
 
 
 
 
 
 
 
 
Record SAEs related to study participation  
● 
● 
● 
● 
● 
● 
● 
 
Screening/Study Conclusion 
 
 
 
 
 
 
 
 
Screening conclusion  
● 
 
 
 
 
 
 
 
Study conclusion 
 
 
 
 
 
 
● 
 
Investigator sign-off on eCRF before analysis  
● 
 
 
 
 
 
● 
 
SAE = serious adverse event; ● is used to indicate a study procedure that requires documentation in the individual electronic case report form (eCRF)  
 ○ is used to indicate a study procedure that does not require documentation in the individual eCRF. 
1 Refer to Section 6.2.1, sixth bullet.  
2  If delivery occurs prematurely, skip to Visit 5 ("at delivery").  
3  Visit 6 (Day 42) may take place in the subject’s home or at the investigator’s clinical facility as appropriate to the circumstances in the judgment of the investigator  
4  To coincide with Visit 2-NB (Day 42) for infants.  
5  Information from additional antenatal / medical evaluations (external to study visits/procedures) may be collected during, before or after a scheduled study visit but should only be 
recorded in the additional antenatal/medical evaluations eCRF  
6 To be performed preferentially by local healthcare providers as per local practice. To be performed by the investigator/site staff ONLY if not done by the local healthcare provider 
within 2 weeks before the study visit. If results are abnormal, subjects will be referred per local standard of care.  
7   If results of an oral glucose challenge / tolerance test are not available to confirm that the subject does not have Gestational Diabetes at screening, then fasting blood glucose or 
hemoglobin A1C test results (if performed by local healthcare provider and available) may be used as described in Table 27.  
8  The Investigator/ site staff will perform a urine dipstick test to detect the presence of proteins, glucose, RBC and WBC.  
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9  If ultrasound results are not available at time of screening, the ultrasound can be performed as a study procedure under certain conditions. Refer to SPM for further details. If 
abnormal, subjects will be referred per local standard of care. 
10  Where HIV testing is not part of the standard of care for pregnant women, the screening HIV test can be performed locally as a study procedure. Refer to SPM for further details. If 
results are positive, subject will be referred per local standard of care.  
11   Height at screening. Weight, temperature, systolic/diastolic blood pressure, heart rate and respiratory rate after at least 10 minutes of rest, blood oxygen saturation by pulse 
oximetry, fetal heart tones, fetal movement, and fundal height at Screening and Visits 1 – 4.  Temperature, systolic/diastolic blood pressure, heart rate and respiratory rate after at 
least 10 minutes of rest, and blood oxygen saturation by pulse oximetry at Visit 6.  
12  Includes date and time of rupture of membranes, date and time of delivery, type of delivery, and other delivery information related to the health and safety of the mother and fetus.  
13 Beginning the month before the estimated date of conception and while on study.  (Routine medications administered during labor and delivery need not be collected.)  
14 Record clinically significant abnormal results    
15Includes events or diagnoses that could impact the pregnancy including COVID-19 cases  
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Table 6 
List of study procedures for neonates/ infants (Amended 29-MAY-2020)    
Epoch 
Epoch 002  
Epoch 003  
Epoch 002 and Epoch 003  
Age 
0-21 days  
42 Days 
6 Months 
12 months 
0-12 months 
Type of contact 
Visit 1-NB  
Visit 2-NB b   
Visit 3-NB b   Visit 4-NB b  
Contact for 
active/ passive 
surveillance 
Visit to assess 
potential LRTI b   
Timepoints 
Birth  
Day 42 
M6 
Y1  
 
 
Check inclusion/exclusion criteria  
● 
 
 
 
 
 
Obtain post-delivery informed consent from parent(s)/LAR(s) if 
required per local regulations  
● a  
 
 
 
 
 
Record infant’s subject number  
● 
 
 
 
 
 
Record Apgar assessment  
● 
 
 
 
 
 
Record demographic data  
● 
 
 
 
 
 
Record lifestyle characteristics  
 
● 
 
 
 
 
Distribute Infant's Subject Card  
O 
 
 
 
 
 
Distribute infant diary card d  
O 
O  
O 
 
 
O 
Review infant diary card  
 
O  
O 
O 
 
O 
Collect infant diary card e  f  
 
O  
O  
O  
 
O  
Transcribe applicable infant diary card data to eCRF  
 
●  
● 
● 
 
● 
Weight, length, head circumference, results of targeted medical 
history, and results of physical examination  
● 
● 
● 
● 
 
 
Record prescription medications / vaccinations  
● 
● 
● 
● 
●  
● 
Record neonatal events of interest  
● 
● 
● 
● 
 
 
Clinical evaluation of potential LRTI  
 
 
 
 
 
● 
Nasal swab b  
 
 
 
 
 
● c  
Record all hospitalizations and clinically significant events h  
● 
● 
● 
● 
● 
● 
Record SAEs related to study participation  
● 
● 
● 
● 
● 
● 
Study conclusion  
 
 
 
●  
 
 
Investigator sign-off on eCRF before analysis  
 
● 
● g  
● 
 
 
LAR = legally acceptable representative; LRTI = lower respiratory tract illness; NB = newborn; RTI = respiratory tract illness; SAE = serious adverse event; M=month; Y = year.  Grey 
shaded columns represent study procedures to be performed for active/passive surveillance of RTIs/LRTIs which are applicable throughout the entire study period (from birth up to 
study end). Note: The double-line borders indicate primary analyses. 
● is used to indicate a study procedure that requires documentation in the individual electronic case report form (eCRF).   
○ is used to indicate a study procedure that does not require documentation in the individual eCRF. 
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a  If local regulations require that written consent / confirmation of consent for the infant’s participation be obtained at birth.  
b   Visits 2-, 3-, and 4-NB and LRTI assessment visits may take place in the subject’s home (if the standard of care allows for home visits), at the investigator’s clinical facility or at 
another facility per the investigator’s judgment.  
c  If more than one assessment visit is conducted to evaluate a potential LRTI, additional nasal swabs may be collected at the discretion of the Investigator.  
d Distribute at V1-NB:  Distribute additional diary cards at subsequent visits as needed.  
e  Collect diary cards that are fully filled out and / or document (L)RTI symptoms that have ended.  Provide new diary cards as needed.  
f  Collect all diary cards for potential RTIs that are considered resolved. Collect the diary card for the current potential LRTI once the LRTI symptoms have ended.  
g  When approximately 50% of infants have completed up to Visit 3-NB, an interim analysis may be conducted to assess the accumulated RSV LRTI cases and the distribution of 
maternal and cord blood serum RSV Ab. . 
h Includes COVID-19 cases 
 
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8.4. 
Intervals between study visits (Amended 29-MAY-2020) 
Whenever possible, the investigator should arrange study visits within the interval 
described in Table 7. 
Table 7 
Intervals between study visits/contacts/observations* (Amended 29-
MAY-2020)    
Interval 
Optimal interval 
Allowed interval** 
Screening → Visit 1  
1 days  
0 - 28 days  
Visit 1 → Visit 2** 
28 days  
21 –35 days  
Visit 1 → Visit 3** 
56 days  
49 – 63 days  
Visit 1 → Visit 4** 
84 days  
77 – 91 days  
Maternal blood sample collection “at” Visit 5 
(delivery) 
0 days 
0 (Start of labor) - 3 days (i.e., 72 hours 
post-delivery) 
Visit 5 → Visit 6 
42 days  
35 – 49 days  
Birth → Visit 1-NB  
0 days  
0 - 21 days  
Birth → Visit 2-NB  
42 days  
35 - 49 days  
Birth → Visit 3-NB  
180 days  
166 -194 days  
Birth → Visit 4-NB  
365 days  
351 - 379 days  
*If other visits and medical evaluations are performed (outside of study visits/procedures), data should be collected in 
the electronic case report forms (eCRFs) (see Section 8.5.7). 
**If a subject returns for the visit outside the allowed time interval, he/she may still be considered for analysis. 
Investigators should make at least 3 documented attempts (through telephone call(s) or 
any other convenient procedure) to contact (as relevant) the pregnant woman/mother or 
the child’s parents/ LAR(s) (or their designates) if they do not return for scheduled visits 
or follow-up. Additional details can be found in the SPM. 
8.5. 
Description of study procedures for maternal subjects   
This section lists procedures to be performed / data to be recorded during the study and 
presents additional details where relevant.  For the study procedures schedule, refer to 
Table 5.  
8.5.1. 
Eligibility Review and Confirmation    
• 
Obtain Informed consent as described in Sections 6.2.1 and 7.1.  
• 
Check all applicable inclusion and exclusion criteria as described in Sections 6.2 and 
6.3 before enrollment and record results. 
• 
Assign / record subject study number (pregnant woman) 
• 
Assign subject study number (infant) for eligible pregnant women who complete 
Visit 1. 
• 
For eligible pregnant women who complete visit 1 (are enrolled): ensure that site 
study physicians (both obstetrician(s) and pediatrician(s)) are informed.  In 
particular, the study pediatrician and/or staff should be notified as soon as possible 
after a pregnant woman’s enrolment to ensure the study pediatrician is informed of 
the approximate date of delivery and potential enrolment of the neonate. 
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8.5.2. 
History for maternal subjects   
• 
Distribute the Maternal Subject Card (Section 9.3).  
• 
Distribute the Maternal Diary Card to the subject (Section 8.5.4).   
• 
Record demographic data, which may include (but are not limited to) information 
such as geographic ancestry (race), month and year of birth, and ethnicity.    
• 
Record information about lifestyle characteristics (exposures), which may include 
(but are not limited to) data on highest level of education, factors such as smoking 
status/exposures, household environment, and other factors that could place subjects 
at risk of study outcomes. 
• 
Record information about whether (during the current pregnancy) the subject has 
travelled to / is living in countries / regions with Zika virus transmission.  
• 
Where authorized by the local Ethics Committee, inquire whether mother would 
have agreed to take part in the study if an investigational vaccine were given and 
record the answer.  
• 
Record outcome of Level 2 ultrasound (fetal morphology assessment). Please see 
GLOSSARY OF TERMS for description.  If Level 2 ultrasound results are not 
available at screening, then the ultrasound can be performed as a study procedure 
under certain conditions. Refer to the SPM for further details. 
• 
ONLY record outcome(s) of any subsequent ultrasound(s) if clinically significant. 
• 
Record the subject’s pre-pregnancy weight (i.e., weight during the months before the 
subject became pregnant) in the subject’s eCRF.  This information can be obtained 
either via medical record review or subject interview. 
• 
Confirm that the subject’s pre-pregnancy BMI is within the range specified in 
Section 6.2.1.  This information can be obtained from the medical record, or, if 
unavailable, may be calculated based on the subject’s height and reported pre-
pregnancy weight. 
• 
Obtain the subject’s medical and obstetric history by interview and/or review of her 
medical records. Record any pre-existing conditions or signs and/or symptoms 
present before participation in the study 
− 
For past pregnancies, record: 
o 
Number of past pregnancies and their outcome(s), 
o 
Presence of caesarian section scars (if any). 
− 
For the current pregnancy, record: 
o 
Gestational age, along with GAIA level of certainty, using priorities defined 
in APPENDIX C. 
o 
Expected date of delivery (EDD) and method of estimation 
o 
Number of prenatal visits attended up to the date of the study Screening 
visit, 
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o 
Approximate date of first prenatal visit, 
o 
Results of any clinically significant, abnormal pregnancy screening 
laboratory tests, 
o 
Results of any procedures intended to screen for congenital anomalies. 
8.5.3. 
Examinations of maternal subjects   
Record results of General and Obstetric examinations.  
• 
Record height at screening. Height measurements should be performed preferentially 
by local healthcare providers, in which case the information will be collected and 
recorded in the mother’s eCRF. If not done by the local healthcare provider as per 
local practice, the investigator/study staff should perform the measurement.  
• 
Unless the study visit is performed concurrently with a routine care visit at which the 
below data are collected, the investigator/study staff should perform General and 
Obstetric examinations as follows:  
− 
Screening and Visits 1 - 4 should include assessment of weight, fetal heart tones, 
fetal movement, and fundal height; 
− 
Screening, Visits 1 to 4, and Visit 6 should include assessment of temperature, 
systolic/diastolic blood pressure, heart rate and respiratory rate after at least 10 
minutes of rest) and blood oxygen saturation by pulse oximetry. 
− 
If the Screening Visit and Visit 1 occur on the same day, only one General and 
Obstetric examination will be performed. 
8.5.4. 
Maternal Diary Card    
A maternal diary card will be provided to each subject at visit 1, then collected and 
replenished throughout the study as needed. It will document any prescription 
medications, folate and/or iron (independently or included in a multivitamin) taken, any 
vaccinations received during pregnancy and after delivery, and any additional visits the 
subject may make to a healthcare provider not affiliated with the study.  
The diary card will be reviewed with the subject during study visits.  If review indicates 
that the subject visited a healthcare provider not affiliated with the study, study staff 
should (if permitted by local regulation) contact that healthcare provider to obtain the 
medical record(s) for the visit.   
Refer to the SPM for additional details. 
8.5.5. 
Biological Specimens / Laboratory Data for maternal subjects  
• 
The Investigator/site staff will arrange for collection of maternal blood and cord 
blood samples at delivery. 
• 
The Investigator/site staff will perform urine dipstick tests using supplies provided 
by GSK. 
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• 
If HIV test results are not available at time of screening, the HIV test can be 
performed as a study procedure under certain conditions.  Refer to the SPM for 
further details. If results are positive, the subject will be referred per local standard of 
care. 
• 
It is preferred that local healthcare providers perform hematology and biochemistry 
tests per local practice; the investigator/site staff will then collect and record the 
results. The investigator/site staff will only perform hematology/biochemistry tests if 
not done by the local healthcare provider within 2 weeks before a study visit. 
• 
If performed by local healthcare provider and results are available, the 
investigator/site staff will also: 
− 
Record oral glucose challenge / oral glucose tolerance test results 
− 
Record any positive urine bacterial culture results  
− 
Record abnormal and clinically significant laboratory test results  
− 
Record results of Group B Streptococcus screening test(s). 
8.5.6. 
Labor / Delivery    
Record information related to labor and delivery, including:  
• 
Any medications administered during labor and delivery as per standard of care if 
not considered routine 
• 
Date and time of rupture of membranes 
• 
Date and time of delivery 
• 
Type of delivery 
• 
Other delivery related information relevant to the health and safety of the mother and 
fetus 
8.5.7. 
Medications, vaccinations, and supplements administered to 
maternal subjects as per standard of care  
Record medications / vaccinations / folate and iron supplements beginning the month 
before the estimated date of conception and while on study.  Folic acid and/or iron 
supplements should be reported when taken independently and/or when included in a 
multivitamin mineral supplement.  
8.5.8. 
Outcomes and Events of Interest in maternal subjects (Amended 
29-MAY-2020) 
• 
Record delivery and pregnancy outcomes. Of note, fetal death/stillbirth has multiple 
subcategories. For example, fetal death/stillbirth with no congenital anomalies is an 
outcome with two subcategories that include: 1) antepartum stillbirth; 2) intrapartum 
stillbirth. For each outcome, the investigator should select the applicable sub-
category. 
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• 
If there is no live birth, all study visits and procedures related to the maternal subject 
should still be followed up to study end.  
• 
Record pregnancy related events of interest. 
− 
The investigator will review all medical records pertaining to prenatal care 
based on GAIA definitions (APPENDIX D) when applicable.  
− 
Maternal events of interest (including, but not limited to, those described in 
Section 11.1.1) occurring up to Visit 6 (Post-delivery Day 42) should be 
recorded in the eCRF along with additional details pertinent to the diagnosis, 
GAIA assessment and level of diagnostic certainty (APPENDIX D), when 
applicable. Of note, some events of interest fall under a single category but have 
multiple subcategories. For example, hypertensive disorders of pregnancy is an 
event with three subcategories that include: 1) gestational hypertension; 2) pre-
eclampsia; and 3) pre-eclampsia with severe features (including eclampsia). For 
each event, the investigator should identify the event and select the applicable 
sub-category. 
− 
Information about maternal hospitalizations, clinically significant events, and 
diagnoses that could impact the pregnancy will be recorded. 
− 
Any events of interest in mother or fetus will be referred to and managed by the 
routine health services as locally appropriate. 
• 
Record all hospitalizations and/or clinically significant events, including COVID-19 
cases.  
• 
Record all study participation related SAEs as specified in Section 9. 
8.5.9. 
Additional Antenatal / medical evaluations external to study visits 
/ procedures 
For any additional antenatal / medical evaluations at which a pregnancy related event of 
interest is identified, record information that supports the diagnosis of the event, if 
available. 
8.6. 
Description of study procedures for Neonates / Infants 
(Amended 29-MAY-2020) 
This section lists procedures to be performed / data to be recorded during the study and 
presents additional details where relevant.  For the study procedures schedule, refer to 
Table 6.  Note that the investigator or study staff will perform (if not performed by local 
healthcare provider) a minimum of 2 clinical examinations: one at birth (or up to 21 days 
after birth), and another at approximately 42 days of age.   
8.6.1. 
Eligibility Review and Confirmation for Neonates  
• 
Check all applicable inclusion and exclusion criteria as described in Sections 6.2.2 
and 6.3.2.  
• 
Record subject study number. 
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8.6.2. 
History and Examinations for Neonates / Infants (Amended 29-
MAY-2020)   
• 
Record demographic data including month and year of birth, gender, geographic 
ancestry (race) and ethnicity.  
• 
Record Apgar scores at 1, 5, 10 min after birth (when available). 
• 
Record lifestyle characteristics. Data may include (but are not limited to) passive 
smoking and contact with young children under 6 years of age. 
• 
Record weight, length, head circumference, results of targeted medical history, and 
results of physical examinations. 
• 
Record prescription medications/ vaccinations. 
• 
Distribute the Infant Subject Card to the parent(s)/LAR(s)/designate(s). (Section 
9.3). 
• 
Distribute the Infant Diary Card to the parent(s)/LAR(s)/designate(s) (Section 8.6.3).   
• 
Record all hospitalizations and/or clinically significant events, including COVID-19 
cases. For hospitalizations where an RSV infection is suspected, refer to Section 
8.6.8. 
• 
Record all study participation related SAEs (Section 9). 
8.6.3. 
Infant Diary Cards  
Infant diary cards will be provided at the infant Visit 1 NB.  They should be completed 
by the Parent(s)/LAR(s)/designate(s) of the infant subject.   
The infant diary cards will be used to document: 
• 
RTI symptoms experienced by the infant, including start and end dates for those 
symptoms, and 
• 
Additional visits to a pediatric healthcare provider not affiliated with the study, as 
well as prescription medications (including those taken to treat an RTI) and 
vaccinations administered to the infant. (If the infant subject was taken to a 
healthcare provider not affiliated with the study, the study staff should (if permitted 
by local regulation) contact that healthcare provider to obtain the medical record(s) 
for the visit.)   
At each study visit (including any assessment visits), RTI symptoms may have ended or 
may be ongoing.  
If blocked nose, cough and symptoms of difficulty in breathing (including wheezing) 
have ended by the time of a study visit: 
− 
Study staff should collect the Diary card(s), and replenish the 
parent(s)/LAR(s)/designate(s) supply of blank cards as needed.  
If blocked nose, cough or symptoms of difficulty in breathing (including wheezing) are 
ongoing at the time of a study visit (including any assessment visit): 
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− 
Study staff should review the diary card, make a photocopy of it, and return it to 
the parent(s)/LAR(s)/designate(s) so information can continue to be collected 
until the symptoms have ended.  
− 
As soon as possible after these symptoms have ended, study staff must collect 
the completed diary card by a site visit, home visit, or postal mail, whichever is 
most effective based on local practice.  The site should make every effort to 
collect completed diary cards as soon after the symptoms have ended as 
possible. If diary card collection occurs during a visit to the study site or to the 
subject’s home, a brief clinical evaluation may be performed to confirm that the 
symptoms have ended.  
Refer to the SPM for additional details. 
8.6.4. 
Surveillance for Neonatal events of interest  
To detect events of interest in neonates, the investigator will collect a medical history and 
review all medical records pertaining to medical events in the neonatal period (birth – 28 
days), including assessment of congenital anomalies.   
8.6.5. 
Surveillance for potential Lower Respiratory Tract Illness (LRTI) 
8.6.5.1. 
Definitions 
Symptoms of Respiratory Tract Illness (RTI) include: 
• 
Regular bursts of cough,  
• 
Nasal discharge running freely out of the infant’s nose (runny nose), or  
• 
Breathing through the mouth because the infant’s nose is blocked (blocked nose).  
A potential lower respiratory tract illness (LRTI) is one in which the infant has one or 
more of the RTI symptoms listed above AND at least one of the following: 
• 
Difficulty in breathing (fast breathing, poor feeding, working hard to breathe, or 
making unusual sounds when breathing); 
• 
Wheezing (a whistling sound when the infant breathes out) (another sign of difficulty 
in breathing); 
• 
Parental concern (the parent(s)/LAR(s) or their designate(s) are concerned about the 
infant’s respiratory tract illness, or general health in the context of the respiratory 
tract illness, and intend to seek medical care). 
Worsening means any clinically observed/diagnosed symptoms and signs that are 
reported during the same respiratory tract illness and reflect a deterioration in the child’s 
respiratory tract functions. 
Start and stop dates will be collected in the diary card for cough, runny nose, blocked 
nose, wheezing and difficulty in breathing. 
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Start dates for all symptoms will also be recorded in the eCRF. 
Only stop dates for cough and difficulty in breathing will be recorded in the eCRF so that 
GSK may later define the end of each LRTI episode (Section 5.4) 
8.6.5.2. 
Overview (Amended 29-MAY-2020) 
Surveillance for potential LRTIs begins at birth (or after additional consent, has been 
provided for the infant’s participation in the study, if required,) and ends with the Year 
1 study visit.   
It will be accomplished via two types of contact.  Both may be made with/ by either the 
Parent(s)/ LAR(s), or a person designated by the parent(s)/LAR(s), such as grandparents 
or a nanny (as long as the parent(s)/LAR(s) have given approval).  
• 
In an Active contact, site personnel contact the subject’s parent(s) / LAR(s) or their 
designate(s).  Active contacts will occur at regular intervals and will be scripted.  
• 
In a Passive contact, the subject’s parent(s) / LAR(s) or their designate(s) contact site 
personnel. Site personnel will use a script to guide data collection once a passive 
contact has been made. 
Site staff will use information gathered during each active or passive surveillance contact 
to determine whether a visit to assess a potential LRTI (Sections 8.6.6 and 8.6.7) should 
be scheduled.  
For all interactions between parent(s)/LAR(s)/designates and study staff, the safety 
of the infant is paramount. For any reported illness, the investigator/study staff 
should assess the need for any intervention and advise the parent(s) / LAR(s) to seek 
care as necessary.  This study is not intended to replace local standards of care. 
A decision tree for active and passive surveillance is provided in Figure 2, which is 
presented on the next page. 
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Figure 2 
Active and Passive Surveillance Decision Tree  
 
RR: Respiratory rate: SpO2: Blood oxygen saturation by pulse oximetry. 
1Details regarding Active and Passive Surveillance are provided in Sections 8.6.5.3, 8.6.5.4, and the SPM. 
2Cough, runny nose, blocked nose, difficulty in breathing, wheezing and parental concern are defined in Section 
8.6.5.1. 
3Details regarding the assessment visit to evaluate a potential LRTI are provided in Sections 8.6.6 and 8.6.7 and the 
SPM. 
4 Post-visit follow up is described in Section 8.6.8 and in the SPM. Worsening is defined in Section 8.6.5.1   
5If a follow-up assessment visit is conducted, collection of additional nasal swabs are at the Investigator’s discretion.  
Active or Passive surveillance 
contact 1
Yes
Yes
No
Yes
No
No
Perform assessment visit 3, 4 ideally
within 3 days:
•
Document signs and symptoms
•
Record RR and SpO2 
•
Record health care utilization
•
Nasal swab 5
OR
•
Document details from medical records
Difficulty in breathing OR 
wheezing OR parental 
concern? 2
Cough OR runny nose OR 
blocked nose OR difficulty in 
breathing OR wheezing? 2
Remind to report any worsening 
of symptoms
Remind to report any future 
symptoms
Worsening of 
symptoms? 4
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8.6.5.3. 
Active surveillance    
In countries where RSV transmission is seasonal:  The study staff will contact the 
infant’s parents/ LAR(s) (or their designates) (phone call, SMS or by other means, 
depending on local best practice) approximately every week during the RSV season and 
approximately every month outside the RSV season, up to study end.  
In countries with year-round RSV transmission:  The study staff will contact the infant’s 
parents/ LAR(s) (or their designates) (phone call, SMS or by other means, depending on 
local best practice) approximately every 2 weeks, up to study end.  
Three attempts should be made to contact the infant’s parents/ LAR(s) (or their 
designates) within the week of a scheduled contact.  If these attempts are unsuccessful, 
that active contact is considered a missed contact. The next active contact will be made 
according to schedule. 
The purpose of the contact is to check with the infant’s parent(s)/LAR(s) or their 
designate(s) if, as defined in Section 8.6.5.1:  
• 
the infant has developed (new) symptoms of RTI, difficulty in breathing, or 
wheezing;  
• 
there is parental concern as defined in Section 8.6.5.1.  
8.6.5.4. 
Passive surveillance 
Infants’ parents/LAR(s) or their designate(s) will be instructed to contact the site 
whenever: 
• 
the infant has developed (new) symptoms of RTI, difficulty in breathing, or 
wheezing as defined in Section 8.6.5.1,  
• 
the infant’s symptoms worsen as defined in Section 8.6.5.1, 
• 
there is parental concern as defined in Section 8.6.5.1. 
Contact may be via phone call, SMS or other means, depending on local best practice.  If 
the study site is the primary treating facility for the child, Parent(s)/LAR(s) or their 
designate(s) may also make “contact” by taking the child directly to the study site. 
8.6.6. 
Decision to conduct a Visit to assess a potential LRTI    
If there is NO suspicion of difficulty in breathing, nor wheezing, nor parental concern in 
the context of the RTI: 
• 
No assessment visit will be conducted. 
• 
The study staff will remind the infant’s parent(s)/LAR(s) to report any worsening of 
symptoms. 
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If there IS difficulty in breathing, or wheezing (both based on parental assessment), or 
there is parental concern in the context of the RTI:  
An assessment visit will be conducted as soon as possible, ideally within 3 calendar days 
after learning of the potential LRTI case. Note that the visit may be conducted, and a 
nasal swab collected, even if beyond the ideal 3-day window as long as symptoms are 
ongoing. 
8.6.7. 
Visit to assess a potential LRTI  
8.6.7.1. 
Overview (Amended 29-MAY-2020) 
The purpose of the visit is to objectively document signs and symptoms by an 
appropriately qualified person (i.e. medical or nursing), provide medical advice, and take 
a nasal swab for detection of RSV infection. 
The appropriately qualified person will also evaluate whether the LRTI might be 
related to COVID19. The appropriately qualified person must follow the local standard 
of care regarding the reporting, and management of COVID-19 cases (suspected, 
probable or confirmed COVID-10 case), and complete both the COVID-19 form and 
LRTI form in the CRF.  Refer to Section 8.7. 
The visit may take place in the subject’s home (if allowed per standard of care), the 
investigator’s clinical facility or another medical facility, as appropriate per the judgment 
of the investigator. 
Note that if the reported symptoms are severe enough to warrant urgent care, the 
parent(s)/LAR(s)/designates should be advised to seek such care (e.g. Emergency 
Room).  
8.6.7.2. 
Clinical evaluation (Amended 29-MAY-2020)  
The investigator/study staff will evaluate the clinical signs and symptoms of the RTI. 
Data to be collected and recorded include (but are not limited to): 
• 
Temperature 
• 
Respiratory rate 
• 
Blood oxygen saturation (measured by pulse oximetry in room air, if feasible) 
• 
Signs of difficulty in breathing (including wheezing, tachypnoea, nasal flaring, chest 
in-drawing and apnoea)  
• 
Possible presence of COVID-19 infection (Section 8.7). As noted above, both the 
LRTI and COVID-19 eCRFs are to be completed (whether or not the 
investigator/study staff consider the LRTI to be due to COVID-19. 
Refer to the Study Procedures Manual (SPM) for additional details. 
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8.6.7.3. 
Nasal swab  
A nasal swab will be collected using sponsor-provided supplies and sent to the sponsor 
(or sponsor-designated) laboratory for detection of RSV-A/B using quantitative RT-
qPCR.  
Each nasal swab positive for RSV by quantitative RT-qPCR will also be assessed using a 
multiplex PCR for detection of a panel of respiratory viruses (AllplexTM Respiratory 
Panel or similar). Further assessment of RSV-A/B negative samples with multiplex PCR 
may be performed if deemed necessary. 
If more than one assessment visit is conducted to evaluate a potential LRTI, additional 
nasal swabs may be collected (using sponsor-provided supplies and sent to the sponsor 
laboratory) at the discretion of the Investigator. 
Note: Only the results generated by the sponsor (or sponsor-designated) laboratory 
(analyzing nasal swabs collected using sponsor-provided supplies) will be used when 
applying the case definitions for data analysis in Table 3.  If other nasal swabs are 
collected and tested locally as per routine standard of care, results will be required to be 
entered into the eCRF however this will not form part of the sponsor’s application of case 
definitions for data analysis.  
Therefore where mandated by the protocol every effort should please be made to obtain 
samples for analysis by the sponsor (or sponsor-designated) laboratory.  
8.6.7.4. 
Missed assessment visit    
If the criteria for an assessment visit have been met, but the visit cannot take place while 
symptoms are ongoing, it is a missed assessment visit. 
If it is truly not possible to perform an assessment visit (for example, if the child develops 
a potential LRTI while the family is travelling, and all symptoms have resolved by the 
time the family returns), then the LRTI assessment visit page of the eCRF should be 
filled in as completely as possible using available medical history and medical records.   
8.6.8. 
Follow-up after an assessment visit to evaluate a potential LRTI     
After an assessment visit (Section 8.6.7) the child will be followed with at least weekly 
active surveillance contacts, until the RTI/LRTI has resolved. During these active 
contacts, worsening of symptoms (clinically observed/diagnosed symptoms and signs that 
are reported during the same respiratory tract illness and reflect a deterioration in the 
child’s respiratory tract functions; for example, onset of additional symptoms or an 
increase in the intensity of a previously reported symptom) will be assessed. Parent(s) / 
LAR(s) / designate(s) will be reminded to call/contact/visit the site if symptoms worsen.  
If parent(s)/LAR(s)/designates report during an active or passive contact that symptoms 
have worsened, the site should perform a follow-up visit. 
During the follow-up visit, collection of a nasal swab is at the Investigator’s discretion.  
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After symptoms that resulted in one or more assessment visits have ended (Section 
8.6.5.1), site staff will ensure that the diary card for those symptoms is returned to the site 
via site visit, home visit, or postal mail (depending on the most effective local best 
practice for prompt retrieval of the completed infant diary card following the end of the 
symptoms).  
Important details are provided in the SPM.   
8.6.9. 
RSV Hospitalization 
If the child is admitted to hospital for an acute medical event and RSV infection is 
suspected, during the surveillance period: 
• 
The event will be documented in the eCRF.  
• 
If possible, a nasal swab will be collected from any subject who is hospitalized with 
a RTI (or soon after release, as long as symptoms are ongoing, per SPM 
specifications). The nasal swab should be collected using sponsor-provided supplies, 
for transmission to and testing by the sponsor laboratory.   
• 
If other specimens are collected and tested locally as per routine standard of care, 
results will be entered into the eCRF. However, only the sponsor laboratory results 
will be used when applying the case definitions for data analysis in Table 3. 
8.7. 
Reporting Covid-19 Cases – Maternal and Infant subjects 
(Amended 29-MAY-2020) 
In addition to satisfying local reporting requirements for COVID-19 cases, maternal 
and infant COVID-19 cases identified within the existing framework of the study will 
be captured and reported on the COVID-19 eCRF for the study. 
COVID-19 cases should be reported in the eCRF according to the WHO Case 
Definition [WHO, 2020] using one of the following terms:  
• 
Suspected COVID-19 infection  
• 
Probable COVID-19 infection 
• 
Confirmed COVID-19 infection 
8.8. 
SAEs related to study participation 
The subjects will be instructed to contact the investigator immediately should they (or 
their neonates/infants) manifest any signs or symptoms they perceive as serious. 
Refer to Section 9 for procedures for the investigator to record SAEs, and for guidelines 
on how to submit SAE reports to GSK Biologicals. 
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8.9. 
Study Conclusion 
The investigator will review data collected to ensure accuracy and completeness and 
complete the Study Conclusion screen in the pregnant woman’s (mother’s) and infant’s 
eCRFs.  
8.10. 
Screening failures 
Screening failures are defined as subjects who withdraw or are withdrawn from the study 
after giving informed consent, but before study eligibility (presence of all inclusion and 
absence of all exclusion criteria) is confirmed. 
Discovery during screening of any pregnancy related-event of interest or other condition 
that violates the requirements for study eligibility should be considered a screening 
failure.  
Discovery during Visit 1 of any condition that violates the requirements for study 
eligibility should also be considered a screening failure.  
The development of such conditions (after Visit 1) does not constitute screening failure 
and should be captured on the eCRF, as applicable.  
Limited data for screening failures will be reported to the eCRF.  This limited data set is 
specified in the eCRF. 
8.11. 
Biological sample handling and analysis 
Please refer to the SPM for details of biospecimen management (handling, storage and 
shipment). 
Samples will not be labeled 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 of 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. 
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Information on further investigations and their rationale can be obtained from GSK 
Biologicals. 
If additional testing is performed, the priority ranking given in Section 8.11.4.1 may be 
changed.  
Any sample testing will be done in line with the consent of the individual 
subject/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 visit, unless local rules, regulations or guidelines require 
different timeframes or different procedures, which will then be in line with the subject 
consent. These extra requirements need to be communicated formally to and discussed 
and agreed with GSK Biologicals. 
8.11.1. 
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 per-protocol analysis (See Section 11.3 for the definition of study 
cohorts/data sets to be analyzed). 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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8.11.2. 
Biological samples 
Table 8 
Biological samples 
Sample Type† 
Quantity 
Unit 
Timepoint 
Group 
Samples collected by Investigator / site staff  
Maternal Blood for antibody titers  
 5  
ml 
Visit 5 (Delivery) 
All Maternal subjects  
Cord blood 
 5 up to 
10  
ml 
Visit 5 (Delivery) 
All Maternal subjects  
Urine (dipstick) 
- 
- 
Visit 1 (Day 1) 
 
 
 
 
 
Visit 2 (Day 28) 
All Maternal subjects 
 
 
 
 
Visit 3 (Day 56) 
 
 
 
 
 
Visit 4 (Day 84) 
 
Nasal swab 
- 
- 
Visit to assess 
potential LRTI  
All Infants event-driven 
Samples preferentially collected by local health care provider per local practice1 
Maternal Blood for hematology/ 
biochemistry 1 
Up to 5.5  
ml  
Visit 1 (Day 1) 
All Maternal subjects 
Maternal Blood for Hemoglobin  
Up to 2  
ml  
Visit 3 (Day 56) 
1To be performed preferentially by local healthcare providers, as per local practice. To be performed by the 
investigator/study staff ONLY if not done by the local healthcare provider within 2 weeks before the study visit. 
8.11.3. 
Laboratory assays 
Please refer to APPENDIX A for a detailed description of the assays performed in the 
study. Please refer to APPENDIX B for the addresses of the clinical laboratories used for 
sample analysis. 
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. 
8.11.3.1. 
Antibody determination (Amended 29-MAY-2020) 
• 
Functional (neutralizing) antibody titers against RSV-A will be measured by 
neutralization assay on serum samples (Table 9). 
Table 9 
Humoral immunity (Antibody determination) (Amended 29-MAY-
2020)   
System 
Component 
Method 
Kit / Manu-
facturer 
Unit 
Cut-off 
Laboratory* 
SERUM 
Respiratory 
Syncytial 
Virus A Ab  
NEUTRALISATION 
In house 
ED60 
and/or 
IU/ML 
ED60: 18; 
IU/ml: 56 
GSK Biologicals** or 
GSK designated 
lab*** 
Ab = antibody; ED60 = serum dilution inducing 60% inhibition in plaque forming units; IU/mL: International 
Unit/milliliter 
* Refer to APPENDIX B for the laboratory addresses. 
** GSK Biologicals laboratory refers to the Clinical Laboratory Sciences (CLS) in Rixensart, Belgium; Wavre, Belgium. 
Marburg, Germany   
*** Testing may possibly be outsourced to a laboratory designated by GSK. In this case, the method and unit may be 
different than the one indicated in this table. 
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8.11.3.2. 
Molecular biology 
Table 10 
Molecular biology    
System 
Component**** 
Kit / 
Manufacturer 
Method 
Unit 
Laboratory 
Nasal 
swab 
RSV A RNA 
RSV B RNA 
In-house 
QRTPCR* 
Copies/ml  
GSK Biologicals 
or GSK 
designated lab** 
Nasal 
swab 
Influenza A virus (Flu A) 
Human Influenza A virus subtype H1 
(FLU A-H1) 
Human Influenza A virus subtype H3 
(FLU A-H3) 
Human Influenza A virus subtype 
H1pdm09 (FLU A-H1pdm09) 
AllplexTM 
Respiratory 
Panel 
(Seegene) or 
equivalent*** 
Multiplex 
real-time 
PCR 
Qualitative 
assay 
(positive 
/negative) 
GSK Biologicals 
or GSK 
designated lab**  
 
Influenza B virus (Flu B) 
Human respiratory syncytial virus A 
(RSV A) 
Human respiratory syncytial virus B 
(RSV B) 
Human adenovirus (AdV) 
Human metapneumovirus (MPV) 
Human enterovirus (HEV) 
Human parainfluenza virus 1 (PIV1) 
Human parainfluenza virus 2 (PIV2) 
Human parainfluenza virus 3 (PIV3) 
Human parainfluenza virus 4 (PIV4) 
Human bocavirus 1/2/3/4 (HBoV) 
Human rhinovirus A/B/C (HRV) 
Human coronavirus 229E (229E) 
Human coronavirus NL63 (NL63) 
Human coronavirus OC43 (OC43) 
 
 
 
 
* RSV-A/B quantitative reverse transcription PCR will be performed on all specimens of infants with RTI with suspicion 
of difficulty in breathing/wheezing or parental concern, reported during active or passive surveillance.  
** GSK Biologicals laboratory refers to the Clinical Laboratory Sciences (CLS) in Rixensart, Belgium; Wavre, Belgium. 
Marburg Germany   
*** Respiratory Viruses Panel (Allplex PCR) will be performed for all specimens RSV A/B-positive and if deemed 
necessary for RSV A/B-negative samples. 
****The list of components might be subject to change in case equivalent kit is used for multiplex RVP testing. 
8.11.3.3. 
Hematology, biochemistry and urinalysis    
Hematology and biochemistry tests are to be performed preferentially by local healthcare 
providers, as per local practice. They are to be performed by the investigator/study staff 
ONLY if not done by the local healthcare provider within 2 weeks before the study visit. 
The investigator will perform urine dipstick tests to detect the presence of proteins, 
glucose, RBCs and/or WBCs. These tests do not replace those performed by local 
healthcare practitioners, per local practice, for clinical management of study subjects.  
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Table 11 
Hematology, biochemistry, urine tests    
System 
Discipline 
Component 
Time 
Point 
Method 
Scale 
Laboratory 
Whole  
Hematology 
Hemoglobin 
Visit 1  
As per local  Quantitative 
Local  
blood 
 
 
Visit 3  
practice 
 
laboratory 
 
 
Leukocytes (White Blood 
Cells)  
Visit 1  
 
 
 
 
 
Neutrophils 
Visit 1  
 
 
 
 
 
Lymphocytes 
Visit 1  
 
 
 
 
 
Monocytes 
Visit 1  
 
 
 
 
 
Basophils 
Visit 1  
 
 
 
 
 
Eosinophils 
Visit 1  
 
 
 
 
 
Platelets 
Visit 1  
 
 
 
Serum 
Biochemistry 
Alanine Aminotransferase 
(ALT)  
Visit 1  
As per local 
practice 
Quantitative 
Local 
laboratory 
 
 
Aspartate Aminotransferase 
(AST) 
Visit 1  
 
 
Creatinine 
Visit 1  
 
 
Urea Nitrogen 
Visit 1  
Urine 
- 
Protein  
Visit 1  
As per local 
practice, 
dipsticks 
provided by 
GSK 
Biologicals 
Ordinal 
Local 
laboratory 
 
 
 
Visit 2  
 
 
 
Visit 3  
 
 
 
Visit 4  
 
 
Glucose 
Visit 1  
 
 
 
Visit 2  
 
 
 
Visit 3  
 
 
 
Visit 4  
 
 
Hemoglobin 
Visit 1  
 
 
(RBC) 
Visit 2  
 
 
 
Visit 3  
 
 
 
Visit 4  
 
 
Leukocyte esterase 
Visit 1  
 
 
(WBC) 
Visit 2  
 
 
 
Visit 3  
 
 
 
Visit 4  
8.11.3.4. 
Additional tests 
Additional exploratory testing on the disease under study and/or other respiratory tract 
infections or infections of relevance to pregnant women and their newborns may be 
performed within the framework of the study if deemed necessary for accurate 
interpretation of the data/ should such assay(s) become available at GSK. These assays 
may not be represented in the objectives/ endpoints of the study protocol. 
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8.11.4. 
Biological samples evaluation 
8.11.4.1. 
Immunological read-outs 
Table 12 
Immunological read-outs   
Blood sampling 
timepoint 
Group 
No. subjects 
Component 
Component 
priority rank 
Type of contact and 
time point 
Maternal Blood 
Visit 5 (Delivery) 
All Maternal subjects  
2300  
Respiratory Syncytial Virus A Ab 
(RSV-A neutralising antibody) 
1 
Cord Blood 
Visit 5 (Delivery) 
All Maternal subjects 
(provides infant 
antibody levels) 
2300 
Respiratory Syncytial Virus A Ab 
(RSV-A neutralising antibody) 
1 
8.11.4.2. 
Molecular biology 
Table 13 
Molecular biology for nasal swab specimen analysis 
Nasal swab sampling 
timepoint 
Group 
No. 
subjects 
Component 
Type of contact 
(timepoint) 
Sampling 
timepoint 
Visit to assess 
potential LRTI  
Unscheduled 
All 
Infants * 
Event-
driven** 
QRTPCR (quantitative reverse transcription PCR): 
RSV A RNA and RSV B RNA 
Visit to assess 
potential LRTI 
Unscheduled 
All 
infants* 
Event-
driven*** 
Multiplex PCR including: 
Influenza A virus (Flu A) 
Influenza B virus (Flu B) 
Human respiratory syncytial virus A (RSV A) 
Human respiratory syncytial virus B (RSV B) 
Human Influenza A virus subtype H1 (Flu A-H1) 
Human Influenza A virus subtype H3 (Flu A-H3) 
Human Influenza A virus subtype H1pdm09 (Flu A-H1pdm09) 
 
 
 
 
Human adenovirus (AdV) 
Human metapneumovirus (MPV) 
Human enterovirus (HEV) 
Human parainfluenza virus 1 (PIV1) 
Human parainfluenza virus 2 (PIV2) 
Human parainfluenza virus 3 (PIV3) 
 
 
 
 
Human parainfluenza virus 4 (PIV4) 
Human bocavirus 1/2/3/4 (HBoV) 
Human rhinovirus A/B/C (HRV) 
Human coronavirus 229E (229E) 
Human coronavirus NL63 (NL63) 
Human coronavirus OC43 (OC43) 
* Refer to Section 8.6.7. 
** RSV-A/B quantitative PCR (RSV-A/B RNA) will be performed on all specimens. 
*** Respiratory Viruses Panel (Multiplex PCR) will be performed for all specimens RSV-A/B positive and if deemed 
necessary for RSV-A/B-negative sample.  
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8.11.4.3. 
Hematology/blood chemistry 
Table 14 
Hematology/blood chemistry tests    
Blood sampling timepoint 
Group 
No. 
subjects 
Component 
Type of contact (timepoint) 
Visit 1 (Day 1) 
All maternal 
subjects 
2300* 
Hematology (Leukocytes, Hemoglobin, Platelets) 
Biochemistry (ALT, AST, Creatinine, blood urea 
nitrogen) 
Visit 3 (Day 56) 
All maternal 
subjects 
2300  
Hematology (Hemoglobin) 
* 200 to 300 subjects per country. Tests to be performed preferentially by local healthcare providers and information 
will be collected and recorded in the eCRF. The investigator/study staff will collect biological samples for the 
specified testing if not done by the local healthcare provider as per local practice.  
9. 
SERIOUS ADVERSE EVENTS RELATED TO STUDY 
PARTICIPATION 
The investigator or site staff is/are responsible for the detection, documentation and 
reporting of events meeting the SAE definition.  
Treatment of any SAE related to study participation (e.g., protocol-mandated 
procedures, invasive tests) is at the sole discretion of the investigator and according to 
current good medical practice. 
9.1. 
Definition 
An SAE related to study participation (e.g., protocol-mandated procedures, invasive 
tests) is any untoward medical occurrence related to study participation that: 
• 
Results in death, 
• 
Is life-threatening, 
Note: The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in 
which the subject was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, had it been more severe. 
• 
Requires hospitalization or prolongation of an existing hospitalization, 
Note: In general, hospitalization signifies that the subject has been admitted at the 
hospital or emergency ward for observation and/or treatment that would not have 
been appropriate in the physician’s office or in an out-patient setting.  
Complications that occur during hospitalization are also considered AEs. If a 
complication prolongs hospitalization or fulfils any other serious criteria, the event 
will also be considered serious. When in doubt as to whether ‘hospitalization’ 
occurred or was necessary, the AE should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition (known or 
diagnosed prior to informed consent signature) that did not worsen from baseline is 
NOT considered an SAE. 
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• 
Results in disability/incapacity,  
Note: The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions. This definition is not intended to include experiences 
of relatively minor medical significance such as uncomplicated headache, nausea, 
vomiting, 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 emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization. 
9.2. 
Event Identification  
Blood and urine samples will be collected from pregnant women enrolled in the study.  
Nasal swabs will be collected from neonates/ infants enrolled in the study.  Serious 
adverse events (SAEs) associated with collection of these biological specimens or any 
other study procedures will be documented and reported from the time the pregnant 
woman (mother) consents to participate / consents to her infant’s participation until the 
pregnant woman (mother) / her infant is discharged from the study. 
Each subject/ 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. 
9.3. 
Subject cards 
Study subjects/parents/LARs must be provided with the address and telephone number of 
the main contact for information about the clinical study. The investigator (or designate) 
must therefore provide subjects/parents/LARs with a “subject card.”   
For this study, a subject card will be provided to each pregnant woman who enrolls.  A 
second subject card will be provided for each infant who is enrolled.  
In an emergency situation these cards serve to inform the responsible attending 
physician(s) that the subject is in a clinical study and that relevant information may be 
obtained by contacting the investigator.  
In a non-emergency situation, if subjects visit a local healthcare provider not affiliated 
with the study, these cards serve to inform the responsible local healthcare provider that 
the subject is in a clinical study and that relevant information may be obtained by 
contacting the investigator. Further, subject will have information on the card to contact 
the study site at any time.  
Subjects/parents/LARs must be instructed to keep the subject cards in their possession at 
all times during the study.  
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9.4. 
GSK Contact information, GSK Reporting Timeframes, and 
Regulatory reporting requirements 
Procedure related SAEs that occur during the study will be reported to the GSK 
representatives specified in Table 15, within the timeframes described in Table 16 once 
the investigator determines that the event meets the protocol definition provided in the 
Glossary of Terms. 
The investigator will promptly report all SAEs related to study participation to GSK 
Biologicals as detailed in Table 15 and Table 16. GSK Biologicals has a legal 
responsibility to promptly notify, as appropriate, both the local regulatory authority and 
other regulatory agencies (as applicable, per country) about the event. 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. 
Table 15 
Contact information for reporting SAEs related to study participation 
to GSK 
Study Contact for Reporting SAEs: 
Refer to the local study contact information document. 
Back-up Study Contact for Reporting SAEs: 
24/24 hour and 7/7 day availability: 
GSK Biologicals Clinical Safety & Pharmacovigilance 
Outside US & Canada sites: 
Fax: 
 or 
 
Email address: 
 
Table 16 
Timeframes for submitting SAEs related to study participation to 
GSK 
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. 
** Timeframe allowed after the diagnosis is established and known to the investigator. 
‡The investigator will be required to confirm review of the procedure related SAE causality by ticking the ‘reviewed’ box 
in the electronic Expedited Adverse Event Report within 72 hours of submission of the procedure related SAE 
9.5. 
Information to be reported 
The nature of the SAE, date and time of onset, outcome, intensity and possible 
relationship to the study procedure(s) should be established and recorded in the eCRF.  
Any medication administered for the treatment of the SAE should be recorded in 
Expedited Adverse Event Report of the subject’s eCRF. 
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The outcome of the SAE related to study participation should be assessed, as follows: 
• 
Recovered/ resolved. 
• 
Recovering/ resolving. 
• 
Not recovered/ not resolved. 
• 
Recovered with sequelae/ resolved with sequelae. 
• 
Fatal. 
9.6. 
SAE Report Completion and transmission to GSK 
Once an investigator becomes aware that a study-related SAE has occurred in a study 
subject, the investigator (or designee) must complete the information in the electronic 
Expedited Adverse Event Report WITHIN 24 HOURS. The report will always be 
completed as thoroughly as possible with all available details of the event. Even if the 
investigator does not have all information regarding 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. 
9.6.1. 
Back-up system in case the electronic reporting system does not 
work 
If the electronic reporting system does not work, the investigator (or designee) must 
complete, then date and sign a paper Expedited Adverse Event Report and fax it to the 
Study Contact for Reporting SAEs (refer to the Sponsor Information) or to the GSK 
Biologicals Clinical Safety and Pharmacovigilance department within 24 hours.  
This back-up system should only be used if the electronic reporting system is not working 
and NOT if the system is slow. As soon as the electronic reporting system is working 
again, the investigator (or designee) must complete the electronic Expedited Adverse 
Event Report within 24 hours. The final valid information for regulatory reporting will be 
the information reported through the electronic reporting system.  
9.6.2. 
Updating of SAE information after removal of write access to the 
subject’s eCRF 
When additional SAE information is received after removal of write access to the 
subject’s eCRF, new or updated information should be recorded on a paper Expedited 
Adverse Event 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 16. 
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9.7. 
Follow-up of SAEs related to study participation (Amended 
29-MAY-2020) 
The investigator will follow-up subjects with SAEs related to study participation until the 
event has resolved, subsided, stabilized, disappeared, or until the event is otherwise 
explained, or the subject is lost to follow-up. 
9.7.1. 
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 16). 
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 
last visit of the subject. 
9.7.2. 
Follow-up after the subject is discharged from the study 
(Amended 29-MAY-2020) 
If the investigator receives additional relevant information on a previously reported SAE, 
he/ she will provide this information to GSK Biologicals using a paper Expedited 
Adverse Event Report. 
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. 
10. 
SUBJECT COMPLETION AND WITHDRAWAL 
10.1. 
Subject completion 
A subject who returns for the concluding visit foreseen in the protocol is considered to 
have completed the study. 
10.2. 
Subject withdrawal  
Subjects who are withdrawn because of an event of interest or SAEs related to study 
participation must be clearly distinguished from subjects who are withdrawn for other 
reasons. The investigator will follow subjects who are withdrawn as the result of an SAE 
related to study participation until resolution of the event (see Section 9.7.2). 
Withdrawals will not be replaced. 
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From an analysis perspective, a ‘withdrawal’ from the study refers to any subject who did 
not come back for the concluding visit in the protocol. 
All data collected until the date of withdrawal/last contact of the subject will be used for 
the analysis. 
A subject is considered a ‘withdrawal’ from the study when no study procedure has 
occurred, no follow-up has been performed and no further information has been collected 
for this subject from the date of withdrawal/last contact. 
Investigators will make at least 3 attempts to contact a subject who does not return for a 
scheduled visit as described in Section 8.4 and in the SPM.  
A subject will be defined as lost to follow-up if there is no contact with the subject 
/subject’s parent(s) / LAR(s) over a period of at least 3 months after a planned visit (see 
SPM for details). Efforts to contact the subject/subject’s parents should be recorded in the 
source documents.  The subject’s data will be censored at the time of last contact once 
this definition is met. 
Information relevant to the withdrawal will be documented in the eCRF. The investigator 
will document whether the decision to withdraw a subject from the study was made by 
the subject herself, 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: 
• 
Study participation related SAE. 
• 
Pregnancy related event of interest(specify). Note: includes maternal deaths. 
• 
Maternal deaths not related to pregnancy/delivery (specify cause).  
• 
Neonatal event of interest(specify). Note: includes death in infants from birth – 28 
days old 
• 
Death in infants > 28 days old (specify cause). Note that death in neonates from birth 
– 28 days old is captured as a neonatal event of interest).   
• 
Protocol violation (specify). 
• 
Consent withdrawal*. 
• 
Moved from the study area. 
• 
Lost to follow-up. 
• 
Other (specify). 
*In case a subject is withdrawn from the study because she/the subject’s parent(s)/ 
LAR(s) has withdrawn consent, the investigator will document the reason for withdrawal 
of consent, if specified by the subject/ the subject’s parent(s)/LAR(s), in the CRF. 
Subjects who are withdrawn from the study because of study participation 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 result of a study 
participation related SAE until resolution of the event (see Section 9.7.2). 
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11. 
STATISTICAL METHODS 
The primary analysis will be performed by country and possibly by region or other 
relevant grouping if standard of antenatal care is similar in the different sites. This will be 
determined during site selection when more information is available.  
11.1. 
Endpoints 
11.1.1. 
Primary endpoints   
11.1.1.1. 
Pregnancy outcomes.   
These include: 
• 
Live birth with no congenital anomalies,  
• 
Live birth with congenital anomalies,  
• 
Fetal death/stillbirth (loss at or after 22 weeks of gestation) with no congenital 
anomalies,  
− 
Antepartum stillbirth 
− 
Intrapartum stillbirth 
• 
Fetal death/still birth (loss at or after 22 weeks of gestation) with congenital 
anomalies,  
− 
Antepartum stillbirth 
− 
Intrapartum stillbirth 
• 
Elective/therapeutic termination with no congenital anomalies,  
• 
Elective/therapeutic termination with congenital anomalies. 
• 
Of note, fetal death/stillbirth has multiple subcategories. For example, fetal 
death/stillbirth with no congenital anomalies is an outcome with two subcategories 
that include: 1) antepartum stillbirth; 2) intrapartum stillbirth. For each outcome, the 
investigator should select the applicable sub-category. 
11.1.1.2. 
Pregnancy related events of interest from Visit 1 through Visit 6. 
Although pregnancy related events of interest occur within the first 42 days after delivery 
they may only be detected later, and are to be reported throughout the study. They are 
listed below.  Of note, some events of interest fall under a single category but have 
multiple subcategories. For example, hypertensive disorders of pregnancy is an event 
with three subcategories that include: 1) gestational hypertension; 2) pre-eclampsia; and 
3) pre-eclampsia with severe features (including eclampsia). For each event, the 
investigator should select the event and the applicable sub-category. 
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• 
Maternal death 
• 
Hypertensive disorders of pregnancy:  
− 
Gestational hypertension,  
− 
Pre-eclampsia,  
− 
Pre-eclampsia with severe features (including eclampsia)  
• 
Antenatal bleeding:  
− 
Morbidly adherent placenta 
− 
Placental abruption 
− 
Cesarean Scar Pregnancy 
− 
Uterine rupture 
• 
Postpartum hemorrhage 
• 
Fetal growth restriction 
• 
Dysfunctional labor 
− 
first stage of labor 
− 
second stage of labor 
• 
Gestational diabetes mellitus,  
• 
Non reassuring fetal status 
• 
Pathways to preterm birth:  
− 
Premature preterm rupture of membranes,  
− 
Preterm labor,  
− 
Provider-initiated preterm birth. 
• 
Chorioamnionitis 
• 
Oligohydramnios 
• 
Polyhydramnios 
• 
Gestational Liver Disease: 
− 
Intrahepatic Cholestasis of Pregnancy (ICP)  
− 
Acute Fatty Liver of Pregnancy  
• 
Maternal Sepsis 
• 
Any other pregnancy related event considered by the investigator to be of concern 
(specify) 
For events of interest that include subcategories, the frequency of the main event of 
interest and of each event subcategory will be included in the analysis. The overall 
frequency will include mothers who present with at least one of the subcategory events. 
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11.1.1.3. 
Neonatal events of interest from birth through 28 days of age   
Neonatal events of interest occur within the first 28 days after birth, but may only be 
detected later and are to be reported throughout the study.  They include: 
• 
Small for gestational age, 
• 
Low birth weight including very low birth weight, 
• 
Neonatal encephalopathy, 
• 
Congenital microcephaly,  
− 
Postnatally diagnosed 
− 
Prenatally diagnosed 
• 
Congenital anomalies, 
− 
Major external structural defects 
− 
Internal structural defects 
− 
Functional defects 
• 
Neonatal death, 
− 
Neonatal death in a preterm live birth (gestational age>=28 to < 37 weeks) 
− 
Neonatal death in a term live birth 
• 
Neonatal infections, 
− 
Blood stream infections 
− 
Meningitis 
− 
Respiratory infection 
• 
Respiratory distress in the neonate, 
• 
Preterm birth, 
• 
Failure to thrive, 
• 
Large for gestational age, 
• 
Macrosomia, 
• 
Any other neonatal event considered by the investigator to be of concern (specify, 
e.g. neurodevelopment delay) 
For events of interest that include subcategories, the frequency of the main event of 
interest and of each event subcategory will be included in the analysis. The overall 
frequency will include infants who present at least one of the subcategory events.  
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11.1.2. 
Secondary endpoints  
• 
Pregnancy related events of interest from Visit 1 through Visit 6 (as defined in 
primary endpoints) for each GAIA level of diagnostic certainty (where applicable 
and feasible). 
• 
Neonatal events of interest from birth through 28 days of age (as defined in primary 
endpoints) for each GAIA level of diagnostic certainty (where applicable and 
feasible). 
Of note, some events of interest fall under a single category but have multiple 
subcategories. For each event, the investigator should identify the event and select the 
applicable sub-category and the GAIA level of diagnostic certainty. 
• 
RSV-A neutralizing antibody titers in maternal blood at delivery  
• 
RSV-A neutralizing antibody titers in cord blood at delivery.  
• 
Episode(s) of RSV-LRTI from birth up to 1 year of age. 
• 
Episode(s) of RSV hospitalization from birth up to 1 year of age.  
11.1.3. 
Tertiary endpoints (Amended 29-MAY-2020) 
• 
Co-infections of RSV-LRTI with other respiratory viruses in infants, confirmed by 
PCR of nasal swabs in infants from birth up to 1 year of age:  
− 
Influenza A virus (Flu A) 
− 
Influenza B virus (Flu B) 
− 
Human Influenza A virus subtype H1 (Flu A-H1)  
− 
Human Influenza A virus subtype H3 (Flu A-H3) 
− 
Human Influenza A virus subtype H1pdm09 (Flu A-H1pdm09) 
− 
Human adenovirus (AdV) 
− 
Human metapneumovirus (MPV) 
− 
Human enterovirus (HEV) 
− 
Human parainfluenza virus 1 (PIV1) 
− 
Human parainfluenza virus 2 (PIV2) 
− 
Human parainfluenza virus 3 (PIV3) 
− 
Human parainfluenza virus 4 (PIV4) 
− 
Human bocavirus 1/2/3/4 (HBoV) 
− 
Human rhinovirus A/B/C (HRV) 
− 
Human coronavirus 229E (229E) 
− 
Human coronavirus NL63 (NL63)  
− 
Human coronavirus OC43 (OC43) 
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• 
Potential risk factors for pregnancy related and neonatal events of interest.  
• 
Any further exploratory characterization of immune responses to RSV and/or other 
respiratory tract infections or infections of relevance to pregnant women and their 
newborns (based on maternal serum and cord blood)  (For example, levels of RSV-B 
neutralizing antibodies.)   
• 
Episode(s) of RSV-LRTI/severe LRTI based on alternative case definitions, from 
birth up to 1 year of age. 
11.2. 
Determination of sample size   
The target will be to enroll up to approximately 200 to 300 eligible subjects (pregnant 
women) by country. Subjects may drop-out from the study due to a variety of reasons, 
e.g. migration from the study area. Assuming a drop-out rate of about 10% during the 
course of follow-up, there will be up to approximately 180 to 270 evaluable subjects by 
country. 
Considering a sample size of up to approximately 180 to 270 evaluable subjects by 
country, Table 17 illustrates the precision (exact 95% confidence interval [CI]) one can 
get on the percentage of subjects with maternal, fetal and neonatal events of interest. 
Precision (exact 95% CI) has also been computed for a sample size of 270, 180 and 100 
evaluable subjects for estimate by study site. 
The percentages of subjects with maternal, fetal and neonatal events of interest for the 
primary objectives are expected to range from 0 to 35%. 
Table 17 
Precision (exact 95% confidence interval) on the percentage of 
subjects with maternal, fetal and neonatal events of interest for 
sample size of 270, 180 and 100 subjects   
270 subjects 
180 subjects 
100 subjects 
% 
N 
Lower 
Upper 
N 
Lower 
Upper 
N 
Lower 
Upper 
limit  
limit  
limit  
limit  
limit  
limit  
35 
94.5 
29.3 
41 
63 
28.1 
42.4 
35 
25.7 
45.2 
30 
81 
24.6 
35.8 
54 
23.4 
37.3 
30 
21.2 
40 
25 
67.5 
19.9 
30.6 
45 
18.9 
32 
25 
16.9 
34.7 
20 
54 
15.4 
25.3 
36 
14.4 
26.6 
20 
12.7 
29.2 
15 
40.5 
11 
19.8 
27 
10.1 
21.1 
15 
8.6 
23.5 
10 
27 
6.7 
14.2 
18 
6 
15.3 
10 
4.9 
17.6 
5 
13.5 
2.7 
8.3 
9 
2.3 
9.3 
5 
1.6 
11.3 
3 
8.1 
1.3 
5.8 
5.4 
1 
6.8 
3 
0.6 
8.5 
1 
2.7 
0.2 
3.1 
1.8 
0.1 
3.9 
1 
0 
5.4 
0 
0 
0 
1.4 
0 
0 
2 
0 
0 
3.6 
%= Percentage of subjects with maternal, fetal and neonatal events of interest 
N= Number of subjects with maternal, fetal and neonatal events of interest 
Lower and upper limits are exact 95% confidence intervals 
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11.3. 
Cohorts for Analyses (Amended 29-MAY-2020) 
11.3.1. 
Exposed Sets (ES) 
11.3.1.1. 
Pregnant women (mothers) 
The ES will include all pregnant women (mothers) who signed a valid informed consent 
form. 
11.3.1.2. 
Neonates/Infants 
Not applicable. 
11.3.2. 
Enrolled sets  
11.3.2.1. 
Pregnant women (mothers) 
The enrolled set will include all pregnant women (mothers) with a valid informed 
consent who completed Visit 1. 
11.3.2.2. 
Neonates/Infants 
The Enrolled Set will include all neonates/infants 
• 
born to pregnant women in the enrolled set, and  
• 
Who have  a valid ICF signed by the mother/ parent(s) /LAR(s) (as appropriate per 
local regulations). 
11.3.3. 
Per Protocol Sets (PPS) (Amended 29-MAY-2020) 
11.3.3.1. 
Pregnant women (mothers) 
The maternal PPS will include all pregnant women (mothers) in the enrolled set who 
meet all eligibility criteria up to the time of their censoring, either at study completion or 
prematurely as drop-out (e.g. withdrawn consent, lost-to-follow-up). 
11.3.3.2. 
Neonates/Infants  
The infant PPS will include all neonates / infants  
• 
born to pregnant women in the PPS and  
• 
who meet all eligibility criteria up to the time of their censoring, either at study 
completion or prematurely as drop-out (e.g. withdrawn consent, lost-to-follow-up) 
who have at least one time point evaluation (see Table 5).  
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11.4. 
Derived and transformed data 
Age of the infant 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 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 when ICF was first signed by the subject / 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 Table 3). The cases will also be classified according to the classification of WHO 
[Modjarrad, 2016].  
11.4.1. 
Handling of missing values/censoring/discontinuations 
For a given subject and a given demographic variable, missing measurements will not be 
replaced. 
The number of missing values per variable may be provided for selected variables of 
interest as a separate category. Missing values will be examined to help determine if it is 
necessary to use multiple imputation or other techniques to deal with missing data. 
11.5. 
Analysis of demographic and baseline characteristics 
For the maternal PPS cohort, analyses of demographic and baseline characteristics at 
Visit 1 will be described.  
For the infant PPS cohort, analyses of demographic characteristics at Visit 1-NB will be 
described.  Analyses of lifestyle characteristics will be described at Visit 2 NB. 
For Screening Failures, reasons for non-eligibility will be described. 
Continuous variables will be summarized by providing the number of observations, 
mean, 95% confidence interval (CI), standard deviation (SD), median, and range. 
Categorical variables will be summarized by tabulating counts (N) and the percentage 
(%) of total subjects having the given characteristics, with missing data considered a 
separate category. 
11.6. 
Analysis of primary objectives (Amended 29 May 2020)  
The primary objectives analyses will be performed on the PPS cohorts overall and 
possibly by region or other relevant grouping.  If there is a difference of 5% or more 
between the number of participants in the enrolled set and the PPS, primary objectives 
analyses on the enrolled set will also be performed. 
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In healthy pregnant women with uncomplicated pregnancies at time of enrollment: 
• 
To determine the frequencies of pregnancy outcomes.  
The number and percentage (with exact 95% CI) of women presenting the following 
outcomes: live birth, fetal death/stillbirth (antepartum or intrapartum), and 
elective/therapeutic termination will be reported for each event by presence or 
absence of congenital anomalies.  
• 
To determine the frequencies of pregnancy related events of interest as specified in 
Section 11.1.1.2. 
The number and percentage (with exact 95% CI) of pregnant women presenting with 
the events of interest specified in Section 11.1.1.2 will be tabulated for each event 
within appropriate time windows to be specified in the statistical analysis plan 
(SAP). Missing data may be considered a separate category.  
In all neonates live-born to women enrolled in the study: 
• 
To determine the frequencies of neonatal events of interest. as specified in Section 
11.1.1.3. 
The number and percentage (with exact 95% CI) of neonates presenting the events of 
interest specified in Section 11.1.1.3 will be tabulated for each event. Missing data 
may be considered a separate category. 
11.7. 
Analysis of secondary objectives (Amended 29-MAY-2020)  
The secondary objectives analyses will be performed on the PPS cohorts (maternal or 
infant as applicable) overall and possibly by region or other relevant grouping.  If there is 
a difference of 5% or more between the number of participants in the enrolled set and 
the PPS, secondary objectives analyses on the enrolled set will also be performed. 
In healthy pregnant women with uncomplicated pregnancies at time of enrollment: 
• 
To determine frequencies of pregnancy related events of interest according to GAIA 
levels of diagnostic certainty (where these are specified) (APPENDIX D) 
− 
Considering all pregnant women followed from enrollment through Visit 6, the 
number and percentage of subjects with at least one maternal event of interest 
will be computed by GAIA levels of diagnostic certainty, with exact 95% CI.  
• 
To describe the distribution of RSV-A antibody titers in maternal blood at delivery.  
− 
Geometric mean titers (GMTs) will be tabulated with 95% CI.  
− 
Percentage of subjects above thresholds will be tabulated. 
In all neonates live-born to women enrolled in the study: 
• 
To determine frequencies of neonatal events of interest according to GAIA levels of 
diagnostic certainty (where these are specified). (APPENDIX D) 
− 
Considering all neonates the number and percentage of subjects with at least one 
neonatal event of interest will be computed by GAIA levels of diagnostic 
certainty, with exact 95% CI.  
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• 
To describe the distribution of RSV-A antibody titers in cord blood at delivery.  
− 
Geometric mean titers (GMTs) will be tabulated with 95% CI.  
− 
Percentage of subjects above thresholds will be tabulated. 
In all neonates/infants live-born to women enrolled in the study:  
• 
To determine the incidence of all, of severe, and of very severe RSV-lower 
respiratory tract illnesses (LRTIs).  
− 
Considering all infants followed from visit 1-NB to visit 4-NB, the percentage 
of subjects with at least one LRTI illness, exact 95% CI will be presented. 
− 
Incidence rates of LRTI illnesses will be calculated, with exact 95% CI. 
− 
Frequencies of repeat occurrences of LRTI will be tabulated. 
• 
To determine the incidence of RSV hospitalization.  
− 
Considering all infants followed from visit 1-NB to visit 4-NB, the percentage 
of subjects with at least one RSV hospitalization, with exact 95% CI. 
− 
Incidence rates of RSV hospitalizations will be calculated, with exact 95% CI. 
− 
Frequencies of repeat occurrences of RSV hospitalization will be tabulated. 
Continuous variables will be summarized by providing the number of observations, 
mean, 95% CI, SD, median, and range. Categorical variables will be summarized by 
tabulating N and % of total subjects having the given characteristics, with missing data 
considered a separate category. 
11.8. 
Analysis of tertiary objectives (Amended 29-MAY-2020) 
The following tertiary objectives analyses will be performed on infants within the PPS 
cohort,overall and possibly by region or other relevant grouping. If there is difference of 
5% or more between the number of participants in the enrolled set and the PPS, 
tertiary objectives analyses on the enrolled set will also be performed. 
• 
To describe co-infections of RSV-LRTI with other respiratory viruses in infants.  
− 
Considering all infants followed from visit 1-NB to visit 4-NB, the percentage 
of subjects with the occurrence of RSV-LRTI and having other respiratory viral 
co- infection identified by multiplex PCR, with exact 95% CI; classified by 
respiratory viruses. 
• 
To estimate the association of RSV-LRTI in neonates/infants and the level of RSV 
neutralizing antibodies in cord blood.  
− 
Correlation analysis will be done comparing the levels of RSV antibodies 
present in cord blood and the presence or absence of RSV-associated LRTI, 
RSV-associated severe LRTI, and RSV-associated very severe LRTI in infants. 
Details will be described in the SAP. 
The following tertiary objectives analyses will be performed on the PPS cohorts 
(maternal or infant as applicable) by country, region, or other relevant grouping: 
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• 
To determine risk factors for pregnancy-related and neonatal events of interest.  
− 
Risk factors will be described in the SAP. 
− 
The maternal events of interest will be described according to variables 
collected in the mother’s clinical examination and obstetric risk factors. 
Frequency tables will be generated for categorical variables.  
− 
The neonatal events of interest will be described according to variables collected 
in the mother’s clinical examination and obstetric risk factors. Frequency tables 
will be generated for categorical variables.  
− 
Furthermore, multiple variable analyses (such as multiple logistic regression for 
binary outcomes and multiple Poisson/negative binomial and/or other 
appropriate models for count outcomes) will be conducted to adjust for 
covariates of interest, provided there are sufficient numbers of events of interest. 
• 
To determine the incidence of LRTIs/Severe LRTIs (using alternative case 
definitions) 
• 
If deemed necessary, to further characterize the immune responses to RSV and other 
infections in maternal subjects and infants (based on maternal serum and cord 
blood).  
− 
For example, for levels of neutralizing antibodies to RSV-B: 
o 
GMTs/ GMCs may be tabulated with 95% CI.  
o 
Percentage of subjects above various thresholds, depending on the antibody 
tested, may be tabulated with exact 95% CI. 
o 
Other relevant exploratory analyses may be defined in the SAP.  
11.9. 
Interpretation of analyses 
Analyses will be descriptive with the aim to characterize different sub-groups of women. 
These sub-groups will be defined prior to analyses and will be related to e.g. risk factors 
for maternal and neonatal events of interest and endemic disease. These descriptive 
analyses should be interpreted with caution considering that there is no adjustment for 
multiplicity for these comparisons. 
Further details will be provided in the SAP. 
11.10. 
Analysis of safety 
Serious adverse events (SAEs) related to study participation will be recorded throughout 
the study period. In case of occurrence of SAE(s) related to study participation, a listing 
of SAEs will be provided. 
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11.11. 
Conduct of analyses   
All analyses will be done on cleaned data. 
Analyses will be performed in a stepwise manner after all subjects in all countries have 
completed all study visits in Epoch 002 and again after completion of all study visits in 
Epoch 003.   
Analyses of pregnancy outcomes, pregnancy related events of interest, and neonatal 
events of interest will be performed when all data up to 42 days post-delivery are 
available (Epoch 002). For these analyses a statistical report but no CSR will be prepared. 
Final analyses will be performed when all data up to study end are available (Epoch 002 
and Epoch 003). An integrated CSR including all available data will be written and made 
available to the investigator(s).  
If the data for tertiary endpoints become available at a later stage, additional 
analysis/analyses will be performed. These data will be documented in annex(es) to the 
study report and made available to the investigators. 
Additional analyses may be performed if deemed necessary to inform the design or 
implementation of future clinical trials. 
Analyses, and the sequence in which they will occur, will be described in detail in the 
SAP. 
Any deviation(s) or change(s) from the original statistical plan outlined in this protocol 
will be described and justified in the final study report. 
11.11.1. 
Statistical considerations for interim analyses (Amended 29-
MAY-2020)    
Interim analysis for RSV LRTIs   
If deemed necessary, an interim analysis may be performed on RSV surveillance data as 
part of the secondary objective of determining incidence of RSV LRTI. This interim 
analysis may be performed to obtain preliminary information on the performance of the 
case definitions used for RSV LRTI, severe LRTI, and very severe LRTI (Table 3) and to 
assess levels of RSV neutralising antibody in maternal and cord blood at delivery. The 
interim analysis may occur after the database freeze at the time point when approximately 
50% of infants will have completed up to 6 months of follow up during the surveillance 
period following birth (up to Visit 3-NB). If an interim analysis is performed, data 
cleaning plans will be scheduled as needed to supply data for interim analyses in a timely 
manner. This interim analysis may be performed on data that is as clean as possible. 
Preliminary results will be made available in a timely manner for use in the potential 
adjustment of the RSV LRTI case definitions to be used in pivotal clinical trials 
scheduled to begin shortly thereafter. The results pertaining to this analysis (if 
performed) will be purely descriptive, with no adjustment of type I error, and will be 
reported in an interim statistical report. No CSR will be prepared. 
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12. 
ADMINISTRATIVE MATTERS 
To comply with ICH GCP administrative obligations relating to data collection, 
monitoring, archiving data, audits, confidentiality, ownership, public disclosure 
requirements and publications must be met. 
12.1. 
Electronic Case Report Form instructions   
A validated GSK defined electronic data collection tool will be used as the method for 
data collection. 
In all cases, subject initials will not be collected nor transmitted to GSK. Subject data 
necessary for analysis and reporting will be entered/transmitted into a validated database 
or data system. Clinical data management will be performed in accordance with 
applicable GSK standards and data cleaning procedures. 
While completed eCRFs are reviewed by a GSK Biologicals’ Site Monitor at the study 
site, omissions or inconsistencies detected by subsequent eCRF review may necessitate 
clarification or correction of omissions or inconsistencies with documentation and 
approval by the investigator or appropriately qualified designee. In all cases, the 
investigator remains accountable for the study data.  
12.2. 
Study monitoring by GSK Biologicals 
GSK will monitor the study to verify that, amongst other items, the:  
• 
Data are authentic, accurate, and complete. 
• 
Safety and rights of subjects are being protected. 
• 
Study is conducted in accordance with the currently approved protocol, any other 
study agreements, GCP and all applicable regulatory requirements.  
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents. 
The investigator must ensure provision of reasonable time, space and qualified personnel 
for monitoring visits. 
Direct access to all study-site related and source data is mandatory for the purpose of 
monitoring review. The monitor will perform an eCRF review and a Source Document 
Verification (SDV). By SDV we understand verifying eCRF entries by comparing them 
with the source data that will be made available by the investigator for this purpose.  
The Source Documentation Agreement Form describes the source data for the different 
data in the eCRF. This document should be completed and signed by the site monitor and 
investigator and should be filed in the investigator’s study file. Any data item for which 
the eCRF will serve as the source must be identified, agreed and documented in the 
source documentation agreement form. 
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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. 
12.3. 
Study and site closure   
GSK or its designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of GSK, provided there is sufficient notice given 
to account for patient’s safe exit from study participation. Study sites regular closure will 
be upon study completion. A study site is considered closed when all required 
data/documents and study supplies have been collected and a study-site closure visit has 
been performed.  
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to: 
• 
Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines 
• 
Inadequate recruitment of subjects by the investigator 
• 
Discontinuation of further study treatment development 
12.4. 
Record retention 
Following closure of the study, the investigator must maintain all site study records 
(except for those required by local regulations to be maintained elsewhere) in a safe and 
secure location. The records must be easily accessible, when needed (e.g., audit or 
inspection), and must be available for review in conjunction with assessment of the 
facility, supporting systems, and staff. Where permitted by applicable laws/regulations or 
institutional policy, some or all of these records can be maintained in a validated format 
other than hard copy (e.g., microfiche, scanned, electronic); however, caution needs to be 
exercised before such action is taken. The investigator must ensure that all reproductions 
are legible and are a true and accurate copy of the original and meet accessibility and 
retrieval standards, including re-generating a hard copy, if required. Furthermore, the 
investigator must ensure that an acceptable back-up of the reproductions exists and that 
there is an acceptable quality control procedure in place for making these reproductions. 
GSK will inform the investigator/institution of the time period for retaining these records 
to comply with all applicable regulatory requirements. The minimum retention time will 
meet the strictest standard applicable to a particular site, as dictated by ICH GCP any 
institutional requirements or applicable laws or regulations, or GSK standards/procedures 
otherwise, the minimum retention period will default to 25 years after completion of the 
study report. 
The investigator/institution must notify GSK of any changes in the archival 
arrangements, including, but not limited to, archival at an off-site facility and transfer of 
ownership of the records in the event the investigator leaves the site.  
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12.5. 
Quality assurance 
To ensure compliance with GCP and all applicable regulatory requirements, GSK may 
conduct a quality assurance audit. Regulatory agencies may also conduct a regulatory 
inspection of this study. Such audits/inspections can occur at any time during or after 
completion of the study. If an audit or inspection occurs, the investigator and institution 
agree to allow the auditor/inspector direct access to all relevant documents and to allocate 
his/her time and the time of his/her staff to the auditor/inspector to discuss findings and 
any relevant issues. 
12.6. 
Posting of information on publicly available registers and 
publication policy 
GSK assures that the key design elements of this protocol will be posted on the GSK 
website and in publicly accessible database(s) such as clinicaltrials.gov, in compliance 
with the current regulations. 
GSK also assures that results of this study will be posted on the GSK website and in 
publicly accessible regulatory registry(ies) within the required time-frame, in compliance 
with the current regulations. 
Studies that do not evaluate vaccines/products are progressed for publication in the 
scientific literature when the results provide important scientific or medical knowledge or 
are relevant for patient care, and will be considered for disclosure on the GSK website 
and in publicly accessible regulatory registry(ies). 
12.7. 
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. 
12.8. 
Data Sharing 
Under the framework of the SHARE initiative, results of GSK studies may be combined 
with non- GSK studies, to investigate further about the study product(s) and other 
product(s), and /or the disease/condition under investigation and related diseases and 
conditions. 
13. 
COUNTRY SPECIFIC REQUIREMENTS 
Not applicable. 
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14. 
REFERENCES (AMENDED 29-MAY-2020) 
Barbas CF, Crowe JE, Cababa D, et al. Human monoclonal Fab fragments derived from a 
combinatorial library bind to respiratory syncytial virus F glycoprotein and neutralize 
infectivity. Proc Natl Acad Sci U S A. 1992;89(21):10164-8. 
Bates JT, Keefer CJ, Slaughter JC, et al. Escape from neutralization by the respiratory 
syncytial virus-specific neutralizing monoclonal antibody palivizumab is driven by 
changes in on-rate of binding to the fusion protein. Virology. 2014; 454-455:139-144. 
Bauwens J, Bonhoeffer J, Chen RT, editors. Harmonising Immunisation Safety 
Assessment in Pregnancy. Vaccine. 2016. 34 (49): 5991 – 6110. 
Bonhoeffer J, Kochhar S, Hirschfeld S, et al. Global alignment of immunization safety 
assessment in pregnancy - The GAIA project. Vaccine. 2016;34(49):5993-5997. doi: 
10.1016/j.vaccine.2016.07.006.  
Boyce TG, Mellen BG, Mitchel EF Jr et al. Rates of hospitalization for respiratory 
syncytial virus infection among children in medicaid. J. Pediatr. 2000; 137: 865-70. 
Centers for Disease Control and Prevention (CDC). Updated recommendations for use of 
tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine (Tdap) in 
pregnant women. Advisory Committee on Immunization Practices (ACIP) - 2012.  
MMWR. 2013a ; 62 (7) :131 -135. 
Centers for Disease Control and Prevention (CDC). Influenza Vaccination Coverage 
Among Pregnant Women — United States, 2012–13 Influenza Season. MMWR.  2013b; 
62 (38): 787–792. 
Deshpande SA and Northern V. The clinical and health economic burden of respiratory 
syncytial virus disease among children under 2 years of age in a defined geographical 
area. Arch. Dis. Child. 2003; 88: 1065-9. 
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. 
Holman RC, Curns AT, Cheek JE et al. Respiratory syncytial virus hospitalizations 
among American Indian and Alaska Native infants and the general United States infant 
population. Pediatrics. 2004; 114: e437-44. 
Iwane MK, Edwards KM, Szilagyi PG et al. Population-based surveillance for 
hospitalizations associated with respiratory syncytial virus, influenza virus, and 
parainfluenza viruses among young children. Pediatrics. 2004; 113: 1758-64. 
Jones CE, Munoz FM, Kochhar S et al. Guidance for the collection of case report form 
variables to assess safety in clinical trials of vaccines in pregnancy. Vaccine. 2016; 
34(49):6007-6014. 
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Kochhar S, Bauwens J, Bonhoeffer J, editors. Harmonising Immunization Safety 
Assessment in Pregnancy – Part II. Vaccine. 2017. 35 (48): 6469-6582. 
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.  
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. 
Vicente D, Montes M, Cilla G et al. Hospitalization for respiratory syncytial virus in the 
paediatric population in Spain. Epidemiol. Infect. 2003; 131: 867-72. 
World Health Organization (WHO). WHO recommendations on antenatal care for a 
positive pregnancy experience. Published in 2016. 
http://www.who.int/reproductivehealth/publications/maternal_perinatal_health/anc-
positive-pregnancy-experience/en. Last accessed on 09 February 2017. 
World Health Organization [WHO]. Global Surveillance for COVID-19 caused by 
human infection with COVID-19 virus: Interim Guidance. March 2020. Available at: 
https://apps.who.int/iris/rest/bitstreams/1272502/retrieve.  Accessed 8 May 2020. 
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APPENDIX A 
LABORATORY ASSAYS 
Assay descriptions could be subjects to change, due to assay re-development and/or 
qualification. 
Neutralization assay 
The serum neutralization assay is a functional assay that measures the ability of serum 
antibodies to neutralize RSV entry and replication in a host cell line. 
Virus neutralization is performed by incubating a fixed amount of RSV-A strain (Long, 
ATCC No. VR-26) or RSV-B strain (18537, ATCC No. VR-1580) with serial dilutions of 
the test serum. The serum-virus mixture is then transferred onto a monolayer of Vero 
cells (African Green Monkey, kidney, Cercopitheus aethiops, ATCC CCL-81) and 
incubated for three days to allow infection of the Vero cells by non-neutralized virus and 
the formation of plaques in the cell monolayer. Following a fixation step, RSV-infected 
cells are detected using a primary antibody directed against RSV (anti-RSV IgG) and a 
secondary antibody conjugated to horse-radish peroxidase (HRP), allowing the 
visualization of plaques by immunofluorescence after coloration with TrueBlueTM 
peroxidase substrate. Viral plaques are counted using an automated microscope coupled 
to an image analyzer (Scanlab system with Axiovision software). For each serum 
dilution, a ratio, expressed as a percentage, is calculated between the number of plaques 
at that dilution and the number of plaques in the virus control wells (no serum added). 
The serum neutralizing antibody titer is expressed in ED60 (Estimated Dilution 60) and 
corresponds to the inverse of the interpolated serum dilution that yields a 60% reduction 
in the number of plaques compared to the virus control wells, as described by others 
[Barbas, 1992; Bates, 2014]. 
PCR 
• 
Quantitative RT-PCR able to discriminate RSV-A and RSV-B subtypes: 
Briefly, RSV A and RSV B RNAs extracted from the nasal swabs are detected in a 
duplex PCR format using specific amplification primers and fluorescent probes designed 
in the RSV N gene, encoding the RSV nucleocapsid protein. The process involves 
nucleic acids extraction, conversion of RNA to complementary deoxyribonucleic acid by 
reverse transcription and detection by real- time PCR reaction using a calibration curve 
(absolute quantitation). The RSV viral load is reported as copies of RSV RNA per mL of 
sample. 
• 
Qualitative multiplex RT-PCR for detection of a panel of viruses. 
A qualitative RT-PCR multiplex assay is used for the detection and identification of 
multiple respiratory virus nucleic acids in nasal swabs from individuals suspected of 
respiratory tract infections. The following virus types and subtypes can be identified in 
the assay: 
• 
Influenza A virus (Flu A) 
• 
Influenza B virus (Flu B) 
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• 
Human Influenza A virus subtype H1 (Flu A-H1) 
• 
Human Influenza A virus subtype H3 (Flu A-H3) 
• 
Human Influenza A virus subtype H1pdm09 (Flu A-H1pdm09) 
• 
Human respiratory syncytial virus A (RSV A) 
• 
Human respiratory syncytial virus B (RSV B) 
• 
Human adenovirus (AdV) 
• 
Human metapneumovirus (MPV) 
• 
Human enterovirus (HEV) 
• 
Human parainfluenza virus 1 (PIV1) 
• 
Human parainfluenza virus 2 (PIV2) 
• 
Human parainfluenza virus 3 (PIV3) 
• 
Human parainfluenza virus 4 (PIV4) 
• 
Human bocavirus 1/2/3/4 (HBoV) 
• 
Human rhinovirus A/B/C (HRV) 
• 
Human coronavirus 229E (229E) 
• 
Human coronavirus NL63 (NL63) 
• 
Human coronavirus OC43 (OC43) 
Following total nucleic acids extraction, viruses are detected by multiplex real-time RT-
PCR assays targeting the above mentioned viruses. A comparative analysis of the 
fluorescence intensities of each target is performed to detect the viruses present in the 
sample. 
APPENDIX B 
CLINICAL LABORATORIES 
Table 18 
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 
GSK Vaccines GmbH 
Clinical Laboratory Sciences, 
Marburg, Germany 
Emil-von-Behring-Str. 76 
35041 Marburg 
Germany 
Table 19 
Outsourced laboratories    
Laboratory 
Address 
DDL Diagnostic Laboratory B.V. 
Headquarters 
Visseringlaan, 25 
2288 ER Rijswijk - NL 
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APPENDIX C 
GAIA GESTATIONAL AGE ASSESSMENT FORM 
This gestational age (GA) assessment tool is based on the maternal immunization 
guideline matrix prepared by Jones, 2016 (March GAIA Meeting Washington, DC, 29 
March 2016). 
LEVELS OF CERTAINTY OF GESTATIONAL AGE ASSESSMENT 
Level 
Description 
Level 1 
Highest level of 
certainty 
• 
Certain LMP or IUI date or ET WITH confirmatory 1st trimester U/S, 
or 
• 
1st trimester U/S 
Level 2A 
• 
Certain LMP WITH 2nd trimester U/S*, 
or 
• 
Certain LMP WITH 1st trimester physical examination** 
Level 2B 
• 
Uncertain LMP WITH 2nd trimester U/S 
Level 3A 
• 
Certain LMP WITH 3rd trimester U/S***,  
or 
• 
Certain LMP WITH confirmatory 2nd trimester FH, 
or 
• 
Certain LMP WITH birth weight, 
or 
• 
Uncertain LMP WITH 1st trimester physical examination 
Level 3B 
Lowest level of 
certainty 
• 
Uncertain LMP WITH FH, 
or 
• 
Uncertain LMP WITH neonatal physical assessment (New Ballard 
score), 
or 
• 
Uncertain LMP WITH birth weight 
grey highlights: applicable for enrollment in this study.  
1st trimester U/S: ≤136/7 weeks, 2nd trimester U/S: 140/7 to 276/7 weeks, 3rd trimester U/S: ≥280/7 weeks. 
GA: gestational age; U/S: ultrasound examination; LMP: last menstrual period; IUI: intrauterine insemination; ET: 
embryo transfer, FH: fundal height;  
* If LMP and U/S do not correlate, default to U/S GA assessment 
** For singleton pregnancies only. Unreliable if obesity, or uterine anomalies. 
*** Depending on gestational age at Screening Visit/ Visit 1 and depending on the local standard of care, this will be 
applicable for inclusion in the study. 
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METHODS OF GESTATIONAL AGE ASSESSMENT 
Adapted from [ACOG, 2014]: The American College of Obstetricians and Gynecologists 
(ACOG) Committee on Obstetric Practice, American Institute of Ultrasound in Medicine 
and Society for Maternal-Fetal. Committee Opinions: Method for estimating Due Date. 
Number 611, October 2014 (accessed on-line on 13/Oct/2014 at: 
http://www.acog.org/Resources-And-Publications/Committee-Opinions/Committee-on-
Obstetric-Practice/Method-for-Estimating-Due-Date). 
Gestational age range 
Method of measurement 
Discrepancy between U/S dating and LMP 
dating 
1st trimester      ≤136/7 weeks 
≤86/7 weeks 
90/7 to 136/7 weeks 
CRL 
> 5 days 
> 7 days 
2nd trimester      140/7 to 276/7 weeks 
140/7 to 156/7 weeks 
BPD, HC, AC, FL 
> 7 days 
160/7 to 216/7 weeks 
> 10 days 
220/7 to 276/7 weeks 
> 14 days 
U/S: ultrasound examination; LMP: last menstrual period; CRL: crown-rump length; BPD: biparietal diameter; HC: head 
circumference; AC: abdominal circumference; FL: femur length 
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APPENDIX D 
DEFINITIONS OF MATERNAL, FETAL AND 
NEONATAL EVENTS OF INTEREST AS PER GAIA 
The articles explaining the events of interest in detail and all corresponding information 
can be found in the following issues of Vaccine:  
Bauwens J, Bonhoeffer J, Chen RT, editors. Harmonising Immunisation Safety 
Assessment in Pregnancy. Vaccine. 2016. 34 (49): 5991 – 6110. 
Kochhar S, Bauwens J, Bonhoeffer J, editors. Harmonising Immunization Safety 
Assessment in Pregnancy – Part II. Vaccine. 2017. 35 (48): 6469-6582. 
References specific to each event of interest are given at the end of the relevant Table. 
Definitions and Levels of Diagnostic Certainty are presented in the following Tables. 
Pregnancy Outcomes   
Stillbirth 
Table 20 
Maternal Events of Interest 
Maternal Death 
Table 21 
Hypertensive Disorders of Pregnancy 
Table 22 
Antenatal bleeding 
Table 23 
Postpartum hemorrhage 
Table 24 
Fetal Growth restriction 
Table 25 
Dysfunctional Labor 
Table 26 
Gestational Diabetes Mellitus 
Table 27 
Non-reassuring fetal status 
Table 28 
Pathways to Preterm Birth 
Table 29 
Standard definitions for events of interest not defined as such in GAIA 
(Chorioamnionitis, Oligohydramnios, Polyhydramnios, Intrahepatic Cholestasis of 
Pregnancy (ICP), Acute Fatty Liver of Pregnancy, Maternal Sepsis) 
 
Table 30 
Neonatal Events of Interest 
Small for Gestational Age 
Table 31 
Low Birth Weight 
Table 32 
Neonatal encephalopathy 
Table 33 
Congenital Microcephaly 
Table 34 
Congenital Anomalies 
Table 35 
Neonatal Death 
Table 36 
Neonatal Infections 
Table 37 
Respiratory Distress in the Neonate 
Table 38 
Preterm Birth 
Table 39 
Failure to thrive 
Table 40 
Standard definitions for events of interest not defined as such in GAIA (large for 
gestational age, macrosomia) 
Table 41 
 
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Table 20 
Fetal death / Stillbirth 
Fetal death occurring before birth after 20 to 28 weeks of gestation (variation due to 
country definitions). Descriptions are provided for reference in selecting the appropriate 
subcategory (antepartum or intrapartum).  GAIA levels of diagnostic certainty will not be 
assessed in this protocol. 
Antepartum Stillbirth (Fetal death occurs prior to the evidence of labor.) 
Level 
Description 
1 
Delivery of an infant with no of signs of life at birth (No spontaneous movements, no umbilical cord pulse, 
no heartbeat, no respirations, Apgar score of 0 at 1 and 5 min) determined by physical examination after 
delivery (with or without electronic monitoring of heart rate, respiratory rate, and pulse oximetry).  
AND  
Prenatal ultrasound examination documenting lack of fetal cardiac activity or movement before the onset 
of labor.  
OR 
Auscultation for fetal heart tones (using electronic devices or non-electronic devices) documenting lack of 
fetal heartbeat.  
AND 
Maternal report of lack of fetal movement for 24 h or more.  
OR 
Maternal physical examination confirming lack of fetal movement.  
OR 
Radiology findings consistent with intrauterine fetal death.  
AND 
Attended delivery followed by fetal physical examination afterbirth consistent with antepartum death, by 
obstetrician, neonatologist, pediatrician, maternal-fetal medicine specialist, or pathologist. In the setting 
where access to a specialist is not feasible, diagnosis by a health care provider trained or experienced to 
make the diagnosis is acceptable (e.g. general practice physician, mid-wife, nurse practitioner, a 
physician’s assistant or other qualified trained practitioner).  
OR 
Fetal/placental pathology report consistent with antepartum death.  
AND 
•Gestational age within pre-defined range for selected stillbirth definition as assessed by maternal and/or 
fetal parameters (Level1 or 2 in GA assessment algorithm). 
2 
Delivery of an infant with no of signs of life at birth (No spontaneous movements, no umbilical cord pulse, 
no heartbeat, no respirations, Apgar score of 0 at 1 and 5 min) determined physical examination after 
delivery. AND 
Maternal report of lack of fetal movement for 24 h or more. 
 OR 
Maternal physical examination confirming lack of fetal movement.  
OR 
Auscultation for fetal heart tones (using electronic or non-electronic devices) documenting lack of fetal 
heartbeat.  
AND 
Attended delivery followed by physical examination after birth consistent with antepartum death, by 
specialist or qualified trained practitioner appropriate to the health care setting.  
OR 
Fetal/placental pathology report consistent with antepartum death.  
AND 
•Gestational age within pre-defined range for selected stillbirth definition as assessed by maternal and/or 
fetal parameters (Level1–2 in GA assessment algorithm). 
 
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Antepartum Stillbirth (Fetal death occurs prior to the evidence of labor.) (continued) 
Level 
Description 
3 
Delivery of an infant reported to have no of signs of life at birth(No spontaneous movements, no umbilical 
cord pulse, no heart-beat, no cry or spontaneous respirations, no chest movement, and whole body 
cyanosis). AND 
Maternal report of lack of fetal movement for 24 h or more prior to delivery.  
OR 
Report of auscultation for fetal heart tones (using electronic or non-electronic devices) documenting lack 
of fetal heartbeat.  
AND 
Non-attended delivery followed by physical examination of the fetus after birth consistent with antepartum 
death by a healthcare professional appropriate to the level of standard of care in the health care setting.  
OR 
Verbal history by a trained health care provider, non-medical witness or the mother of a fetus born with no 
signs of life or unresponsive to resuscitation efforts immediately after birth and with physical features 
consistent with antepartum death.  
AND 
•Gestational age within pre-defined range for selected stillbirth definition as assessed by maternal and/or 
fetal parameters (Level2–3 in GA assessment algorithm). 
4 
Report of stillbirth but fetus is not available for physical examination after birth (no objective assessment 
can be made) 
•Maternal information insufficient to assess gestational age 
Intrapartum stillbirth (Fetal death occurs during labor and before delivery) 
Level 
Description 
1 
Delivery of an infant with no of signs of life at birth, including: No spontaneous movements, no umbilical 
cord pulse, no heartbeat, no respirations, and Apgar score of 0 at 1 and 5 min 
Determination of the absence of signs of life is made by physical examination after delivery, with or 
without electronic monitoring of heart rate, respiratory rate, and pulse oximetry.  
AND 
Evidence of live fetus prior to onset of labor (documentation of fetal movement and of fetal heart tones by 
ultrasound prior to onset of labor) (Note: in the absence of evidence of a live fetus prior to the onset of 
labor, the fetal death should be reported as a stillbirth or an antepartum stillbirth). 
AND 
Attended delivery followed by physical examination afterbirth consistent with intrapartum death by 
obstetrician, neonatologist, pediatrician, maternal-fetal medicine specialist, pathologist. In the setting 
where access to a specialist is not feasible, diagnosis by a health care provider trained or experienced to 
make the diagnosis is acceptable (e.g. general practice physician, midwife, or other qualified trained 
practitioner). 
AND 
Gestational age within pre-defined range for selected stillbirth definition as assessed by maternal and/or 
fetal-neonatal parameters (Level 1 in GA assessment algorithm) 
 
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Intrapartum stillbirth (Fetal death occurs during labor and before delivery) (continued) 
Level 
Description 
2 
Delivery of an infant with no of signs of life at birth, including: No spontaneous movements, no umbilical 
cord pulse, no heartbeat, no respirations, and Apgar score of 0 at 1 and 5 min. 
Determination of the absence of signs of life is made by physical examination after delivery, with or 
without electronic monitoring of heart rate, respiratory rate, and pulse oximetry OR documentation of lack 
of response to resuscitation efforts.  
AND 
Evidence of live fetus prior to onset of labor (maternal report of fetal movement prior to onset of labor and 
documentation of fetal heart tones by auscultation or hand held Doppler) (Note: in the absence of 
evidence of a live fetus prior to the onset of labor, the fetal death should be reported as a stillbirth or an 
antepartum stillbirth).  
AND 
Attended delivery followed by physical examination after birth consistent with intrapartum death by a 
health care professional appropriate to the level of standard of care in the health care setting.  
AND 
Gestational age within pre-defined range for selected stillbirth definition as assessed by maternal and/or 
fetal parameters (Level1–2 in GA assessment algorithm). 
3 
Delivery of an infant reported to have no of signs of life at birth, including: No spontaneous movements, 
no umbilical cord pulse, no heartbeat, no cry, no spontaneous respirations or chest movement, and whole 
body cyanosis.  
AND 
Evidence of live fetus prior to onset of labor (maternal report of fetal movement prior to onset of labor OR 
auscultation of fetal heart tones) (Note: in the absence of evidence of a live fetus prior to the onset of 
labor, the fetal death should be reported as a stillbirth or an antepartum stillbirth). 
AND 
(Non-attended delivery followed by physical examination of the fetus after birth consistent with 
intrapartum death by a healthcare professional appropriate to the level of standard of care in the health 
care setting OR  
Verbal history by a trained health care provider, non-medical witness or the mother of a fetus born with no 
signs of life or unresponsive to resuscitation efforts immediately after birth.)  
AND 
Gestational age within pre-defined range for selected stillbirth definition as assessed by maternal and/or 
fetal parameters (Level2–3 in GA assessment algorithm). 
4 
Report of stillbirth but fetus is not available for physical examination after birth (no objective assessment 
can be made). 
Maternal information insufficient to assess gestational age. 
Reference: DaSilva FT, Gonik B, McMillan M, et al. Stillbirth: Case definition and guidelines for data collection, 
analysis, and presentation of maternal immunization safety data. Vaccine. 2016; 34(49):6057-6068. 
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Table 21 
Maternal Death 
The death of a woman while pregnant or within 42 days of termination of pregnancy, 
irrespective of the duration and site of the pregnancy, from any cause related to or 
aggravated by the pregnancy or its management but not from accidental or incidental 
causes. (As ICD-10 terminology). 
In the context of immunization: “Death of a woman during pregnancy, childbirth and the 
puerperium that is closely related temporally to an immunization event of the mother 
which is likely the single or contributory cause 
Levels of Diagnostic Certainty 
(Highest level (1) to lowest level of certainty) 
Level 
Description 
1 
Diagnosis of pregnancy established by any of the following documented criteria: 
a. Ultrasound examination 
b. Fetal heart tones 
c. Positive serum or urine human chorionic gonadotropin pregnancy test 
d. Delivery of a neonate or other products of conception (abortus, stillborn)  
AND 
Death of the mother while pregnant or within 42 days of termination of pregnancy, irrespective of the 
duration and site of the pregnancy AND 
Documentation of Cause of death as: 
a. Direct: abortive outcome, hypertensive disorder, obstetric hemorrhage, pregnancy related infection, 
other obstetric complications, unanticipated complications  
b. Indirect: non obstetric complications  
c. Death during pregnancy, childbirth and the puerperium: other or coincidental 
2 
Diagnosis of pregnancy established by any of the following criteria in the absence of Level 1 criteria: 
a. LMP date 
b. Serial Symphysio Fundal Height examinations 
AND 
Death of the mother while pregnant or within 42 days of termination of pregnancy, irrespective of the 
duration and site of the pregnancy And  
Documentation of Cause of death as: 
a. Direct: abortive outcome, hypertensive disorder, obstetric hemorrhage, pregnancy related infection, 
other obstetric complications, unanticipated complications 
b. Indirect: non-obstetric complications  
c. Death during pregnancy, childbirth and the puerperium: other or coincidental 
d. Unspecified: unknown or undetermined 
3 
Absence of Level 1 or 2 criteria for establishing diagnosis of pregnancy and: 
a. Unsure LMP 
b. No clinical examination documented  
AND 
Death of the mother temporal to pregnancy, childbirth or the postpartum period when exact timing of 
death is unknown 
AND 
Documentation of cause of death as: 
a. Direct: abortive outcome, hypertensive disorder, obstetric hemorrhage, pregnancy related infection, 
other obstetric com-plications, unanticipated complications 
b. Indirect: non-obstetric complications 
c. Death during pregnancy, childbirth and the puerperium: other or coincidental 
d. Unspecified: unknown or undetermined. 
Reference: Patwardhan M, Eckert LO, Spiegel H, et al. Maternal death: Case definition and guidelines for data 
collection, analysis, and presentation of immunization safety data. Vaccine. 2016;34(49):6077-6083. 
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Table 22 
Hypertensive disorders of pregnancy (Gestational hypertension, 
Pre-eclampsia, Pre-eclampsia with severe features including 
eclampsia) 
Levels of Diagnostic Certainty (Highest level (1) to lowest level of certainty) 
Gestational Hypertension  
Level 
Description 
All 
Clinical syndrome characterized by pregnancy ≥20 weeks 
AND 
New onset hypertension (systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg) 
sustained on two measurements over a minimum of 1 h 
WITHOUT severe features (see preeclampsia with severe features category) and WITHOUT proteinuria 
1 
No proteinuria (as defined by 24 h urine collection < 300 mg, spot protein:creatinine ratio <0.3) 
2 
No proteinuria (as defined by urine dipstick negative or trace)  
In Ev 
Blood pressure cannot be measured OR 
No proteinuria evaluation is available 
Preeclampsia has conventionally been defined as the development of gestational hypertension and proteinuria 
after 20 weeks gestation.  Proteinuria can be quantified by: - 24 h urine collection, - a spot protein:creatinine ratio, 
or - with urinary dipstick. Proteinuria of ≥300 mg in a 24 h urine specimen (the gold standard for measurement of 
proteinuria), or ≥0.30 on a spot protein:creatinine ratio, or ≥1+ on a dipstick meets the criteria for preeclampsia. 
Level 
Description 
All 
Clinical syndrome characterized by pregnancy ≥20 weeks  
AND  
New onset hypertension (systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg) 
sustained on two measurements over a minimum of 1 h  
AND  
New onset proteinuria  
1 
Proteinuria diagnosed with ≥300 mg of protein on 24 h urine collection OR ≥0.3 on spot protein:creatinine 
ratio  
2 
Proteinuria diagnosed with ≥1+ protein on urine dipstick 
In Ev. 
Blood pressure cannot be measured  
OR  
no proteinuria evaluation is available (note diagnosis of preeclampsia with severe features does not 
require proteinuria, see definition below) 
In Ev = Insufficient Evidence 
 
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Hypertensive Disorders of Pregnancy Continued 
Preeclampsia with severe features  NOTE :can be diagnosed in the presence or absence of proteinuria. 
•Vascular: 
◦ Severely elevated blood pressures, with systolic blood pressure≥160 mmHg and/or diastolic blood pressure ≥110 
mmHg, which is confirmed after only minutes (to facilitate timely anti-hypertensive treatment) 
•Neurologic: 
◦ Development of a severe headache (which can be diffuse, frontal, temporal or occipital) that generally does not 
improve with over the counter pain medications (such as acetaminophen/paracetamol) 
◦ Eclampsia 
◦ Development of visual changes (including photopsia, scotomata,cortical blindness) 
•Hematologic: 
◦ New onset thrombocytopenia, with platelet count <100,000/L 
•Gastrointestinal: 
◦ New onset of nausea, vomiting, epigastric pain 
◦ Transaminitis (AST and ALT elevated to twice the upper limit of normal) 
◦ Liver capsular hemorrhage or liver rupture 
•Renal: 
◦ Worsening renal function, as evidenced by serum creatinine level greater than 1.1 mg/dL or a doubling of the 
serum creatinine(absent other renal disease) 
◦ Oliguria (urine output <500 mL/24 h) 
•Respiratory: 
◦ Pulmonary edema (confirmed on clinical exam or imaging) 
Level 
Description 
All 
Clinical syndrome characterized by pregnancy ≥20 weeks  
AND  
New onset hypertension (systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg) 
sustained on two measurements over a minimum of 1 h  
AND  
At least one of the criteria for severe disease: 
1 
At least one of the following:  
• 
Systolic blood pressure ≥160 mmHg and/or diastolic blood pressure ≥110mmHg, which is 
confirmed after only minutes OR  
• 
Development of severe, persistent headache OR 
• 
Development of visual changes OR  
• 
Eclampsia* OR  
• 
New onset thrombocytopenia (platelets <100,000/L) OR 
• 
New onset unremitting epigastric pain OR 
• 
AST and ALT elevated to twice upper limit of normal OR 
• 
Evidence of liver capsular hematoma or liver rupture (diagnosed on clinical exam or with imaging) 
OR 
• 
Worsening renal function, as evidenced by serum creatinine level greater than 1.1 mg/dL or a 
doubling of the serum creatinine (absent other renal disease) or oliguria (<500 cc/24 h) OR 
• 
Pulmonary edema (confirmed on imaging with chest X-ray, or on clinical exam) 
2 
New onset nausea and vomiting  
In Ev 
Blood pressure cannot be measured 
◦* ECLAMPSIA, or new-onset grand mal seizures in a patient with pre-eclampsia, without other provoking factors 
(such as evidence of cerebral malaria or preexisting seizure disorder). Seizures are often preceded by 
headaches, visual changes or altered mental status:  
In Ev = Insufficient Evidence 
Reference: Rouse CE, Eckert LO, Wylie BJ, et al. Hypertensive disorders of pregnancy: Case definitions &amp; 
guidelines for data collection, analysis, and presentation of immunization safety data. Vaccine. 2016;34(49):6069-
6076 
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Table 23 
Antenatal Bleeding 
Antenatal bleeding is a clinical syndrome characterized by bleeding in the second or third 
trimester of pregnancy. Pathologic etiologies attributable to the pregnant state include 
placenta previa, vasa previa and intra-abdominal pregnancy (categories that are not 
applicable in this study, as women with these conditions are ineligible), and morbidly 
adherent placentation, placental abruption, cesarean scar pregnancy and uterine rupture. 
For both levels of diagnostic certainty for each etiology of antenatal bleeding: 
Bleeding is either documented vaginally or suspected to be occurring intrauterine, 
intraperitoneally, or (rarely) retroperitoneally, based on clinical signs and symptoms. 
In the case of ultrasound-based diagnosis, transvaginal ultrasound is more specific than 
transabdominal ultrasound, and transvaginal ultrasound is recommended where available. 
Levels of Diagnostic Certainty (Highest level (1) to lowest level of certainty) 
Morbidly adherent placenta 
Level 
Description 
1 
There are two definitions of equal specificity. 
1. 
Second- or third-trimester ultrasound or MRI evidence of placenta previa, 
AND  
One of the following ultrasound features:  
• 
Greyscale: loss of the retroplacental sonolucent zone, irregular retroplacental sonolucent zone, 
thinning or disruption of the hyperechoic serosa–bladder interface, presence of focal exophytic 
masses invading the urinary bladder, abnormal placental lacunae  
• 
Color Doppler: diffuse or focal lacunar flow, vascular lakes with turbulent flow (peak systolic velocity 
over 15 cm/s), hypervascularity of serosa–bladder interface, markedly dilated vessels over 
peripheral subplacental zone 
• 
3D Power Doppler: numerous coherent vessels involving the whole uterine serosa–bladder junction 
(basal view), hypervascularity (lateral view), inseparable cotyledonal and intervillous circulations, 
chaotic branching, detour vessels (lateral view) 
AND  
One of the risk factors: prior cesarean delivery, prior uterine surgery (including endometrial ablation or 
dilation and curettage) or cesarean scar pregnancy 
OR 
2. 
Morbidly adherent placentation found on histology in a hysterectomy or partial wedge resection 
specimen. 
2 
There are two definitions of equal specificity. 
1. 
Ultrasound evidence of placenta previa, 
AND  
hypervascularity at the site of the uteroplacental 
interface,, diagnosed at laparotomy. 
OR 
2. 
Difficulty with placental separation after delivery of the infant, at either a vaginal or cesarean delivery 
with resultant hemorrhage due to partial separation. 
 
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Antenatal Bleeding continued 
Placental abruption 
Level 
Description 
1 
There are two definitions of equal specificity. 
1. 
In the absence of placenta previa on ultrasound, vaginal bleeding in the second or third trimester, 
AND one of the following: 
Either uterine irritability or labor, 
Or  
clinical signs of hypovolemic shock or coagulopathy. 
OR 
2. 
Placental pathology with histologic findings of a chronic abruption. 
2 
There are two definitions of equal specificity. 
1. 
Vaginal bleeding in the second or third trimester, 
AND  
uterine irritability or labor, without clinical signs of hypovolemic shock or coagulopathy 
OR 
2. 
Vaginal bleeding in the second or third trimester, 
AND  
Clinical evidence of retroplacental clot or visually evident placental infarcts at the time of delivery. 
Cesarean Scar Pregnancy 
Level 
Description 
1 
There are two definitions of equal specificity. 
1. 
Transvaginal ultrasound with the following characteristics: empty uterine cavity,  
AND  
Empty cervical canal, without contact with the gestational sac, AND  
Presence of gestational sac, +/- fetal pole, +/- cardiac activity, in the anterior uterine segment adjacent to 
the cesarean scar, AND  
Absence or defect in myometrium between bladder and gestational sac,  
AND  
Gestational sac well perfused on Doppler ultrasound (to differentiate from an expulsing, avascular 
gestational sac). 
OR 
2. 
Hysterectomy specimen with evidence of pregnancy implanted into the cesarean scar. 
2 
There is no Level 2 definition for this event. 
Uterine Rupture 
Level 
Description 
1 
Complete uterine disruption at the time of laparotomy in the context of vaginal or intra-abdominal bleeding. 
2 
There is no Level 2 definition for this event. 
Reference: Prabhu M, Eckert LO, Belfort M et al. Antenatal bleeding: Case definition and guidelines for data collection, 
analysis, and presentation of immunization safety data. Vaccine. 2017; 35: 6529-6537. 
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Table 24 
Postpartum hemorrhage 
Genital tract bleeding after delivery (up to 42 days) of a foetus or infant that leads to an 
adverse clinical outcome, such as hypovolemia or anaemia e.g. exertional dyspnoea, 
postural presyncope, tiredness or reduced consciousness. At the furthest extreme 
uncorrected hypovolaemic shock can lead to organ-dysfunction and maternal death. 
ICD-10 definition: “heamorrhage after delivery of a foetus or infant” 
Levels of Diagnostic Certainty (Highest level (1) to lowest level of certainty) 
Level 
Description 
1 
Genital bleeding after delivery leading to severe maternal out-come (maternal death or maternal near 
miss) as defined by WHO1.  
2 
Genital bleeding after delivery with at least one of the following: measured abnormal bleeding (1000 ml or 
more), or any bleeding leading to hypotension or blood transfusion. 
3 
Genital bleeding after delivery estimated at 1000 ml or more 
Reference: Kerr R, Eckert LO, Winikoff B, et al. Postpartum haemorrhage: Case definition and guidelines for data 
collection, analysis, and presentation of immunization safety data. Vaccine. 2016;34(49):6102-6109. 
1 Can be found in Kerr (op cit), Table 1.  
Table 25 
Fetal growth restriction 
A fetus with a sonographic estimation of fetal weight below the tenth percentile for a 
given gestational age with increasing specificity for adverse perinatal outcomes below the 
third percentile. 
Levels of Diagnostic Certainty (Highest level (1) to lowest level of certainty) 
Level 
Description 
 
Fetal growth restriction is a sonographic finding characterized by: 
1a 
Level 1* evidence of pregnancy dating  
AND 
Estimated fetal weight below 3% using locally-accepted growth curve  
OR 
• 
Estimated fetal weight below 10% using locally-accepted growth curve  
AND 
• 
Absent or reversed end-diastolic flow of the umbilical artery Doppler  
OR 
• 
Oligohydramnios as defined as amniotic fluid index (AFI) < 8 cm or deepest vertical pocket (DVP) < 
2 cm in the presence of intact membranes without concern for fetal anomalies contributing to its 
etiology 
1b 
Level 1* evidence of pregnancy dating  
AND 
Estimated fetal weight below 10%ile using locally-accepted growth curve  
AND 
Lack of absent or reversed end-diastolic flow of the umbilical artery or oligohydramnios (as defined above, 
cfr. Level 1a) 
2a  
Level 2 evidence of pregnancy dating  
AND 
• 
Estimated fetal weight below 3% using locally-accepted growth curve  
OR 
• 
Estimated fetal below 10% using locally-accepted growth curve  
AND 
• 
Absent or reversed end-diastolic flow of the umbilical artery Doppler.  
OR 
• 
Oligohydramnios (as defined above, cfr. Level 1a). 
 
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Fetal Growth Restriction continued 
Level 
Description 
2b 
• 
Level 2 evidence of pregnancy dating  
AND 
Estimated fetal weight below 10%ile using locally-accepted growth curve  
AND 
No findings of absent or reversed end-diastolic flow of the umbilical artery or oligohydramnios (as defined 
above, cfr Level 1a).  
OR 
• 
Level 1* evidence of pregnancy dating  
AND 
Estimated fetal weight below 10% using locally-accepted growth curve with no findings of 
oligohydramnios (as defined abopve, cfr. Level 1a) with inability to assess umbilical artery Doppler. 
In Ev 
Absence of ultrasound for use in assessment of estimated fetal weight. 
*Level 1 evidence of pregnancy dating as defined by the Preterm Birth Working Group of the Brighton Collaboration. 
Level 1 pregnancy dating depends on a confirmatory ultrasound performed ≤13 6/7 weeks gestation 
In Ev = Insufficient Evidence 
Reference: Easter SR, Eckert LO, Boghossian N, et al. Fetal growth restriction: Case definition & guidelines for data 
collection, analysis, and presentation of immunization safety data. Vaccine. 2017; 35: 6546-6554.  
Table 26 
Dysfunctional labor 
This is defined as prolonged labor at or after 37 weeks and before 42 weeks of gestational 
age in singleton pregnancies. 
Levels of Diagnostic Certainty (Highest level (1) to lowest level of certainty) 
First stage of labor 
For both levels of diagnostic certainty the woman is in established labor defined by regular contractions and cervical 
dilation of at least 4cm. 
Level 
Description 
1 
Progress of less than 0.5 cm cervical dilation per hour, for at least 4 hours, in women in established labor 
(i.e. have regular contractions and cervical dilation of at least 4cm) and with confirmed ruptured 
membranes. 
2 
Progress of less than 0.5cm cervical dilation per hour in women, for at least 4 hours, with established 
labor, (i.e. that is, regular contractions and cervical dilation of at least 4cm) without certainty of ruptured 
membranes. 
Second stage of labor 
The definitions below are applicable in cases with or without regional analgesia. 
Level 
Description 
1 
Full dilation of the cervix  
AND 
onset of the active stage (active maternal effort (i.e. pushing) or visible baby)  
AND 
In nulliparous women:> 2h of pushing  
In multiparous women: > 1h of pushing 
OR 
Use of instrument delivery (forceps  vacuum/ventouse) for the indication of dystocia 
OR 
Caesarean delivery for the indication of dystocia. 
2 
Full dilation of the cervix in any phase of the second stage  
AND  
         no delivery within 3 hours of full dilation  
OR  
use of instrument for the indication of dystocia 
OR  
caesarean delivery for the indication of dystocia. 
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Reference: Boatin AA, Eckert LO, Boulvain M, et al. Dysfunctional labor: Case definition & guidelines for data 
collection, analysis, and presentation of immunization safety data. Vaccine. 2017; 35:6538-6545. 
Table 27 
Gestational diabetes mellitus (pregnancy induced hyperglycemia) 
Gestational diabetes mellitus (GDM) is a clinical syndrome characterized by the absence 
of pre-gestational diabetes diagnosis, defined by 
• 
Previous diagnosis of diabetes while not pregnant 
OR 
• 
First trimester hemoglobin A1c level of ≥ 6.5% (47.5 mmol/mol)  
OR 
• 
First trimester fasting blood glucose 126 mg/dL / ≥ 7mmol/L  
AND 
Identification of sustained hyperglycemia during pregnancy not due to other known 
causes (i.e. corticosteroids, beta-mimetics, etc.) 
Levels of Diagnostic Certainty (Highest level (1) to lowest level of certainty) 
Level 
Description 
1 
Absence of pre-gestational diabetes mellitus diagnosis in the first trimester as defined above with level 1-
2 certainty for gestational age using GAIA definition for gestational age (APPENDIX C)  
AND 
Diagnosis of gestational diabetes based on a positive internationally recognized oral glucose tolerance 
test (“major criteria” 1,2) using venous blood sample/samples 
2 
Absence of pre-gestational diabetes mellitus diagnosis in the first trimester as defined above with at least 
level 1-2 certainty for gestational age using GAIA definition for gestational age (APPENDIX C)   
AND 
Diagnosis of gestational diabetes based on positive internationally recognized oral glucose tolerance test 
(“major criteria” 1,2) using capillary blood sample/samples 
 
Gestational Diabetes Mellitus continued 
Level 
Description 
3 
Absence of pre-gestational diabetes mellitus diagnosis in the first trimester as defined above with at least 
level 3 certainty for gestational age using GAIA definition for gestational age  
AND 
Diagnosis of gestational diabetes based on positive internationallyrecognized oral glucose tolerance test 
(see below ‘‘major criteria”1,2)using venous blood or capillary blood sample/samples 
OR 
Diagnosis of gestational diabetes based on fasting plasma glucose of 5.1-6.9 mmol/l (92-125 mg/dL) 
using venous or capillary blood samples. 
In Ev 
Blood glucose cannot be measured  
OR 
Elevated postprandial blood glucose level without confirmatory 
fasting venous blood or capillary glucose level 
OR 
Use of Hemoglobin A1c alone for the diagnosis of GDM without a diagnostic oral glucose tolerance test 
(OGTT) or elevated fasting plasma glucose level.  
OR 
Clinical and laboratory findings such as glucosuria, fundal height greater than dates, obesity, prior history 
of GDM or family history for the diagnosis of gestational diabetes mellitus without a diagnostic test. 
In Ev = Insufficient Evidence 
Reference(s): Kachikis A, Eckert LO, Walker C, et al. Gestational diabetes mellitus: Case definition & guidelines for 
data collection, analysis, and presentation of immunization safety data. Vaccine. 2017; 35:6555-6562. 
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1  Major criteria (presented in Kachikis op cit) 
 
2 Further details regarding oral glucose tolerance tests presented in footnote 1 (Major Criteria); also presented in 
Kachikis (op cit) 
 
Table 28 
Non-reassuring fetal status 
Indicator of underlying event resulting in temporary or permanent oxygen deprivation to 
the fetus which may lead to fetal hypoxia and metabolic acidosis 
Levels of Diagnostic Certainty (Highest level (1) to lowest level of certainty) 
Level 
Description 
1 
Category III fetal heart rate tracings detected via continuous cardiotocography as defined by NICHD  
Absent baseline fetal heart rate variability AND any of the following: 
- recurrent late decelerations 
- recurrent variable deceleration 
- bradycardia (<110 bpm)  
OR 
Sinusoidal pattern  
AND 
Umbilical cord blood analysis consistent with metabolic acidosis (pH < 7.0 and Base deficit >12 mmol/L) 
2 
Category III fetal heart rate tracings detected via continuous cardiotocography as defined by NICHD  
Absent baseline fetal heart rate variability AND any of the following: 
- recurrent late decelerations 
- recurrent variable deceleration 
- bradycardia (<110 bpm) 
OR 
Sinusoidal pattern 
3 
Fetal heart pattern detected via intermittent auscultation suggestive of fetal hypoxia  
Baseline Fetal Heart rate (FHR) <110 bpm or >160 bpm 
Presence of repetitive or prolonged (>3 min) decelerations 
More than 5 contractions in a 10 min period 
Reference: Gravett C, Eckert LO, Gravett MG, et al. Non-reassuring fetal status: Case definition & guidelines for data 
collection, analysis, and presentation of immunization safety data. Vaccine. 2016;34(49):6084-6092. 
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Table 29 
Pathways to preterm birth 
Premature preterm rupture of membranes; Preterm labor; Insufficient cervix (not 
applicable to this study, as women with insufficient cervix are ineligible); Provider-
initiated preterm birth 
Preterm = Birth at less than 37 gestation-completed weeks (less than 259 days).  
Levels of Diagnostic Certainty (Highest level (1) to lowest level of certainty) 
Premature Preterm rupture of membranes 
Level 
Description 
All 
Patient is determined to be preterm as defined above.  
On presentation, patient is determined to not be in preterm labor, having ≤4 contractions per hour 
documented clinically or on tocodynometer, with <2 cm cervical dilation (greater than 4 contractions per 
hour would qualify the patient as having preterm labor)  
Fluid can be noted to be clear, blood-tinged, meconium-tinged (fetal stool), purulent-tinged (yellowish, 
suggesting infection) 
1 
Clinical history of rupture of membranes  
AND 
Visible leakage of fluid on vaginal speculum exam  
AND 
Visible arborization (ferning) on microscopy of amniotic fluid  
OR 
Ultrasound with oligohydramnios (AFI <5 or MVP <2)  
AND 
Documented membrane rupture by a diagnostic test (one of the below options): 
Positive intra-amniotic dye-injection method 
Positive result on amniotic fluid alpha-fetoprotein test kit  
Amniotic fluid pH measurement (nitrazine paper test) 
Amniotic fluid placental alpha macroglobulin-1 protein assay (PAMG-1) test (AmniSure test)  
Amniotic fluid insulin-like growth factor binding protein(IGFBP-1) test (Actim PROM test) 
2 
Clinical history of rupture of membranes  
AND 
Visible leakage of fluid on vaginal speculum examination  
AND 
Visible arborization (ferning) on microscopy of amniotic fluid  
OR 
Documented membrane rupture by a diagnostic test (one of those listed above)  
OR  
Ultrasound with oligohydramnios (AFI <5 or MVP <2) 
3 
Clinical history of rupture of membranes  
AND 
Visible leakage of presumed amniotic fluid; this may be on vaginal speculum examination (pooling in 
vagina), on inspection of the perineum (wet perineum due to leakage of fluid from the vagina), or fluid 
soaked cloth/clothes/sanitary pad. 
 
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Preterm labor 
Level 
Description 
All 
Patient is determined to be have delivered preterm (at less than 37 gestation-completed weeks (less than 
259 days)).  
1 
On presentation, >4 documented uterine contractions per hour as determined by a tocodynometer  
AND 
Documented change in length or dilation of cervix by physical examination or transvaginal ultrasound 
over a two hour period, with clinical criteria for documenting cervical change by exam including: 
a. Cervical dilation 2 cm or greater at the internal os by digital examination  
b. Cervical length of 1 cm or less by digital examination 
c. 50% or greater effacement by digital examination 
2 
Greater than 4 uterine contractions per hour as determined by a tocodynometer or clinical assessment  
AND 
Documented change in length or dilation of cervix by physical examination, with clinical criteria including:  
a. Cervical dilation 2 cm or greater at the internal os by digital examination 
b. Cervical length of 1 cm or less by digital examination 
c. 50% or greater effacement by digital examination 
3 
Greater than 4 documented uterine contractions per hour determined by clinical assessment  
AND 
 Documented change in cervical examination (change in dilation or effacement) over a two hour period 
Provider-initiated preterm birth 
Level 
Description 
All 
Patient is determined to be preterm (birth at less than 37 gestation-completed weeks (less than 259 
days).  
1 
Documentation in the healthcare record by a patient’s delivering provider that there were no signs or 
symptoms of the spontaneous onset of preterm labor  
AND 
Documentation in the healthcare record by a patient’s delivering provider that the patient needed to 
undergo induction of labor or cesarean delivery which led to the preterm delivery  
2 
From recall, delivering provider confirms that there was an absence of any signs or symptoms of the 
spontaneous onset of preterm labor  
AND 
Delivering provider reports from recall that he or she decided that the patient needed to undergo induction 
of labor or cesarean delivery 
3 
From recall, patient confirms that there was an absence of any signs or symptoms of the spontaneous 
onset of preterm labor  
AND 
Patient reports from recall that the healthcare provider indicated that she needed to undergo induction of 
labor or cesarean delivery 
Reference: Harrison MS, Eckert LO, Cutland C, et al. Pathways to preterm birth: Case definition and guidelines for 
data collection, analysis, and presentation of immunization safety data. Vaccine. 2016;34(49):6093-6101. 
 
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Table 30 
Standard Definitions for Maternal Events of interest not defined as 
events in GAIA   
Event of 
Interest 
Definition  
Chorioamnionitis 
Chorioamnionitis also known as intra-amniotic infection is an inflammation of the fetal 
membranes due to a bacterial infection. Clinical signs and symptoms of chorioamnionitis 
include the following: 
• 
Fever (an intrapartum temperature >100.4ºF or >37.8ºC)  
• 
Significant maternal tachycardia (>120 beats per minute [bpm])  
• 
Fetal tachycardia (>160-180 bpm)  
• 
Purulent or foul-smelling amniotic fluid or vaginal discharge  
• 
Uterine tenderness  
• 
Maternal leukocytosis (total blood leukocyte count >15,000-18,000 cells/μL)  
Of these criteria, intrapartum maternal fever appears to be the most frequent.  
When at least 2 of the aforementioned criteria are present, the risk of neonatal sepsis is 
increased. Each clinical sign and symptom of chorioamnionitis, however, is by itself of low 
predictive value 
Oligohydramnios 
Amniotic fluid index (AFI) < 8 cm or deepest vertical pocket (DVP) < 2 cm in the presence of 
intact membranes without concern for fetal anomalies contributing to its etiology 
Polyhydramnios 
Polyhydramnios is the presence of excess amniotic fluid in the uterus. By definition, 
polyhydramnios is diagnosed if the deepest vertical pool is more than 8 cm or amniotic fluid 
index (AFI) is more than 95th percentile for the corresponding gestational age 
Gestational liver 
disease 
(Intrahepatic 
Cholestasis of 
Pregnancy or 
ICP)1 
Intrahepatic cholestasis also called obstetric cholestasis should be suspected when pruritis 
develops during pregnancy in the absence of a rash.  Lab evidence of cholestasis includes 
elevated bile acids (Glyco and Taurochenodeoxycholic Acid )(> 10 umol/L).  Up to 60% of 
patients will have elevated transaminases and 20% of patients will have increased direct 
bilirubin levels. 
Jaundice may or may not be present. ICP typically is transient and resolves after delivery. 
Women that had ICP in previous pregnancy have higher risk to developing ICP in the following 
pregnancies or other hepatobiliary disorders in later life. ICP is associated with adverse fetal 
outcome like meconium-stained liquor, fetal asphyxia, spontaneous preterm delivery 
and  intrauterine death.  
Gestational liver 
disease (Acute 
Fatty Liver of 
Pregnancy)2 
Acute fatty liver of pregnancy (AFLP) is a rare, potentially fatal complication that occurs in the 
third trimester or early postpartum period. AFLP is characterized by microvesicular fatty 
infiltration of hepatocytes without any inflammation or necrosis. Most frequent signs and 
symptoms are the following: 
• 
Jaundice 
• 
Abdominal Pain (usually right upper quadrat, midepigastric or radiating to back) 
• 
Central nervous system (altered sensorium, confusion, disorientation, psychosis, 
restlessness, seizures or even coma) 
• 
Disseminated intravascular coagulation 
• 
Nausea and vomiting 
• 
Gastrointestinal bleeding 
• 
Acute renal failure 
• 
Oliguria 
• 
Tachycardia 
• 
Late onset pyrexia 
• 
Hypoglycemia 
• 
ALT<500 U/L 
• 
Hyperbilirubinemia, elevated ammonia, leukocytosis, hypofibrinogenemia 
Ultrasound examination and computed tomography may demonstrate fatty infiltration of the 
liver but are not sufficient for diagnosis 
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Event of 
Interest 
Definition  
Maternal Sepsis3 
Maternal sepsis is a life-threatening condition defined as organ dysfunction resulting from 
infection during pregnancy, child-birth, post-abortion, or post-partum period.  
Organ dysfunction can be identified as an acute change in total SOFA score ≥2 points 
consequent to the infection. 
The baseline SOFA score can be assumed to be zero in patients not known to have preexisting 
organ dysfunction. 
A SOFA score ≥2 reflects an overall mortality risk of approximately 10% in a general hospital 
population with suspected infection. Even patients presenting with modest dysfunction can 
deteriorate further, emphasizing the seriousness of this condition and the need for prompt and 
appropriate intervention, if not already being instituted. 
 
 
 
MAP = mean arterial pressure; qSOFA = quick SOFA; SOFA = Sequential [Sepsis-related] 
Organ Failure Assessment 
References: 
1 Geenes V et al . Intrahepatic cholestasis of pregnancy 
 
 
 
2 Can J Gastroenterol Vol 20 26 No 1 January 2006 
 
 
 
3  Bonet et al. Reproductive Health (2017) 14:67 
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Table 31 
Small for Gestational Age 
Weight below 10th percentile for gestational age as assessed against a validated global, 
regional or local standard. 
Levels of Diagnostic Certainty (1 highest level to 4 lowest level of certainty 
Level 
Description 
1 
• 
Weight below 10th percentile for gestational age 
AND 
• 
The following used in assessment of weight: 
o 
Newborn weighed within 24 hours of birth 
o 
Weight assessed using a calibrated electronic scale with 10 g resolution 
AND 
• 
The following for assessment of gestational age: 
o 
Certain LMP or IUI or embryo transfer date AND confirmatory ultrasound in first trimester  
OR 
o 
First trimester ultrasound 
2a 
• 
Weight below 10th percentile for gestational age  
AND 
• 
The following used in assessment of weight:  
o 
Newborn weighed within 24 hours of birth on any scale with a < 50 g resolution, tared to zero 
and calibrated  
AND 
• 
The following for assessment of gestational age: 
o 
Certain LMP with first or second trimester ultrasound  
OR 
o 
Certain LMP with first trimester physical exam 
2b 
• 
Weight below 10th percentile for gestational age  
AND 
• 
The following used in assessment of weight:  
o 
Newborn weighed within 24 hours of birth on any scale with a < 50 g resolution, tared to zero 
and calibrated  
AND 
• 
The following assessment of gestational age:  
o 
Uncertain LMP with second trimester ultrasound 
3a 
• 
Weight below 10th percentile for gestational age  
AND 
• 
The following used in assessment of weight: 
o 
Infant weighed within the first 48 hours of life 
o 
Newborn weighed on any scale with a < 50 g resolution, tared to zero and calibrated  
AND 
• 
The following assessment of gestational age: 
o 
Certain LMP with third trimester ultrasound  
OR 
o 
Certain LMP with confirmatory 2nd trimester fundal height  
OR 
o 
Certain LMP with birthweight  
OR 
o 
UncCertain LMP with first trimester physical exam  
 
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Small for Gestational Age (continued) 
Level 
Description 
3b 
• 
Weight below 10th percentile for gestational age  
AND 
• 
The following used in assessment of weight:  
- 
Infant weighed within the first 48 hours of life 
- 
Newborn weight assessed by measuring the difference between an adult holding the infant 
and the adult being weighed alone on any scale 
AND 
• 
The following assessment of gestational age: 
- 
Uncertain LMP with fundal height  
OR 
- 
Uncertain LMP with newborn physical assessment  
OR 
Uncertain LMP with birthweight 
4 
• 
Baby noted to be small, but no actual weight 
• 
Baby with GA assessed only by infant examination 
• 
Diagnosis extracted from billing codes or chart, with no documentation of actual birth weight or GA 
Reference: Schlaudecker EP, Munoz FM, Bardají A, et al. Small for gestational age: Case definition & guidelines for 
data collection, analysis, and presentation of maternal immunisation safety data. Vaccine. 2017; 35:6518-6528. 
Table 32 
Low Birth Weight (LBW) 
Regardless of gestational age:  
• 
Low birth weight (LBW): <2500 grams.  
• 
Very low birth weight (VLBW): <1500 grams  
• 
Extremely low birth weight (ELBW): <1000grams 
Levels of Diagnostic Certainty (1 highest level to 4 lowest level of certainty 
Level 
Description 
1 
1.Newborn infant weighed within 24 hours of birth  
AND 
2. Use electronic scale which is graduated to 10 grams  
AND 
3. Scale is calibrated at least once a year  
AND 
4. Scale placed on level, hard surface  
AND 
5. Scale tared to zero grams  
AND 
6. Weight recorded as <2500 grams  
OR 
1.Birth weight recorded as <2500 grams  
AND 
2. Birth weight assessed as per health care facility’s standard operating procedure, which fulfills criteria 1 
to 5 above. 
 
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Low Birth Weight (continued) 
Level 
Description 
2 
1. Newborn infant weighed within 24 hours of birth  
AND 
2. Scale (electronic/spring) is graduated to at least 50 grams  
AND 
3. Scale is calibrated at least once a year, or more often if moved  
AND 
4. Scale tared to zero grams or 0.00kg  
AND 
5. Weight recorded as <2500 grams  
OR 
1. Birth weight recorded as <2500 grams AND 
2. Birth weight assessed as per health care facility’s standard operating procedure, which fulfills criteria 1 
to 4 above. 
(Scale used could be electronic or spring scale, including colour-coded scale) 
3 
1. Newborn infant weighed on day 1 or 2 of life (first 48 hours of life)  
AND 
2. Weight measured using dial/spring/colour-coded scale  
AND 
3. Weight assessed as <2500 grams 
4 
1. Newborn weight assessed between day 1 and 2 of life (first 48 hours)  
AND 
2.. Proxy measure (newborn foot length, chest circumference, mid upper arm circumference) of birth 
weight used  
AND 
3. Weight CATEGORY assessed as <2500 grams 
Reference: Cutland CL, Lackritz EM, Mallett-Moore T, et al. Low birth weight: Case definition & guidelines for data 
collection, analysis, and presentation of maternal immunization safety data. Vaccine. 2017; 35:6492-6500. 
Table 33 
Neonatal encephalopathy 
Disease, malfunction of damage of the brain in a newborn (1–28 days) born at or beyond 
35 weeks of gestation, that may be due to a variety of etiologies including but not limited 
to hypoxia/ischemia, metabolic disturbance, infection and traumatic processes 
Levels of Diagnostic Certainty (1 highest level to 4 lowest level of certainty 
Level 
Description 
1 
(Definite) 
Abnormal level of alertness or seizures AND 
Difficulty with initiating and maintaining respiration AND 
Depression of tone 
2 
(Probable) 
Abnormal level of alertness or seizures  
AND 
Difficulty with initiating and maintaining respiration OR Depression of tone 
3 
(Possible) 
Abnormal level of alertness or seizures without difficulty with initiating and maintaining respiration nor 
depression of tone 
Reference: Sell E, Munoz FM, Soe A, et al. Neonatal encephalopathy: Case definition & guidelines for data collection, 
analysis, and presentation of maternal immunisation safety data. Vaccine. 2017; 35: 6501-6505. 
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Table 34 
Congenital Microcephaly 
Congenital microcephaly, also referred to as primary microcephaly due to its presence in 
utero or at birth, is a descriptive term for a structural defect in which a fetus or infant’s 
head (cranium) circumference is smaller than expected when compared to other fetuses or 
infants of the same gestational age, sex and ethnic background 
Levels of Diagnostic Certainty (1 highest level to 4 lowest level of certainty 
Postnatally Diagnosed Microcephaly 
Level 
Description 
1 
Live birth, stillbirth, or spontaneous or therapeutic abortion of at least 24 weeks of Gestational Age (GA)~  
AND  
Head Circumference (HC) 2 Standard Deviations (SD) below mean or <3rd percentile according to GA 
and gender, using appropriate standardized reference charts for the population (e.g., WHO growth 
reference charts if GA ≥37 weeks and Intergrowth-21st reference charts for GA 24–36 weeks)  
AND  
Measured between 24–36 hours after birth or end of pregnancy. 
~GA assessed based on certain Last Menstrual Period (LMP) with confirmatory 1st trimesteror 2nd 
trimester ultrasound (US) scan, intrauterine insemination (IUI), or embryo transfer date 
2a 
Live birth, stillbirth, or spontaneous or therapeutic abortion of at least 24 weeks of GA~  
AND  
HC 2 SD below mean or <3rd percentile according to GA and gender, using appropriate standardized 
reference charts for the population (e.g., WHO growth reference charts if GA ≥37 weeks and Intergrowth-
21st reference charts for GA 24–36 weeks)  
AND  
Measured within the first 24 hours§ 
OR  
>36 hours and up to 6 weeks after birth or end of pregnancy with no apparent post-natal insult resulting in 
microcephaly  
~GA assessed based on certain LMP with confirmatory 1st trimester or 2nd trimester US scan, IUI, or 
embryo transfer date 
§Take into account the variability in this period based on molding of the head 
2b 
Live birth, stillbirth, or spontaneous or therapeutic abortion of at least 24 weeks of GA~  
AND  
HC 2 SD below mean or <3rd percentile according to GA and gender, using appropriate standardized 
reference charts for the population (e.g., WHO growth reference charts if GA ≥37 weeks and Intergrowth-
21st reference charts for GA 24–36 weeks)  
AND  
- 
within the first 24 hours§ 
OR  
>36 hours and up to 6 weeks after birth or end of pregnancy with no apparent post-natal insult resulting in 
microcephaly  
~GA assessed based on uncertain LMP with 2nd trimester US scan 
§Take into account the variability in this period based on molding of the head 
 
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Postnatally Diagnosed Microcephaly (continued) 
Level 
Description 
3a 
Live birth, stillbirth, or spontaneous or therapeutic abortion of 
at least 24 weeks of GA~_ 
AND  
HC 2 SD below mean or <3rd percentile according to GA and gender, using appropriate standardized 
reference charts for the population (e.g., WHO growth reference charts if GA P37 weeks and Intergrowth-
21st reference charts for GA 24–36 weeks)  
AND 
Measured up to 6 weeks after birth or end of pregnancy with no apparent post-natal insult resulting in 
microcephaly 
~GA based on LMP without confirmatory 1st or 2nd trimester 
Ultrasound 
3b 
Live birth, stillbirth, or spontaneous or therapeutic abortion  
AND 
Case meets criteria for microcephaly using a validated algorithm: 1 inpatient diagnosis OR 2 outpatient 
diagnoses OR 1 outpatient diagnosis AND death in first year using the following diagnostic codes ICD-9-
CM code 742.1 or ICD-10-CM code Q02 
4 
Live birth, stillbirth, or spontaneous or therapeutic abortion 
AND  
Diagnosis of congenital microcephaly based on: 
- 
physical inspection without HC measurement  
OR  
- 
ICD-9-CM or ICD-10-CM code that does not meet validated algorithm criteria above.  
Prenatally Diagnosed Microcephaly 
Level 
Description 
1a 
Fetus of at least 24 weeks GA based on certain LMP with confirmatory 1st trimester (<14 weeks) or 2nd 
trimester US scan IUI, or embryo transfer date  
AND  
HC 2 SD below mean or <3rd percentile according to fetal ultrasound (US) examination using appropriate 
standardized reference charts according to GA and gender for the population (eg. WHO growth reference 
charts if GA ≥37 weeks and Intergrowth-21st reference charts for GA 24–36 weeks)  
AND  
Confirmation of microcephaly (i.e., HC 2 SD below mean or <3rd percentile) by: 
- 
at least one additional US after 24 weeks and at least one week after first US  
OR 
- 
HC measurement with standard tape measure at birth or autopsy  
1b 
Fetus of at least 24 weeks GA based on uncertain LMP with 2nd trimester US  
AND  
HC 2 SD below mean or <3rd percentile according to fetal ultrasound (US) examination using appropriate 
standardized reference charts according to GA and gender for the population (eg. WHO growth reference 
charts if GA ≥37 weeks and Intergrowth-21st reference charts for GA 24–36 weeks)  
AND  
Confirmation of microcephaly (i.e., HC 2 SD below mean or <3%) by:  
- 
at least one additional US after 24 weeks and at least one week after first US  
OR  
- 
HC measurement with standard tape measure at birth or autopsy 
 
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Prenatally Diagnosed Microcephaly (continued) 
Level 
Description 
2 
Fetus of at least 24 weeks GA based on certain or uncertain LMP with fundal height and no confirmatory 
1st or 2nd trimester US scan  
AND  
HC 2 SD below mean or <3rd percentile according to fetal US scan using appropriate standardized 
reference charts according to GA and gender for the population (eg. WHO growth reference charts if GA 
≥37 weeks and Intergrowth-21st reference charts for GA 24–36 weeks) with femur length and abdominal 
circumference concordant with GA assessment 
AND  
Confirmation of microcephaly (i.e., HC 2 SD below mean or <3%) by:  
- 
at least one additional US scan after 24 weeks and at least one week after first US  
OR  
- 
HC measurement with standard tape measure at birth or autopsy  
3a 
Fetus of at least 24 weeks GA based on certain LMP with confirmatory 
1st trimester or 2nd trimester US scan, uncertain LMP with 2nd trimester US, IUI, or embryo transfer date 
AND  
HC 2 SD below mean or <3rd percentile according to fetal US scan using appropriate standardized 
reference charts according to GA and gender for the population (eg. WHO growth reference charts if GA 
≥37 weeks and Intergrowth-21st reference charts for GA 24–36 weeks) with femur length and abdominal 
circumference concordant with GA assessment 
AND  
No additional data to confirm microcephaly (i.e., No additional prenatal US scan or confirmation of 
microcephaly with any additional US or by HC measurement at birth or autopsy at birth or autopsy) 
3b 
Fetus of at least 24 weeks GA based on certain or uncertain LMP with fundal height and no confirmatory 
1st or 2nd trimester US   
AND  
HC 2 SD below mean or <3 percentile according to fetal US scan using appropriate standardized 
reference charts according to GA and gender for the population (e.g., WHO growth reference charts if GA 
P37 weeks and Intergrowth-21st reference charts for GA 24–36 weeks) with femur length and abdominal 
circumference concordant with GA assessment 
AND 
No additional data to confirm microcephaly (i.e., No additional prenatal US scan or confirmation of 
microcephaly by HC measurementat birth or autopsy) 
4 
Fetus of at least 24 weeks GA based on certain LMP with confirmatory 1st trimester or 2nd trimester US 
scan, uncertain LMP with 2nd trimester US, IUI, embryo transfer date, or certain or uncertain LMP with 
fundal height and no confirmatory 1st or 2nd trimester US scan 
AND  
HC 2 SD below mean or <3% according to fetal US examination using appropriate standardized 
reference charts according to GA and gender for the population (eg. WHO growth reference charts if GA 
≥37 weeks and Intergrowth-21st reference charts for GA 24–36 weeks)  
AND  
HC at birth or autopsy is in the normal range using appropriate standardized reference charts according 
to GA and gender for the population, which means that this is NOT a case of prenatally diagnosed 
congenital microcephaly 
Reference: DeSilva M, Munoz FM, Sell E, et al.  Congenital microcephaly: Case definition & guidelines for data 
collection, analysis, and presentation of safety data after maternal immunisation. Vaccine.  35; 6472 – 6482. 
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Table 35 
Major Congenital anomalies 
Congenital anomalies, also commonly referred to as birth defects, congenital disorders, 
congenital malformations, or con-genital abnormalities. Major congenital anomalies are 
events of prenatal origin that a represent at birth, potentially impacting an infant’s health, 
development and/or survival. 
Levels of Diagnostic Certainty (1 highest level to 4 lowest level of certainty 
Major External Structural Defects 
Level 
Description 
1 
Alterations in external anatomy visible:  
- 
at the time of live birth and persistent beyond the immediate peripartum period unless surgically 
repaired  
OR 
- 
in a stillbirth or in the products of conception of a spontaneous or therapeutic abortion  
AND 
Confirmed by documentation of a diagnosis made by a clinician experienced in diagnosing congenital 
anomalies and with the highest level of morphology training for the specific setting 
2 
Alterations in external anatomy visible:  
- 
at the time of live birth and persistent beyond the immediate peripartum period unless surgically 
repaired  
OR 
- 
in a stillbirth or in the products of conception of a spontaneous or therapeutic abortion  
AND 
Confirmed by documentation of a diagnosis made by a clinician with some experience diagnosing 
congenital anomalies 
3 
Alterations in external anatomy visible: 
- 
at the time of live birth and persistent beyond the immediate peripartum period unless surgically 
repaired  
OR  
- 
in a stillbirth or in the products of conception of a spontaneous or therapeutic abortion  
AND 
Confirmed: 
by documentation of a diagnosis made by a trained maternal or child health care provider with at least 
minimal experience diagnosing congenital anomalies  
OR 
- 
For live births, by using individual (ICD-9/ICD-10) codes or as part of an ICD-9/ICD-10 code based 
algorithm, where the outcome (individual code or algorithm) has been validated 
4 
(Insufficient evidence to confirm) 
Alterations in external anatomy visible: 
- 
at the time of live birth and persistent beyond the immediate peripartum period unless surgically 
repaired  
OR 
- 
in a stillbirth or in the products of conception of a spontaneous or therapeutic abortion  
AND  
Confirmed: 
- 
by medical record review  
OR 
in claims data (ICD-9/ICD-10 diagnoses)  
 
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Internal Structural Defects 
Level 
Description 
1 
Alterations in internal anatomy present at the time of live birth and persistent beyond the immediate 
peripartum period unless surgically repaired 
AND 
•Confirmed by definitive imaging study or intraoperative diagnosis  
OR  
•Alterations in internal anatomy detected during autopsy for a stillbirth, spontaneous or therapeutic 
abortion confirmed by documentation by a pathologist or other relevant subspecialist  
2 
Alterations in internal anatomy present at the time of live birth and persistent beyond the immediate 
peripartum period unless surgically repaired  
AND 
•Confirmed by documentation of a diagnosis made by a clinician experienced in diagnosing congenital 
anomalies and with the highest level of morphology training for the specific setting without definitive 
imaging or intraoperative evaluation 
OR  
•For stillbirth, spontaneous or therapeutic abortion, internal structural defect is visible by ultrasound or 
other imaging modality prenatally 
3 
•Alterations in internal anatomy present at the time of live birth and persistent beyond the immediate 
peripartum period unless surgically repaired  
AND 
•Confirmed: 
by documentation of a diagnosis made by a clinician with some experience diagnosing congenital 
anomalies  
OR 
using individual (ICD-9/ICD-10) codes or as part of an ICD-9/ICD-10 code based algorithm, where the 
outcome (individual code or algorithm) has been validated 
4 
(Insufficient evidence to confirm) 
Alterations in internal anatomy present: 
 at the time of live birth and persistent beyond the immediate peripartum period unless surgically repaired  
OR 
at time of stillbirth, spontaneous abortion, or induced abortion  
AND 
•Confirmed: 
through medical record review, with the medical record demonstrating that the anomaly was present at 
the time of live birth or time of fetal demise, and that the anomaly was diagnosed by a trained maternal or 
child health care provider with minimal experience diagnosing congenital anomalies  
OR 
by claims data (ICD-9/ICD-10 diagnoses) 
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Functional Defects 
Level 
Description 
1 
For live births, alterations in functioning of one or more organs or body parts not due to a structural 
defect, present at the time of birth (or propensity to develop alteration present at live birth), and persistent 
beyond the immediate peripartum period, unless treated through gene therapy or stem cell 
transplantation  
OR  
•For stillbirths, spontaneous or therapeutic abortions, alterations in functioning of one or more organs or 
body parts, not due to a structural defect  
AND  
•Confirmed by definitive diagnostic study 
2 
For live births, alterations in functioning of one or more organs or body parts not due to a structural 
defect, present at livebirth (or propensity to develop alteration present at live birth),and persistent beyond 
the immediate peripartum period, unless treated through gene therapy or stem cell transplantation  
OR  
•For stillbirths, spontaneous or therapeutic abortions, alterations in functioning of one or more organs or 
body parts, not due to a structural defect  
AND  
•Confirmed by documentation of a diagnosis made by a clinician experienced in diagnosing congenital 
anomalies and with the highest level of training in the diagnosis of functional defects for the specific 
setting 
3 
For live births, alterations in functioning of one or more organs or body parts not due to a structural 
defect, present at livebirth (or propensity to develop alteration present at live birth),and persistent beyond 
the immediate peripartum period, unless treated through gene therapy or stem cell transplantation OR  
•For stillbirths, spontaneous or therapeutic abortions, alterations in functioning of one or more organs or 
body parts, not due to a structural defect  
AND 
•Confirmed: 
- 
by documentation of a diagnosis made by a clinician with some experience diagnosing functional 
defects  
OR 
- 
using individual (ICD-9/ICD-10) codes or as part of an ICD-9/ICD-10 code based algorithm, where 
the outcome(individual code or algorithm) has been validated 
4 
(Insufficient evidence to confirm) 
For live births, alterations in functioning of one or more organs or body parts not due to a structural 
defect, present at the time of live birth (or propensity to develop alteration present at livebirth), and 
persistent beyond the immediate peripartum period, unless treated through gene therapy or stem cell 
transplantation  
OR 
•For stillbirths, spontaneous or therapeutic abortions, alterations in functioning of one or more organs or 
body parts, not due to a structural defect  
AND 
•Confirmed: 
- 
through medical record review, with the medical record demonstrating that the anomaly was 
present at the time of live birth or time of fetal demise, and that the anomaly was diagnosed by a 
trained maternal or child healthcare provider who is not a qualified geneticist, neonatologist, 
pathologist, subspecialist, pediatrician, obstetrician, or family medicine practitioner  
OR  
- 
by claims data (ICD-9/ICD-10 diagnoses) 
Reference: DeSilva M, Munoz FM, Mcmillan M, et al. Congenital anomalies: Case definition and guidelines for data 
collection, analysis, and presentation of immunization safety data. Vaccine. 2016;34(49):6015-6026.  
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Table 36 
Neonatal Death 
Death of a live born infant regardless of gestational age at birth, within the first 28 
completed days of life 
Levels of Diagnostic Certainty (1 highest level to 4 lowest level of certainty 
Neonatal death in a non-viable live birth 
Level 
Description 
1 
1. Live born infant  
AND 
2. Gestational age <22 weeks (GA level of certainty = 1)  
OR 
3. Birth weight <500 g  
AND 
4. Death of infant in first 28 days of life  
AND 
5. Medically-confirmed death 
2 
1. Live born infant  
AND 
2. Gestational age/size of newborn assessed as at least one of: 
a. Gestational age <22 weeks (GA Level of Certainty = 1 OR 2) 
b. Birth weight <500 g  
AND 
3. Death of infant in first 28 days of life  
AND 
4. Medically-confirmed death OR non-medically-confirmed death 
3 
1. Live born infant  
AND 
2. Gestational age <5 months according to parent/family member/delivery attendant (GA Level of 
Certainty = 2 OR 3)  
AND 
3. Death of infant in first 28 days of life  
AND 
4. Medically-confirmed death OR non-medically-confirmed death 
Neonatal death in an extremely preterm live birth 
Level 
Description 
1 
1. Live born infant  
AND 
2. Gestational age ≥22 and <28 weeks (GA Level of Certainty = 1)  
OR 
3. Birth weight ≥500 g but <1000 g  
AND 
4. Death of infant in first 28 days of life  
AND 
5. Medically-confirmed death 
2 
1. Live born infant  
AND 
2. Gestational age/size of newborn assesses as one or more of: 
a. Gestational age ≥22 and <28 weeks (GA Level of Certainty = 1 OR 2)  
b. Birth weight ≥500 g but <1000 g  
AND 
3. Death of infant in first 28 days of life  
AND 
4. Medically-confirmed death OR non-medically-confirmed death 
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Neonatal death in an extremely preterm live birth (continued) 
Level 
Description 
3 
1. Live born infant  
AND  
2. Gestational age ≥5 months but <7 months according to neonate’s parent (mother/father)/family 
member/delivery attendant (GA Level of Certainty = 2 OR 3)  
AND 
3. Death of infant in first 28 days of life  
AND 
4. Medically-confirmed death OR non-medically-confirmed death 
Neonatal death in a preterm live birth (gestational age ≥28to <37 weeks) 
Level 
Description 
1 
1. Live born infant  
AND 
2. Gestational age ≥28 and <37 weeks (Level of Certainty = 1) 
OR 
3. Birth weight ≥1000 g but <2500 g  
AND 
4. Death of infant in first 28 days of life  
AND 
5. Medically-confirmed death 
2 
1. Live born infant  
AND  
2. Gestational age/size of newborn assesses as one or more of: 
a. Gestational age ≥28 and <37 weeks (GA Level of Certainty = 1 OR 2)  
b. Birth weight ≥1000 g but <2500 g  
AND 
3. Death of infant in first 28 days of life  
AND 
4. Medically-confirmed death OR non-medically-confirmed death 
3 
(MAY apply to LMIC- or may be non-viable in LMIC) 
1. Live born infant  
AND 
2. Gestational age ≥7 months but <9 months according to parent/family member/delivery attendant (GA 
Level of Certainty = 2 OR 3)  
AND 
3. Death of infant in first 28 days of life  
AND 
4. Medically-confirmed death OR non-medically-confirmed death 
Neonatal death in a term live birth 
Level 
Description 
1 
1. Live born infant AND 
2. Gestational age ≥37 weeks (GA Level of Certainty = 1) AND 
3. Birth weight >2500 g  
OR  
4. Documented intra-uterine growth retardation if ≤2500 g  
AND 
5. Death of infant in first 28 days of life  
AND 
6. Medically-confirmed death 
 
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Neonatal death in a term live birth (continued) 
Level 
Description 
2 
1. Live born infant  
AND 
2. Gestational age/size of newborn assesses as one or more of: 
a. Gestational age ≥37 weeks (GA Level of Certainty = 1 OR 2) 
b. Birth weight ≥2500 g  
AND 
3. Death of infant in first 28 days of life  
AND 
4. Medically-confirmed death OR non-medically-confirmed death which is confirmed by examination by 
(by at least) non-medically-trained attendant (e.g. undertaker, community member) 
3 
(apply to LowerMiddleIncomeCountries) 
1. Live born infant AND 2. Gestational age ≥9 months according to parent/family member/delivery 
attendant (GA Level of Certainty = 2 OR 3) AND 
3. Death of infant in first 28 days of life  
AND 
4. Medically-confirmed death OR non-medically-confirmed death 
Reference: Pathirana J, Muñoz FM, Abbing-Karahagopian V, et al. Neonatal death: Case definition & guidelines for 
data collection, analysis, and presentation of immunization safety data. Vaccine. 2016;34(49):6027-6037. 
Table 37 
Neonatal Infections 
Neonatal bacteraemia and sepsis (of early or late onset), meningitis, pneumonia and other 
respiratory infections such as bronchiolitis, caused by bacteria, parasites, viruses or fungi. 
Localised eye and ear infections, encephalitis, urinary tract infections and intestinal 
infections were excluded from these guidelines 
Neonatal invasive blood stream infections: bacterial/fungal/viral 
Level 
Description 
1 
Recognised pathogen identified using a validated method and from a normally sterile site. 
2 
Not meeting Level 1 of evidence  
AND  
Meeting 3 or more of the following criteria: 
• Temperature ≥37.5 ◦C or <35.5 ◦C 
• Tachycardia or new or more frequent episodes of bradycardia 
•New or more frequent episodes of apnea or increased oxygen requirement or increased requirement for 
ventilatory support 
• Lethargy or moving only when stimulated or hypotonia or irritability 
• Difficulty in feeding or abdominal distention 
• Pallor or poor perfusion or hypotension 
•Abnormal White Cell Count or I/T ratio >0.2 
• Abnormal platelet count  
•Increased inflammatory markers (CRP, procalcitonin) 
• Metabolic acidosis as defined by a base excess 
 
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Neonatal invasive blood stream infections: bacterial/fungal/viral (continued) 
Level 
Description 
3 
Not meeting Level 1 or 2 of evidence  
AND 
Meeting 2 or more of the following criteria: 
• Temperature ≥37.5 ◦C or <35.5 ◦C 
• Tachypnea or severe chest in drawing or grunting or cyanosis 
• Change in level of activity 
• History of feeding difficulty 
• History of convulsions 
Bacterial/fungal/viral meningitis 
Level 
Description 
1 
Recognised pathogen identified using a validated method from cerebrospinal fluid (CSF) 
2 
CSF pleocytosis OR positive IgM antibodies to a specific pathogen in the CSF  
AND 
Recognised pathogen identified using a validated method from a normally 
sterile site (other than CSF)  
AND 
Temperature ≥37.5 ◦C or <35.5 ◦C  
AND 
1 or more criteria below: 
• History of convulsions 
•Lethargy or irritability 
•Coma 
•Apnea 
•Bulging fontanel 
•Neck stiffness 
3a 
CSF pleocytosis  
AND 
No pathogen identified using a validated method from a normally sterile site AND 
Temperature ≥37.5 ◦C or <35.5 ◦C  
AND 
3 or more criteria below: 
• History of convulsions 
• Lethargy or irritability 
• Coma 
• Apnea 
• Bulging fontanel 
• Neck stiffness 
3b 
No lumbar puncture done or no sample available  
AND 
Temperature ≥37.5 ◦C or <35.5 ◦C  
AND 
4 or more criteria below: 
• History of convulsions 
• Lethargy or irritability 
• Coma 
• Apnea 
• Bulging fontanel 
• Neck stiffness 
 
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Respiratory bacterial/fungal/viral infection 
Level 
Description 
1 
New or progressive or persistent infiltrate or shadowing or fluid in the intrapleural cavity or interlobar 
fissure on chest X-ray  
AND 
Recognised virus identified using a validated assay from an upper respiratory sample  
OR 
Recognised pathogen identified using a validated method and from a normally sterile site  
AND  
3 or more criteria below: 
• Temperature ≥37.5 ◦C or <35.5 ◦C 
• Tachypnea or Nasal flaring or Chest in-drawing or Grunting 
• Desaturations or increased oxygen requirements or increased ventilator requirements or oxygen 
saturation <95% 
• Apneas 
• Increased respiratory secretions or Increased suctioning requirements 
• Cough or wheeze or crepitations 
• Increased CRP or procalcitonin 
2 
New or progressive or persistent infiltrate or shadowing or fluid in the intrapleural cavity or interlobar 
fissure on chest X-ray  
AND  
4 or more criteria below: 
• Temperature ≥37.5 ◦C or <35.5 ◦C 
• Tachypnea or Nasal flaring or Chest in-drawing or Grunting 
• Desaturations or increased oxygen requirements or increased ventilator 
requirements or oxygen saturation <95% 
• Apneas 
• Increased respiratory secretions or Increased suctioning requirements 
• Cough or wheeze or crepitations 
• Increased CRP or procalcitonin 
3 
2 or more criteria below: 
• Difficulty in breathing/Tachypnea 
• Severe chest in-drawing 
• Nasal flaring 
• Grunting 
• Wheezing 
• Stridor 
• Fever 
Reference: Vergnano S, Buttery J, Cailes B, et al. Neonatal infections: Case definition and guidelines for data 
collection, analysis, and presentation of immunisation safety data. Vaccine. 2016;34 (49):6038-6046 
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Table 38 
Respiratory Distress in the Neonate 
Constellation of clinical findings that support the presence of breathing difficulty in the 
neonate (0-28 days of life), independent from etiology or severity, and independent from 
the infant’s gestational age or circumstances at the time of delivery 
Level 
Description 
1 
Newborn 0 to 28 days of life  
AND 
Abnormal respiratory rate: 
Measurement of number of breaths per minute consistent with: 
- 
Tachypnea = respiratory rate of more than 60 breaths per minute 
OR 
- 
Bradypnea = respiratory rate of less than 30 breaths per minute  
OR 
- 
Apnea = cessation of respiratory effort (no breaths) for at least 20 seconds 
AND 
Clinical symptoms consistent with labored breathing: 
- 
Nasal flaring (dilatation of alae nasi)  
OR 
- 
Noisy respirations in the form of expiratory grunting, stridor, or wheeze  
OR 
- 
Retractions or increased chest in-drawings on respiration (subcostal, intercostal, sternal, 
suprasternal notch)  
OR 
- 
Central cyanosis (whole body, including lips and tongue) on room air  
OR 
- 
Low Apgar Score (< 7 points) at 10 min, with respiration score <2  
AND 
Examination and documentation by qualified, trained, health care provider appropriate for the clinical 
setting. 
2 
Newborn 0 to 28 days of life  
AND 
Abnormal respiratory rate: 
Not measured, but reported as “rapid breathing”, “slow breathing”, having periods of “no breathing”, or 
“abnormal breathing”  
AND 
Clinical symptoms consistent with labored breathing: 
- 
Nasal flaring (dilatation of alae nasi)  
OR 
- 
Noisy respirations in the form of expiratory grunting, stridor, or wheeze  
OR 
- 
Retractions or increased chest in-drawings on respiration (subcostal, intercostal, sternal, 
suprasternal notch) or seesaw respirations  
OR 
- 
Central cyanosis (whole body, including lips and tongue) on room air  
OR 
- 
Low Apgar Score (< 7 points) at 10 min, with respiration score <2 
AND 
- 
No medical record documentation, but reporting through either a non-medical observer (e.g. mother, 
father, community worker) or via standard census mechanisms (e.g. Demographic and Health 
Surveillance System)  
OR 
- 
Collection of information from medical record review or billing codes. 
3 
No need for a level 3 per working group. 
4 
Not enough information to ascertain case of respiratory distress. 
5 
Not a case of respiratory distress in the neonate. 
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Reference: Leigh R. Sweet, Cheryl Keech, Nicola P. Klein, et al.  Respiratory distress in the neonate: Case definition & 
guidelines for data collection, analysis, and presentation of maternal immunization safety data. Vaccine. 2017; 35: 
6506-6517. 
Table 39 
Preterm Birth 
Birth in less than 37 gestation-completed weeks (less than 259 days).  
Prematurity and assessment of gestational age 
Level 
Description 
1 
Certain last menstrual period date (LMP) LMP or intrauterine insemination (IUI) date or embryo transfer 
(ET) date with confirmatory 1st trimester scan (≤13 6/7 weeks).  
OR 
1st trimester scan (≤13 6/7 weeks) 
2a 
Certain LMP* with 2nd trimester scan (14 0/7 weeks to 27 6/7weeks). 
Note:  If LMP and U/S do not correlate, default to U/S GA assessment. 
OR 
Certain LMP* with 1st trimester physical examination. 
2b 
Uncertain LMP with 2nd trimester scan (14 0/7 weeks to 27 6/7 weeks). 
3a 
Certain LMP with 3rd trimester scan ≥  28 0/7 weeks   
OR 
Certain LMP with confirmatory 2nd trimester Fundal Height (FH) 
OR 
Certain LMP with birth weight  
OR 
Uncertain LMP with 1st trimester physical examination. 
3b 
Uncertain LMP with FH.  
OR 
Uncertain LMP with newborn physical assessment.  
OR 
Uncertain LMP with Birth weight 
* 
Definitions of LMP, birth weight and physical assessment in referenced article. 
Reference: Quinn JA, Munoz FM, Gonik B, et al. Preterm birth: Case definition & guidelines for data collection, 
analysis, and presentation of immunisation safety data. Vaccine. 2016;34(49):6047-6056. 
 
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Table 40 
Failure to Thrive   
Failure to Thrive (FTT) can be broadly defined as a faltering of growth from a previously 
established pattern of growth. It is universally established that a diagnosis of failure to 
thrive should be based on anthropometric data. However no consensus exits as to which 
measurements achieve the highest specificity and sensitivity. Weight is generally 
regarded is the indicator of choice, particularly a change in growth velocity, and as such 
has been selected as the standard for this case definition with a weight for age 
deceleration as the primary indicator of failure to thrive.  The case definition should be 
applied when there is no clear alternative diagnosis for the reported event to account for 
the combination of symptoms. 
Level 
Description 
1 
Infant age1 determined by a documented birth date 
AND 
Weights obtained using an electronic scale 
AND 
At least 2 weights, measured at least 4 weeks apart 
AND 
Weight for age deceleration2 through at least 2 centile spaces on 
growth chart3 
2a 
Infant age determined by a documented birth date 
AND 
Weights obtained using a beam balance scale 
AND 
At least 2 weights, measured at least 4 weeks apart 
AND 
Weight for age deceleration through at least 2 centile spaces on 
growth chart 
OR 
Infants with an undocumented birth date, where age is determined 
based on Mothers recall to nearest month 
AND 
Weights obtained using electronic scale 
AND 
At least 2 weights, measured at least 4 weeks apart 
AND 
 Weight for age deceleration through at least 2 centile spaces on 
growth chart 
2b 
Infant age determined by a documented birth date 
AND 
Weights obtained using a spring balance scale 
AND 
At least 2 weights, measured at least 4 weeks apart 
AND 
Weight for age deceleration through at least 2 centile spaces on 
growth chart  
OR  
Weight measured using electronic scale or beam balance scale 
AND 
Length taken using Infantometer 
AND 
Weight for length less than or equal to the 3rd centile on the 
appropriate growth chart 
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Level 
Description 
3a 
Infants with an undocumented birth date, where age is determined 
based on Mothers recall to nearest month 
AND 
Weight obtain using either beam balance or spring balance 
scale 
AND 
At least 2 weights, measured as least 4 weeks apart 
AND 
Weight for age deceleration through at least 2 centile spaces on 
growth chart 
3b 
Infants with no weight available 
AND 
Physical examination consistent with FTT4 
AND 
MUAC5 indicative of severe wasting 
1This case definition is limited to infants up to 12 months of age. 
2 Weight should be documented on the appropriate growth chart at the time of assessment. A fall through 2 centile 
spaces may be demonstrated at any point in the first 12 months of life, using any two weights as long as they are 
taken at least 4 weeks apart. Details of use of the weight balances allowable under this case definition and use of 
the Infantometer for length assessment are presented in the reference given below. 
3 For infants born at 37 weeks gestation or above, the WHO growth charts should be applied. When using weight for 
age use the growth chart most accurate for the infants age. The birth to 6 months age range should be used 
where data is available for this range only, the birth to 2 years chart should be used where data is available 
beyond 6 months of life. When using weight for length, use the chart for birth to 2 years. For infants born less than 
37 completed weeks gestation, the Intergrowth charts for postnatal growth standards in preterm infant should be 
used. All infants should be plotted on their respective growth chart using their corrected age. Links to relevant 
growth charts are presented in the reference given below. 
4 Physical examination with signs of Failure to Thrive (must include at least 2 findings, with at least one major finding) 
Major findings: Reduced subcutaneous fat stores; poor muscle mass; loose skin folds; prominent ribs; thin limbs 
Other less specific signs include: sparse hair; rashes; pallor; miserable; lethargy/fatigue. 
5 Mid Upper Arm Circumference (MUAC): For infants 0–6 months, a MUAC of 6 110 mm is indicative of severe 
wasting. For infants 6–12 months, a MUAC of 6 115 mm is indicative of severe wasting. Instructions on 
performing MUAC are presented in the reference given below. 
Reference: Ross E, Munoz F, Edem B et al. Failure to thrive: case definition and guidelines for data collection, 
analysis, and presentation of maternal immunization safety data. Vaccine. 2017; 35:6483-6491. 
Table 41 
Standard Definitions for Neonatal Events of interest not defined as 
events in GAIA  
Event of Interest 
Definition  
Large for gestational age 
Birth weight > 90% for newborns of same gestational age in same population (>4000g 
at term). 
Macrosomia 
BW >4000 g (8 lb, 13 oz). 
 
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APPENDIX E 
AMENDMENTS AND ADMINISTRATIVE 
CHANGES TO THE PROTOCOL 
GlaxoSmithKline Biologicals 
Vaccines R & D 
Protocol Amendment 1  
eTrack study number and Abbreviated Title 
207636 (EPI-RSV-008 BOD) 
Amendment number: 
Amendment 1 
Amendment date: 
12-FEB-2018 
Co-ordinating author: 
, Lead Science Writer 
 
Rationale/background for changes:  
The protocol has been amended to reflect the following changes and provide the 
following clarifications / corrections. 
• 
A separate screening visit has been added. 
• 
Evaluations of GBS rectovaginal colonization of pregnant women, and the 
occurrence of GBS bacteremia/septicemia in their newborn infants, have been 
removed as study objectives. 
• 
The Study Procedures Table and Detailed Descriptions of Study procedures have 
been updated both for consistency with these changes, and for improved 
consistency with the content of the electronic Case Report Forms for the study. 
• 
Parents / LARs/designates are to contact the study site whenever: 
− 
the infant has developed symptoms of respiratory tract infection (RTI),  
− 
the infant has developed symptoms of difficulty in breathing or wheezing,  
− 
the infant’s RTI symptoms have worsened, 
− 
the parent(s)/LAR(s) (or their designate(s)) are concerned about the infant’s 
RTI signs and/or symptoms (parental concern). 
• 
Text describing the content and use of the maternal health memory aid and the 
infant health and RTI memory aid has been updated and clarified. 
• 
Additional editorial changes have been made to ensure consistency with the 
modifications noted above, and typographical errors have been corrected. 
Text that has been moved or added is presented in bold italics and deleted text in 
strikethrough in the following sections. 
Contributing Authors: 
• 
, Clinical Research and Development Lead 
• 
, 
, 
, Epidemiologists 
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PPD
PPD
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PPD

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List of Abbreviations 
GBS 
Group B Streptococcus 
ICH 
International Conference on Council for Harmonisation 
Glossary 
Level 2 ultrasound (or 
fetal morphology 
ultrasound) 
Definition is unchanged.  Only the label has been 
adjusted, as noted on the left.  
Neonatal events of 
interest 
Events as described in Section 11.1 that occur from 
birth through 28 days of age. 
Pregnancy related events 
of interest 
Events as described in Section 11.1 that occur from post-
enrolmentVisit 1 through Visit 6 (Day 42). 
Protocol amendment: 
The International Conference on Council for 
Harmonisation (ICH) ……… 
Respiratory tract infection 
(RTI) with parental 
concern: 
Any RTI for which the parents/ LAR(s) have visited or 
plan to visit a medical health care practitioner. 
End of Study  
(Synonym of End of Trial) 
For studies without collection of human biological 
samples or imaging data, EoS is the Last Subject Last 
Visit (LSLV).  
Synopsis 
Number of 
subjects 
UpApproximatey 4000 pregnant women (up to approximately 400 
pregnant women ≥240/7 weeks and < 280/7 weeks of gestation are 
planned to be enrolled per country.) Neonates of enrolled pregnant 
women who consent to the infant’s continued study participation 
will also be enrolled. 
Sampling 
schedule for 
neonates/infants 
During the 1-year post-birth surveillance period, for each RTI with 
suspicion of difficulty in breathing, or wheezing, or with parental 
concern, a nasal swab will be collected at the LRTI study visit a 
visit to assess potential LRTIs 
Background and Rationale (Section 1.1 and Synopsis “Rationale for the Study and 
Study Design”) 
……… There are also a number of maternal vaccines in development that aim to protect 
neonates and infants from additional pathogens, including respiratory syncytial virus 
(RSV) and group B streptococcus (GBS). GlaxoSmithKline (GSK) will enter Phase II 
with its is developing an investigational vaccine for use in pregnant women, against RSV 
disease. GBS vaccines are also being developed by GSK. Of note, these vaccines are 
developed solely for immunization in pregnancy. 
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Maternal immunization is implemented worldwide and has the potential to make a major 
contribution to reducing RSV lower respiratory tract infections (LRTI) GBS and other 
disease burden in infants globally. 
Whilst there is good documentation of the global burden of RSV disease, incidence of 
RSV-LRTI according to the World Health Organization (WHO) 2015 case definitions 
[Modjarrad, 2016] is lacking in the literature. Hence, this study will also estimate the 
incidence of infant RSV-LRTI using WHO case definitions across geographically distinct 
locations to support incidence rate assumptions for planning of future efficacy trials. 
There are limited data on the prevalence of GBS rectovaginal colonization in pregnant 
women, by serotype, in different global settings and this study will aim to address this 
gap. 
To achieve these goals, GSK will be guided by the WHO recommendations on antenatal 
care for a positive pregnancy experience [WHO, 2016] and the Global Alignment of 
Immunization safety Assessment in pregnancy (GAIA) case definitions [Bonhoeffer, 
2016]. Standardisation of surveillance methodology and case definitions (applicable to 
maternal immunization AEs) may support comparison of data across different countries 
[Jones , 2016 Bauwens 2016; Bonhoeffer 2016; Kochhar 2017]. 
Rationale for the Study Population (Section 1.1.1 and Synopsis) 
………Regardless of enrolment location, healthy pregnant women aged 18 to 40 years 
with normal, uncomplicated, singleton pregnancies, who have had a second trimesterlevel 
2 (fetal morphology) ultrasound without any significant findings will be eligible for 
possible study participation. Inclusion / exclusion criteria have been structured in a way 
that resembles those of Phase II/III exclusion criteria to ensure good comparability 
Pregnant women will be enrolled starting at 240/7 and up to (but not including) 280/7 
weeks of gestation will be enrolled, to ensure that they are followed as of the time of 
potential vaccination in a clinical trial.  
Rationale for the Surveillance System for the detection of pregnancy related events 
of interest (Section 1.1.2) 
…... Study Information obtained from study-specific procedures and laboratory testing 
tests (e.g. blood sampling, vaginal swabs, urine dipstick) will be performed for 
epidemiological purposes only; the information obtained from these procedures and tests 
is not to be relied upon for clinical management of study subjects. 
Rationale for the inclusion of GBS serotyping and surveillance 
In addition to RSV, GSK is developing a GBS maternal vaccine. GBS is the leading 
cause of neonatal sepsis globally, and disease can occur from the time of birth through 3 
months of age. There is a need to address some of the GBS knowledge gaps and if 
possible prepare sites to detect GBS invasive disease. Aligned with this strategy, this 
study may collect vaginal swabs and blood samples to assess GBS colonization and 
serotypes, and antibody levels in maternal and cord blood. Data regarding occurrence of 
GBS invasive disease (sepsis, pneumonia and meningitis) may be collected through 90 
days after birth, if possible. In case of suspected neonatal sepsis, pneumonia or 
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meningitis, GBS culture results will be documented if performed by a local healthcare 
provider. Because GBS testing results from study vaginal swabs will be performed only 
for epidemiological purposes and will not be available in time to inform clinical 
management, the GBS portion of this protocol will only be implemented in settings that 
have ongoing routine implementation of risk based intrapartum antibiotic prophylaxis for 
GBS. Vaginal swabs will only be performed in settings that adhere to this risk based 
approach for intrapartum antibiotic prophylaxis.  
Rationale for the use of Global Alignment of Immunization safety Assessment in 
pregnancy (GAIA) case definitions (Section 1.1.3) 
GAIA, a Brighton collaboration project, aims to develop standardized case definitions 
and criteria for diagnostic certainty of maternal and neonatal outcomes in the context of 
immunization trials [Bonhoeffer, 2016]Bauwens 2016, Bonhoeffer 2016, Kochhar 
2017]. 
Risk Assessment (Section 2.1) 
Vaginal Nasal swab sample 
collection from infant subjects 
may cause discomfort 
Spontaneous 
data 
Sample collection will only be performed by 
appropriately trained personnel. 
 
Sample collection will only performed if amniotic 
membranes are intact 
Subjects Subjects’ parent(s)/LAR(s) will be notified 
of this risk in the informed consent form. 
Benefit Assessment (Section 2.2) 
….. Data collected during the study may enhance understanding of the incidence of 
maternal events of interest in women with low risk pregnancies, neonatal events of 
interest, GBS colonization and serotype distribution in pregnant women, GBS invasive 
disease in neonates and infants, and lower respiratory tract infections associated with 
RSV infection in neonates and infants.   
Overall Benefit / Risk Conclusion (Section 2.3) 
Potential risks to subjects participating in this study are limited to those associated with 
the collection of biological specimens for analysis by the sponsor. 
Primary Objectives (Section 3.1 and Synopsis) 
In healthy pregnant women with uncomplicated pregnancies at the time as of enrolment 
Visit 1: 
Secondary Objectives (Section 3.2 and Synopsis) 
In healthy pregnant women with uncomplicated pregnancies at the timeas of 
enrolmentVisit 1: 
Tertiary Objectives (Section 3.3 and Synopsis) 
• 
To exploredescribe the association of other respiratory viruses with the occurrence of 
RSV-LRTI in infants.  
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• 
To evaluatedescribe the association between RSV-LRTI in infants and the level of 
RSV neutralizing antibodies in cord blood.  
• 
To describe the prevalence of GBS vaginal colonization and serotype distribution in 
pregnant women in the 2nd and 3rd trimester and at delivery (if possible).  
• 
To describe GBS serotype specific antibody concentrations in pregnant women in the 
2nd and 3rd pregnancy trimester and at delivery (if possible)  
• 
To describe GBS serotype specific antibody concentrations in cord blood (if 
possible)  
• 
To describe the occurrence of GBS invasive disease in infants (if possible).  
• 
To describe occurrences of hospitalization and death due to GBS invasive disease (if 
possible). 
Study Design Figure 1 and accompanying footnotes (Section 4.0) 
These have been adjusted to include a screening visit, to clarify that urine dipstick testing 
will be done at study site visits 1 through 4, to remove references to sample collection for 
GBS testing, and to remove the reference to oral glucose challenge/tolerance testing.  
Footnotes have been renumbered for consistency with these changes. 
 
Study Design Footnotes  
D = day; M = month; V = visit; W = week; Y = year. NB = newborn; GA = Gestational age; BS = blood sample; US = 
urine sample for dipstick testing; IMM = immune response; HB = hematology/biochemistry; RBC = red blood 
cell(s); WBC = white blood cell(s); RSV = respiratory syncytial virus; RTI = respiratory tract infection; LRTI = 
lower respiratory tract infection;  
V2 (D28)1
GA: 28 0/7 -
31 6/7w
Screening
GA: 24 0/7
- 27 6/7 w
V5 
Delivery
V6
Day 42
BS:
• IMM 2
• H/B
US 3:
• Glucose 4
• Proteins
• RBC
• WBC
Vaginal swab 5
Up to (approximately) 400 pregnant women (≥ Week 24 of gestation) per country
Up to (approximately) 4,000 pregnant women in total   
Pregnant women (mothers)
BS:
• Imm 2
• H/B 6 3
US 3:
• Glucose 4
• Proteins
• RBC
• WBC
Vaginal 
swab 5
V3 (D56) 1
GA: 32 0/7 -
35 6/7w
BS 7 4
• Imm 2
Cord blood 8 5
• Imm
Vaginal swab 5
Epoch 002
Mother: V1 through V6
Child: V1-NB through V2-NB
V4 (D84) 1
GA: 36 0/7 -
39 6/7w
Analysis 1
Neonates/Infants
V1-NB
Birth
V2-NB
Day 42
V3-NB
Year 1
Final Analysis 
Epoch 003
Child: V3-NB
Neonatal Conditions of Interest 96
RTI / LRTI Surveillance in Neonates / Infants
Pregnancy Outcomes and Pregnancy and Postpartum related Conditions of Interest
Procedure Related Serious Adverse Event Follow-up
US 3:
• Glucose 4
• Proteins
US 3:
• Glucose 4
• Proteins
• RBC
• WBC
V1 (D1)
GA: 24 0/7 -
27 6/7 w
Epoch 001
Screening
Mother 
only
Informed 
consent
Inclusion, 
Exclusion 
Criteria
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1Visits may be replaced by V5 depending on the date of. If delivery occurs prematurely, skip to Visit 5 ("at 
delivery"). 
2 At Delivery, RSV-A antibody titers for all women  
3 Red blood cells, white blood cells will be recorded when available. Record positive results of any urine culture(s), 
if performed.  
4 Results of Oral glucose challenge / oral glucose tolerance test(s) should be recorded, if performed by local 
healthcare provider and available. 
53 At V3, only hemoglobin testing. 
64 Blood sample should be collected within 72 hours after delivery. 
75 RSV-A antibodies in cord blood  
86Neonatal conditions of interest occur (by definition) between 0 and 28 days after birth.  They will be reported once 
site staff become aware of them (whether this occurs during the first 28 days after birth, or at a later time).  
Study population (Section 4.0 and Synopsis) 
• 
Study population (per country): Up to (approximately) 400 pregnant women ≥240/7 
and < 280/7 weeks of gestation (at the first study visit) will be enrolled; neonates of 
consenting parent(s) / LAR(s) will be enrolled at birth.  The study will be conducted 
in up to approximately 10 countries.Study population: The study will be conducted 
in multiple countries, in pregnant women and their neonates.  
• 
Thus the total study population will consist of up to (approximately) 4000 pregnant 
women and their neonates.  
Table 1 and Synopsis Table 1 
Sampling schedule for pregnant women/mothers 
 
 
Visit 
Sample 
Parameter(s) evaluated 
1 
2 
3 
4 
Delivery 
Maternal 
Blood 
Hematology/ biochemistry1,4 
x 
 
x23 
 
 
Antibody titer (RSV-A)  
x 
 
x 
 
≤ 72 hours after delivery35 
Antibody concentration (GBS) 
x4 
 
x4 
 
≤ 72 hours after delivery3 
Cord 
Blood 
Antibody titer (RSV-A)  
 
 
 
 
x 
 
Antibody concentration (GBS) 
 
 
 
 
x 
Urine 
Protein, glucose1 glucose, RBC, 
WBC 2, 4 
x 
x 
x 
x 
 
Vaginal 
swab 
GBS vaginal colonization and 
serotypes 
x4 
 
x4 
 
Before rupture of membranes 
1 Haematology/biochemistry and urine protein/glucose testing will To be performed preferentially by local healthcare 
providersThe, as per local practice. To be performed by the investigator/study staff will collect biological 
samplesONLY if not done by the local healthcare provider as per local practice. When available, within 2 
weeks before the study visit. 
2 The investigator/site staff will perform a urine dipstick results for red blood cells (RBC) and white blood cells 
(WBC) will also be collectedtest using supplies provided by GSK.  
23 Haemoglobin only 
3This4If results are abnormal, subjects will be referred per local standard of care. 
5This sample may also be collected as from start of labor (e.g. when the mother arrives at the hospital to deliver 
and an intravenous line is inserted). 
4 only in countries with routine implementation of risk based intrapartum antibiotic prophylaxis for GBS  
• 
Sampling schedule for neonates/infants: During the 1-year post-birth surveillance 
period, for each RTI with suspicion of difficulty in breathing, or wheezing, or with 
parental concern, a nasal swab will be collected at the LRTI study visit a visit to 
assess potential LRTIs. 
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• 
Primary Completion Date (PCD): 42 days post-delivery/birth (i.e. Visit 6 for the 
mothers and Visit 2-NB for the infants) or last visit of Epoch 1002. 
• 
Duration of the study: Approximately 4.5 to 6 months for all participating pregnant 
women enrolled; approximately 1 year for all participating infants enrolled. 
− 
Epoch 001: Screening  
− 
Epoch 002: Primary starting at Visit 1 and ending 42 days post-delivery/birth 
(Visit 6 for the mothers and Visit 2-NB for the infants).* 
− 
Epoch 002003: Follow-up of infants starting 43 days post-delivery/birth and 
ending at Visit 5-NB (1 year post-birth). 
*Any safety and disease surveillance data collected after Visit 2-NB will be collected in 
Epoch 002 003.  
Table 2 and Synopsis Table 2 
Study groups and epochs foreseen in the study 
Study 
Groups 
Number of subjects 
enrolled 
Age (Min/Max) 
Epochs 
Epoch 001  
Epoch 002  
Epoch 003 
Mothers 
Up to  400 (by per 
country) 
18 years - 40 years  
● 
● 
 
Infants 
Up to  400 (by per 
country) 
NA  
 
● 
● 
To achieve the enrolment targets noted above, the number of pregnant women SCREENED in each 
country may exceed 400 
• 
Surveillance for pregnancy outcomes and pregnancy-related events of interest 
…..from enrolment Visit 1 up to 42 days after delivery. 
• 
Surveillance for neonatal events of interest ….. that occur from birth up to 28 days 
of age. 
• 
Surveillance for GBS invasive disease (refer to Section 8.6) in infants, from birth 
through 90 days of age. 
Case Definitions – Neonatal Events of Interest (Section 5.2) 
Invasive GBS disease 
GBS invasive disease is a serious bacterial infection that requires urgent referral to a 
hospital. A lack of prompt diagnosis and treatment may lead to infant death. Diagnosis of 
a case of GBS invasive disease requires routine collection of blood/cerebrospinal fluid for 
culture, and a subsequent GBS positive local laboratory result. 
Signs and symptoms of potentially serious bacterial infection that may be caused by GBS 
and lead to the routine collection of blood/cerebrospinal fluid for culture may include: 
• 
 not able to feed since birth or stopped feeding well (confirmed by observation) 
• 
convulsions  
• 
fast breathing (60 breaths per minute or more) among infants less than 7 days old 
• 
severe chest in-drawing  
• 
fever (38°C or greater) 
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• 
low body temperature (less than 35.5 °C)  
• 
movement only when stimulated or no movement at all. 
Case Definitions – Respiratory Tract Infection (RTI) / Lower respiratory tract 
infection (LRTI) (Section 5.3) 
During the data analysis of the study data, cases of respiratory tract infection (RTI) 
identified from birth up to 1 year of age will be classified according to the case 
definitions in Table 3. 
Footnote to Table 3: SpO2 = blood oxygen saturation by pulse oximetry. 
Study Population - Number of Subjects / Centres (Section 6.1) 
• 
Up The study will be conducted at multiple centres in multiple countries.  The total 
enrolled study population will consist of up to (approximately) 4004000 pregnant 
women ≥ and their neonates.  
• 
In each participating country, up to (approximately) 400 pregnant women ≥240/7 
weeks and <280/7 weeks of gestation are planned to will be enrolled per country.  . 
Neonates of enrolled pregnant women who consent to their child’s study 
participation will also be enrolled. 
Inclusion Criteria for Enrolment (Section 6.2) 
Pregnant Women 
• 
Healthy pregnant women 18-40 years of age who are ≥ 24 0/7 weeks GA at 
screening and < 28 0/7 weeks GA at Visit 1, as established by ultrasound 
examination and/or last menstrual period (LMP) date 
• 
Women whose pregnancy is considered low risk at the time of enrolment, based on 
medical history, obstetric history, and clinical findings during the current pregnancy  
• 
Women who had no significant findings (such as abnormal fetal morphology, 
amniotic fluid levels, placenta, or umbilical cord) observed during a Level 2 
ultrasound (fetal morphology assessment) after 18 0240/7 weeks and prior to 
enrolment .  
• 
HIV uninfected women who have been tested within the past year and have 
documented HIV negative test results at the time of enrolment.  
• 
Individuals (mother or mother and father) who, at the time of enrolmenttheir 
informed consent t, express willingness to enroll their infant in the study at the time 
of birth.  
• 
Individuals who, at the time of enrolment, are in good health as determined by the 
outcome of medical history, physical examination and clinical judgment of the 
investigator; 
• 
Individuals who, in the opinion of the investigator at enrolment can and will 
comprehend and comply with all study procedures (e.g., return for study follow-up 
visits, be contactable and available on a regular basis for surveillance). 
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Exclusion Criteria for Enrolment (Section 6.3) 
Pregnant Women 
• 
Individuals determined at the time of enrolment to have one of the following 
conditions associated with increased risk for a serious obstetrical complication 
(specify any/all that apply in the eCRF)  
− 
Gestational diabetes uncontrolled by diet and exercise as per American College 
of Obstetricians and Gynecologists guidelines (ACOG Practice Bulletin 2013);  
• 
Individuals determined to have (during the current pregnancy, prior to enrolment) 
one of the following infections or conditions associated with risk of adverse outcome 
(specify any/all that apply in the eCRF): 
• 
Individuals who at the time of enrolment have any underlying condition or infection 
that would predispose them to increased risk for a serious obstetrical complication 
that is not mentioned above 
• 
Individuals who at the time of enrolment have behavioral or cognitive impairment or 
psychiatric disease that, in the opinion of the investigator, could interfere with the 
subject's ability to participate in the study; 
• 
Individuals who at the time of enrolment have known or suspected impairment of the 
immune system, an active autoimmune disorder that is not well-controlled, or who 
are receiving systemic immunosuppressive therapy; 
Subject Identification (Section 8.1) 
Subject numbers for both pregnant women (mothers) consenting who consent to 
participate in the study andwill be assigned at screening.  Subject numbers for their (yet 
to be born) neonates will be assigned at Visit 1.  TheySubject numbers will be assigned 
sequentially according to the range of subject numbers allocated to each study centre.  
Subject numbers of mother –infant pairs will be clearly linked. 
General Study Aspects (Section 8.2) 
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the accompanying Study Procedures Manual (SPM). 
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Outline of Study Procedures (Section 8.3) 
Potential study participants (pregnant women) are to be screened at ≥ 24 0/7 weeks gestational age.  Pregnant women for whom 
eligibility has been confirmed are to complete Visit 1 not later than at 27 6/7 weeks gestational age..   
Table 4, List of Study Procedures (a new column – for the screening visit was added, and text was adjusted. Both the original Table and 
the revised Table are reproduced below.) 
List of study procedures for pregnant women/ mothers (original protocol) 
Gestational age 
24 0/7 - 27 6/7 
28 0/7 - 31 6/7 
32 0/7 - 35 6/7 
36 0/7 - delivery 
- 
- 
 
Epoch 
Epoch 001  
Type of contact 
Visit 1  
Visit 2 1  
Visit 3 1  
Visit 4 1  
Visit 5  
Visit 6 2 , 3  
Additional 
antenatal/medical 
evaluations (external to 
study visits/procedures) 
Timepoints 
Day 1 
Day 28  
Day 56  
Day 84 
At Delivery Post-Delivery 
Day 42  
 
Eligibility Review and Confirmation 
Informed consent  
●  
 
 
 
 
 
 
Check inclusion/exclusion criteria  
●  
 
 
 
 
 
 
Assign subject study number (mother)  
●  
 
 
 
 
 
 
Assign subject study number (child)  
O 
 
 
 
 
 
 
Inform study paediatrician and/or staff of subject’s 
participation  
O 
 
 
 
O 
 
 
Medical History / Examinations 
Distribute maternal health card  
O  
 
 
 
 
 
 
Record demographic and lifestyle characteristics data  
●  
 
 
 
 
 
 
Collect medical history  
●  
 
 
 
 
 
 
Collect obstetric history from current and past 
pregnancies 
●  
 
 
 
 
 
 
Travel history to, or living in, Zika virus endemic 
countries/regions  
●  
 
 
 
 
 ●  
 
Inquire whether mother would have agreed to take part 
in the study if an investigational vaccine were given  
● 
 
 
 
 
 
 
Record outcome of 2d trimester Level 2 ultrasound  
●  
 
 
 
 
 
 
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Gestational age 
24 0/7 - 27 6/7 
28 0/7 - 31 6/7 
32 0/7 - 35 6/7 
36 0/7 - delivery 
- 
- 
 
Epoch 
Epoch 001  
Type of contact 
Visit 1  
Visit 2 1  
Visit 3 1  
Visit 4 1  
Visit 5  
Visit 6 2 , 3  
Additional 
antenatal/medical 
evaluations (external to 
study visits/procedures) 
Timepoints 
Day 1 
Day 28  
Day 56  
Day 84 
At Delivery Post-Delivery 
Day 42  
 
Record outcome(s) of subsequent ultrasounds if 
performed  
●  
●  
●  
●  
 
 
●  
Record gestational age, expected date of delivery and 
method of EDD estimation  
●  
 
 
 
 
 
 
Record height  
●  
 
 
 
 
 
 
Record weight  
●  
●  
●  
●  
 
●  
●  
Record results of antenatal physical examination  
●  
●  
●  
●  
● 
●  
● 
Check and record medications, vaccinations, folate 
and/or iron (independently or included in a multivitamin) 
beginning the month before the estimated date of 
conception and while on study  
●  
●  
●  
●  
●  
●  
●  
Biological Specimens / Laboratory Test Results 
Collect blood sample for antibody assessment by 
sponsor (5 ml) 
● 5  
 
● 5  
 
●  
 
 
Collect cord blood for antibody assessment by sponsor 
(5 to 10 ml) 
 
 
 
 
●  
 
 
Collect vaginal swab to send to sponsor for analysis, 
where relevant   
● 5  
 
● 5  
 
●  
 
●  
Record results of blood sampling for local hematology/ 
biochemical analysis (10 ml) 4  
 ●  
 
 ● 6  
 
 
 
●  
Record results of urine dipstick to check for presence of 
proteins, glucose  4, 7  
●  
 ●  
 ●  
 ●  
 
 
●  
Record results of oral glucose tolerance test if 
performed by local healthcare provider and available  
●  
●  
●  
●  
 
 
●  
Record outcome of urine bacterial culture if performed 
by local healthcare provider and available  
●  
●  
●  
●  
 
 
●  
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Gestational age 
24 0/7 - 27 6/7 
28 0/7 - 31 6/7 
32 0/7 - 35 6/7 
36 0/7 - delivery 
- 
- 
 
Epoch 
Epoch 001  
Type of contact 
Visit 1  
Visit 2 1  
Visit 3 1  
Visit 4 1  
Visit 5  
Visit 6 2 , 3  
Additional 
antenatal/medical 
evaluations (external to 
study visits/procedures) 
Timepoints 
Day 1 
Day 28  
Day 56  
Day 84 
At Delivery Post-Delivery 
Day 42  
 
Record results of any peri-natal laboratory tests 
pertinent to assess maternal safety if performed by 
local healthcare provider and available  
●  
●  
●  
●  
●  
●  
● 
Labor / Delivery 
Record date and time of rupture of membranes  
 
 
 
 
●  
 
 
Record type of delivery 
 
 
 
 
●  
 
 
Record gestational age determined at delivery 
 
 
 
 
●  
 
 
Outcomes and Events of Interest 
Record Pregnancy/Delivery outcome(s)  
 
 
 
 
●  
 
 
Record pregnancy-related events of interest (and 
hospitalisations / other clinically significant events or 
diagnoses that could impact the pregnancy  
 
●  
●  
●  
●  
●  
●  
Serious Adverse Events 
Record SAEs related to study participation  
●  
●  
●  
●  
●  
●  
● 
Study Conclusion 
Study conclusion  
 
 
 
 
 
●  
 
Investigator sign-off on eCRF before analysis  
 
 
 
 
 
●  
 
eCRF = electronic case report form; SAE = serious adverse event; WHO = World Health Organization. 
● 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 The visit may be replaced by Visit 5 depending on the date of delivery. 
2 Visit 6 (Day 42) may take place in the subject’s home or at the investigator’s clinical facility as appropriate to the circumstances in the judgment of the investigator. 
3 To coincide with Visit 2-NB (Day 42) for infants. 
4 To be performed preferentially by local healthcare providers, in which case the information will be collected and recorded in the eCRF. The investigator/study staff will provide these 
procedures if not done by the local healthcare provider as per local practice.  If abnormal, subjects will be referred per local standard of care. 
5  Only in countries with routine implementation of risk based intrapartum antibiotic prophylaxis for GBS  
6 At Visit 3, only hemoglobin testing.  
7 When available, urine dipstick results for red blood cells (RBC) and white blood cells (WBC) will also be collected  
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List of study procedures for pregnant women/ mothers (Amended 12 February 2018) 
Gestational age 
≥ 24 0/7  -  27 
6/7 
24 0/7 –   
27 6/7 
28 0/7 - 
31 6/7 
32 0/7 - 
35 6/7 
36 0/7 - 
delivery 
 
 
 
Epoch 
Epoch 001  
Epoch 002  
Type of contact 
Screening  
Visit 1  
Visit 2 1  
Visit 3 1  
Visit 4 1  
Visit 5  
Visit 6 2 , 3  
Additional 
antenatal/medical 
evaluations (external to 
study visits/procedures) 4  
Timepoints 
 
Day 1 
Day 28 
Day 56 
Day 84 
At 
Delivery 
Post-
Delivery 
Day 42 
 
Eligibility Review and Confirmation 
 
 
 
 
 
 
 
 
Informed consent  
●  
 
 
 
 
 
 
 
Check inclusion/exclusion criteria  
●  
O  
 
 
 
 
 
 
Assign subject study number (mother)  
●  
 
 
 
 
 
 
 
Assign subject study number (child)  
 
O  
 
 
 
 
 
 
Inform study paediatrician and/or staff of subject’s 
participation  
 
O  
 
 
 
O  
 
 
Medical History / Examinations 
 
 
 
 
 
 
 
 
Distribute maternal health memory aid  
 
O   
O  
O  
O  
O   
 
 
Record demographic data  
●  
 
 
 
 
 
 
 
Record lifestyle characteristics  
 
●  
 
  
 
 
 
 
 Record outcome of Level 2 ultrasound (fetal morphology 
scan) 7  
●  
 
 
 
 
 
 
 
Record outcome(s) of subsequent ultrasounds if clinically 
significant 4  
 
O  
O  
O  
O  
O  
 
●  
Review and collect medical history  
O 
●  
 
 
 
 
 
 
Review and collect obstetric history from past pregnancies  
●  
 
 
 
 
 
 
 
Review and collect obstetric history from current 
pregnancy, including: gestational age, expected date of 
delivery and method of EDD estimation  
● 
 
 
 
 
 
 
 
Travel history to, or living in, Zika virus endemic 
countries/regions  
O  
●  
 
 
 
 
 
 
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Gestational age 
≥ 24 0/7  -  27 
6/7 
24 0/7 –   
27 6/7 
28 0/7 - 
31 6/7 
32 0/7 - 
35 6/7 
36 0/7 - 
delivery 
 
 
 
Epoch 
Epoch 001  
Epoch 002  
Type of contact 
Screening  
Visit 1  
Visit 2 1  
Visit 3 1  
Visit 4 1  
Visit 5  
Visit 6 2 , 3  
Additional 
antenatal/medical 
evaluations (external to 
study visits/procedures) 4  
Timepoints 
 
Day 1 
Day 28 
Day 56 
Day 84 
At 
Delivery 
Post-
Delivery 
Day 42 
 
Where authorized by the local Ethics Committee, 
inquire whether mother would have agreed to take part in 
the study if an investigational vaccine were given  
 
●  
 
 
 
 
 
 
Record outcome of HIV test 9  
●  
 
 
 
 
 
 
 
Record results of General and Obstetric examination  10 
●  
●  
●  
●  
●  
 
●  
● 13  
 Check and record prescription medications, vaccinations, 
folate and/or iron (independently or included in a 
multivitamin) 12   
 
●  
●  
●  
●  
●  
●  
 
Biological Specimens / Laboratory Test Results 
 
 
 
 
 
 
 
 
Collect blood sample for antibody assessment by sponsor 
(5 ml) 
 
 
 
 
 
●  
 
 
Collect cord blood for antibody assessment by sponsor 
(5 to 10 ml) 
 
 
 
 
 
●  
 
 
Record results of  local hematology/ biochemical analysis  
(up to 10 ml)  5  
 
●  
 
●  8  
 
 
 
● 13  
Record results of urine dipstick to check for presence of 
proteins, glucose, RBC, WBC  6  
 
● 
 ● 
●  
 ●  
 
 
● 13  
Record results of oral glucose challenge / tolerance test(s) 
if performed by local healthcare provider and available 4  
●  
O  
O  
O  
O  
 
 
● 
Record results of any clinically significant abnormal 
laboratory tests (including positive urine culture) if 
performed by local healthcare provider and available 4  
 
O  
O  
O  
O  
O  
O  
● 
Labor / Delivery 
 
 
 
 
 
 
 
 
Collect and record labor and delivery information 11  
 
 
 
 
 
●  
 
 
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Gestational age 
≥ 24 0/7  -  27 
6/7 
24 0/7 –   
27 6/7 
28 0/7 - 
31 6/7 
32 0/7 - 
35 6/7 
36 0/7 - 
delivery 
 
 
 
Epoch 
Epoch 001  
Epoch 002  
Type of contact 
Screening  
Visit 1  
Visit 2 1  
Visit 3 1  
Visit 4 1  
Visit 5  
Visit 6 2 , 3  
Additional 
antenatal/medical 
evaluations (external to 
study visits/procedures) 4  
Timepoints 
 
Day 1 
Day 28 
Day 56 
Day 84 
At 
Delivery 
Post-
Delivery 
Day 42 
 
Outcomes and Events of Interest 
 
 
 
 
 
 
 
 
Record Pregnancy/Delivery outcome(s)  
 
 
 
 
 
●   
 
 
Record pregnancy-related events of interest and other 
clinically significant events or diagnoses that could impact 
the pregnancy  
 
●   
●   
●   
●   
●   
●  
 
Record all hospitalizations (except hospitalization for 
delivery), and all extensions of hospitalizations (including 
extension of hospitalization for delivery).  
 
●  
● 
● 
● 
● 
●  
 
Serious Adverse Events 
 
 
 
 
 
 
 
 
Record SAEs related to study participation 
 
●  
●  
●  
●  
●  
●   
 
Screening/Study Conclusion 
 
 
 
 
 
 
 
 
Screening conclusion  
●  
 
 
 
 
 
 
 
Study conclusion  
 
 
 
 
 
 
●  
 
Investigator sign-off on eCRF before analysis  
●   
 
 
 
 
 
●  
 
SAE = serious adverse event; ● is used to indicate a study procedure that requires documentation in the individual electronic case report form (eCRF)  
 ○ is used to indicate a study procedure that does not require documentation in the individual eCRF. 
1  If delivery occurs prematurely, skip to Visit 5 ("at delivery").  
2  Visit 6 (Day 42) may take place in the subject’s home or at the investigator’s clinical facility as appropriate to the circumstances in the judgment of the investigator. 
3 To coincide with Visit 2-NB (Day 42) for infants.   
4  Information from additional antenatal / medical evaluations (external to study visits/procedures) may be collected during, before or after a scheduled study visit but should only be 
recorded in the additional antenatal/medical evaluations eCRF. 
5 To be performed preferentially by local healthcare providers as per local practice. To be performed by the investigator/site staff ONLY if not done by the local healthcare provider 
within 2 weeks before the study visit. If results are abnormal, subjects will be referred per local standard of care.  
6  The Investigator/ site staff will perform a urine dipstick test to detect the presence of proteins, glucose, RBC and WBC.   
7 If ultrasound results are not available at time of screening, the ultrasound can be performed as a study procedure under certain conditions. Refer to SPM for further 
details. If abnormal, subjects will be referred per local standard of care.  [Table 4 Footnotes continue on the next page] 
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Table 4 Footnotes Continued 
8 At Visit 3, only hemoglobin testing.  
9 If HIV test results are not available at time of screening, the HIV test can be performed as a study procedure under certain conditions. Refer to SPM for further details. If 
results are positive, subject will be referred per local standard of care.  
10  Height at screening. Weight, vital signs, fetal heart tones, fetal movement, and fundal height at Screening and Visits 1 – 4.  Vital signs at Visit 6.   
11 Includes date and time of rupture of membranes, date and time of delivery, type of delivery, and other delivery information related to the health and safety of the mother 
and fetus. 
12 Beginning the month before the estimated date of conception and while on study.  (Routine concomitant medications administered during labor and delivery need not 
be collected.) 
Table 5, List of Study Procedures (both the table from the original protocol and the amended table are reproduced below). 
List of study procedures for neonates/ infants (original protocol) 
Epoch 
Epoch 001  
Epoch 002  
Epoch 002  
Age 
0-10 days  
42 Days 
12 months 
0-12 months 
Type of contact 
Visit 1-NB  
Visit 2-NB a  
Visit 3-NB a  
Contact for active/ passive 
surveillance b 
LRTI Assessment 
visit a c  
Timepoints 
Birth  
Day 42 
Y1  
 
 
Check inclusion/exclusion criteria  
●  
 
 
 
 
Obtain informed consent of parent(s)/LAR(s) 
● 
 
 
 
 
Record infant’s subject number 
● 
 
 
 
 
Record Apgar assessment  
● 
 
 
 
 
Record demographic and lifestyle characteristics data  
 
● 
 
 
 
Distribute child health card 
O 
 
 
 
 
Distribute RTI episode card (memory aid) to record 
disease symptoms 
O 
 
 
 
O 
Physical examination including weight, length and head 
circumference 
● 
● 
● 
 
 
Record medications / vaccinations / vitamins  
●  
●  
●  
 
 
Record neonatal events of interest  
● 
●  
● 
 
 
Nasal swab  
 
 
 
 
● 
Record occurrences of GBS invasive disease (sepsis, 
pneumonia and meningitis)  
● 
●  
●  
●  
 
Record outcome of GBS blood or cerebrospinal fluid 
testing, if performed by a local healthcare provider  
● 
● 
●  
●  
 
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Epoch 
Epoch 001  
Epoch 002  
Epoch 002  
Age 
0-10 days  
42 Days 
12 months 
0-12 months 
Type of contact 
Visit 1-NB  
Visit 2-NB a  
Visit 3-NB a  
Contact for active/ passive 
surveillance b 
LRTI Assessment 
visit a c  
Timepoints 
Birth  
Day 42 
Y1  
 
 
Record all hospitalizations and/or clinically significant 
events 
● 
● 
● 
● 
● d  
Record SAEs related to study participation  
● 
● 
● 
● 
● 
Study conclusion  
 
 
● 
 
 
Investigator sign-off on eCRF before analysis  
 
● 
●  
 
 
eCRF = electronic case report form; GBS = Group B Streptococcus; LAR = legally acceptable representative; LRTI = lower respiratory tract infection; M = month; NB = newborn; RTI = 
respiratory tract infection; SAE = serious adverse event; Y = year 
Grey shaded columns represent study procedures to be performed for active/passive surveillance of RTIs which are applicable throughout the entire study period (from birth up to study 
end).  
Note: The double-line borders indicate primary analyses. 
● 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. 
a Visit 2-NB (Day 42), Visit 3-NB (Year 1) and LRTI assessment visits may take place in the subject’s home or at the investigator’s clinical facility as appropriate to the circumstances in 
the judgment of the investigator, and if the standard of care allows home visits  
b Supplemental information about invasive GBS disease and hospitalization will be solicited during select RTI active surveillance contacts in order to capture GBS events that occur 
within the first 90 days of life. Relevant medical record abstraction should be performed for identified occurrences. 
c If an LRTI assessment visit is conducted, a nasal swab is collected, and the parents return for a follow-up LRTI assessment visit at which symptoms have diminished / resolved, no 
additional nasal swab need be collected. If an LRTI assessment visit is conducted, a nasal swab is collected, and the parents return for a follow-up LRTI assessment visit because 
symptoms have worsened, an additional nasal swab may be collected at the discretion of the investigator.  
d If not previously communicated during a surveillance contact  
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List of study procedures for neonates/ infants (Amended 12 February 2018) 
Epoch 
Epoch 002  
Epoch 003  
Epoch 002 and Epoch 003  
Age 
0-10 days  
42 Days 
12 months 
0-12 months 
Type of contact 
Visit 1-NB  
Visit 2-NB a  
Visit 3-NB a  
Contact for active/ 
passive 
surveillance   
Visit to 
assess 
potential LRTI 
a  
Timepoints 
Birth  
Day 42 
Y1  
 
 
Check inclusion/exclusion criteria  
●  
 
 
 
 
Obtain informed consent of parent(s)/LAR(s)  
● 
 
 
 
 
Record infant’s subject number  
● 
 
 
 
 
Record Apgar assessment  
● 
 
 
 
 
Record demographic data  
● 
 
 
 
 
Record lifestyle characteristics  
 
●  
 
 
 
Distribute infant health and RTI memory aid  
O  
O  
 
 
O  
Weight, length, head circumference, results of targeted medical history, and results 
of physical examination  
●  
●  
●  
 
 
Record prescription medications / vaccinations 
●   
●   
●   
 
● 
Record neonatal events of interest  
● 
● 
● 
 
 
Clinical evaluation of potential LRTI  
 
 
 
 
●  
Nasal swab b  
 
 
 
 
● b  
Record all hospitalizations and/or clinically significant events  
●  
●  
●  
●  
●  
Record SAEs related to study participation  
●  
●  
●  
●  
●  
Study conclusion  
 
 
●  
 
 
Investigator sign-off on eCRF before analysis  
 
●  
●  
 
 
LAR = legally acceptable representative; LRTI = lower respiratory tract infection; NB = newborn; RTI = respiratory tract infection; SAE = serious adverse event; Y = year.  Grey shaded 
columns represent study procedures to be performed for active/passive surveillance of RTIs/LRTIs which are applicable throughout the entire study period (from birth up to study 
end). Note: The double-line borders indicate primary analyses.   Footnotes to Table 5 continue on the next page.Table 5 footnotes continued 
● is used to indicate a study procedure that requires documentation in the individual electronic case report form ( eCRF).   
○ is used to indicate a study procedure that does not require documentation in the individual eCRF. 
a Visit 2-NB (Day 42), Visit 3-NB (Year 1) and LRTI assessment visits may take place in the subject’s home (if the standard of care allows for home visits), at the investigator’s 
clinical facility or at another facility per the investigator’s judgment. 
b If more than one assessment visit is conducted to evaluate a potential LRTI episode, additional nasal swabs may be collected at the discretion of the Investigator.  
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Intervals Between Study Visits/Contacts (Section 8.4) 
Table 6: Intervals between study visits/contacts/observations 
Interval 
Optimal interval*** 
Allowed interval** 
Screening → Visit 1 
1 days 
0 – 28 days 
**If a subject returns for the visit outside the recommended allowed time interval, he/she will may still be considered 
for the analysis. 
Investigators should make at least 3 documented attempts (through telephone call(s) or 
any other convenient procedure) to contact (as relevant) the pregnant woman/mother 
or the child’s parents/ LAR(s) (or their designates) if they do not return for scheduled 
visits or follow-up. Additional details can be found in the SPM. 
Eligibility Review and Confirmation (Section 8.5.1) 
• 
Check all applicable inclusion and exclusion criteria as described in Sections 6.2 and 
6.3 before enrolment and record resultsfor each criterion in the eCRF.   
• 
Assign / record subject study number (motherpregnant woman) 
• 
Assign subject study number (infant) for eligible pregnant women who complete 
Visit 1. 
• 
Inform study paediatrician and/or staff of subject’s the pregnant woman’s 
participation 
− 
A copy of the informed consent should be forwarded to the study paediatrician 
and/or staff as soon as possible after the subject’s a pregnant woman’s 
enrolment to ensure the study paediatrician is informed in a timely manner of 
the approximate date of delivery and potential enrolment of the neonate. 
History and Examinations for pregnant women/mothers (Section 8.5.2) 
• 
Distribute maternal health card the Maternal Health Memory Aid. It is intended to 
serve as a reference during study visits/contacts, to help the subject provide the 
investigator/ study staff with protocol-specified data (and contact information for 
other healthcare providers, so medical records may be requested if 
required).  (Refer to the SPM for details). 
• 
Record demographic and lifestyle characteristics data. Demographic data, which 
may include (but is not limited to) information such as race, month and year of 
birth, ethnicity, and geographic location. Lifestyle characteristics (exposures) may 
include data on factors such as smoking status/exposures, household environment 
and other factors that could place subjects at risk of study outcomes. 
• 
Record information about lifestyle characteristics (exposures), which may include 
(but are not limited to) data on highest level of education, factors such as smoking 
status/exposures, household environment, and other factors that could place subjects 
at risk of study outcomes. 
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• 
Record outcome of 2d trimester (Level 2 ultrasound (fetal morphology assessment). 
Please see GLOSSARY OF TERMS for description.  If Level 2 ultrasound results 
are not available at screening, then the ultrasound can be performed as a study 
procedure under certain conditions. Refer to the SPM for further details. 
• 
Record outcome(s) of any subsequent ultrasoundsultrasound(s) ONLY if clinically 
significant.Record gestational age along with GAIA level of certainty using 
priorities defined in APPENDIX C  
• 
Record expected date of delivery (EDD) and method of estimation 
• 
Record medical / obstetric history 
− 
Obtain the subject’s medical history by interview and/or review of her medical 
records; record any pre-existing conditions or signs and/or symptoms present 
before participation in the study. Targeted questions may be asked about 
allergies, respiratory diseases (including asthma) and other conditions that may 
be related to study outcomes. 
− 
Obtain the subject’s obstetric history by interview and/or review of her medical 
recordsrecord any data from current and .  
− 
For past pregnancies, record: 
o 
number of past pregnancies and  their outcome(s), 
o 
presence of caesarian section scars (if any). 
− 
For the current pregnancy, record: 
o 
number of prenatal visits attended up to the date of the study Screening 
visit, 
o 
approximate date of first prenatal visit, 
o 
results of any clinically significant, abnormal pregnancy screening 
laboratory tests, 
o 
results of any procedures intended to screen for congenital anomalies. 
Inquire Where authorized by the local Ethics Committee, inquire whether 
mother would have agreed to take part in the study if an investigational vaccine 
were given and record the answer  
• 
Record height at baseline screening and weight at screening and Visits 1-4 and 6. 
Measurements Height measurements should be performed………….. 
• 
Record results of antenatal General and Obstetric examination 
Unless the study visit is performed concurrently with a routine antenatal care visit 
inat which the below data are collected, the investigator/study staff should perform 
an antenatal physical examination: General and Obstetric examinations as follows:  
− 
All visits through Screening, Visits 1 – 4, and Visit 6 should include assessment 
of vital signs (systolic/diastolic blood pressure, heart rate and respiratory rate 
after at least 10 minutes of rest);  
− 
All visits through Visit 5 Screening and Visits 1 - 4 should include assessment 
of fetal heart tones, fetal movement, and fundal height; 
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o 
Visit 1 should include assessment of any scars from prior deliveries. 
− 
If the Screening Visit and Visit 1 occur on the same day, only one General and 
Obstetric examination will be performed. 
• 
Record medications / vaccinations / folate and iron supplements beginning the month 
before the estimated date of conception and while on study(this includes medications 
administered during labor and delivery).  
− 
ONLY medications that are NOT routine should be recorded during labor and 
delivery.  
Biological Specimens / Laboratory Data for pregnant women/mothers (Section 8.5.3) 
Blood samples for assessment of antibody titers/concentrations:  An overall volume of 
approximately 155 mL 
− 
Vaginal Swabs:  
− 
In countries with routine implementation of risk based intrapartum antibiotic 
prophylaxis for GBS, vaginal swabs should be collected at Visits 1, 3, and 5 
(prior to rupture of membranes). In countries without routine implementation of 
risk based intrapartum antibiotic prophylaxis for GBS, vaginal swabs should 
ONLY be collected at Visit 5 (prior to rupture of membranes). 
− 
WHO does not currently recommend the use of vaginal swabs to screen for GBS 
colonization. 
− 
The vaginal swabs collected in this study will be used solely for epidemiological 
purposes. Samples will be analyzed by a central testing laboratory and results 
will not be available for diagnostic purposes. Thus, vaginal swabbing conducted 
as a study procedure is not intended to replace local standard of care practices or 
to inform clinical management.   
• 
The Investigator/site staff will arrange for collection of maternal blood and cord 
blood samples at delivery. 
• 
The Investigator/site staff will perform urine dipstick tests using supplies provided 
by GSK. 
• 
If HIV test results are not available at time of screening, the HIV test can be 
performed as a study procedure under certain conditions.  Refer to the SPM for 
further details. If results are positive, the subject will be referred per local standard 
of care. 
• 
It is preferred that local healthcare providers perform haematology and 
biochemistry tests per local practice; the investigator/site staff will perform these 
procedures then collect and record the results. The investigator/site staff will only 
perform haematology/biochemistry tests if not done by the local healthcare 
provider as per local practice within 2 weeks before a study visit. 
− 
Perform dipstick test for presence of proteins and glucose in urine. When 
available, red blood cell (RBC) and white blood cell (WBC) results will also be 
collected.  
− 
Perform HIV test at Screening (to assess eligibility) 
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• 
If performed record by local healthcare provider and available, the investigator/site 
staff will also: 
− 
Record oral glucose challenge / oral glucose tolerance test results 
− 
If performed, recordRecord any positive urine bacterial culture results  
− 
Record abnormal and clinically significant laboratory test results  
− 
Record results of any laboratory tests pertinent to assess maternal safetyGroup 
B Streptococcus screening test(s). 
Labor and Delivery (Section 8.5.4) 
Record information related to labor and delivery; should include the following:, 
including:  
• 
Medications administered during labor and delivery (if not routine) 
• 
Gestational age as determined at delivery 
Additional antenatal/medical evaluations General and Obstetric examinations 
(Section 8.5.7) 
For any additional antenatal/medical evaluationsGeneral and Obstetric examinations at 
which a pregnancy related event of interest is identified, record information that supports 
the diagnosis of the event. 
Medications, Vaccinations, and Supplements for pregnant women/mothers (Section 
8.5.5) 
• 
Record medications / vaccinations / folate and iron supplements beginning the 
month before the estimated date of conception and while on study. 
− 
Folic acid and/or iron supplements should be reported when taken 
independently and/or when included in a multivitamin mineral supplement.  
− 
ONLY medications that are NOT routine should be recorded during labor and 
delivery.  
Surveillance for Outcomes and Events of Interest in pregnant women/mothers  
(Section 8.5.6) 
− 
Maternal events of interest (including, but not limited to, those described in 
Section 11.1.1) occurring up to Visit 6 (Post-delivery Month 1.5) should be 
recorded in the eCRF along with additional details pertinent to the diagnosis, 
GAIA assessment and level of diagnostic certainty (Appendix D), when 
applicable. 
• 
Record all hospitalizations and/or clinically significant events.  
• 
Record all study participation related SAEs as specified in Section 9. 
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Eligibility Review and Confirmation for Neonates / Infants (Section 8.6.1) 
• 
Check all applicable inclusion and exclusion criteria as described in Sections 6.2 and 
6.3. A pre-selected childA neonate who does not meet the eligibility criteria should 
be considered ineligible. 
• 
Obtain informed consent from parent(s) / LAR(s) at Visit 1-NB, and update as per 
local requirements. 
History and Examinations for Neonates / Infants (Section 8.6.2) 
• 
Record demographic data and lifestyle characteristics at birth, and any changes in 
this information at subsequent visits: Data includes, including date of birth, gender,  
race and ethnicity; living environment and household composition, breastfeeding, 
passive smoking and day-care attendance  
• 
Record lifestyle characteristics. Data may include (but are not limited to) passive 
smoking and day-care attendance. 
• 
Record weight, length,  and head circumference at birth and at subsequent study 
visits.and results of age-targeted medical history, and results of physical 
examination(s).  
• 
Record prescription medications/ vaccinations vitamins 
• 
Record all hospitalizations and/or clinically significant events. For hospitalizations 
where an RSV infection is suspected, refer to Section 8.6.6. 
• 
Distribute Child the Infant Health CardA child health card will be distributedand 
RTI Memory Aid to the parent(s)/LAR(s)/designate(s) at Visit 1-NB if one is not 
already provided by).  Health and RTI Memory Aid to the 
parent(s)/LAR(s)/designate(s).  The memory aid is intended to serve as a reference 
during study visits/contacts, to help parent(s)/LAR(s)/designate(s) provide the 
investigator/ study staff with protocol-specified data (and contact information for 
other healthcare providers, so medical records may be requested if required). Refer 
to the healthcare provider. SPM for additional details. 
• 
Record all hospitalizations and/or clinically significant events. For hospitalizations 
where an RSV infection is suspected, refer to Section 8.6.6. 
• 
Record all study participation related SAEs (Section 9). 
Surveillance for Invasive GBS disease (Deleted Section) 
• 
To ensure that all GBS cases are captured, data regarding occurrence of GBS 
invasive disease (sepsis, pneumonialifestyle characteristics and meningitis) will be 
collected within the first year of life, with a particular emphasis being placed on the 
first 90 days. Instructions will be given to mothers and local health care providers 
(through child health cards) to contact the study staff any subsequent changes in 
case of occurrence of GBS invasive disease. Information regarding GBS blood 
testing in the neonates/infants will be collected if performed by a local healthcare 
provider. In order to identify potential GBS cases that occur beyond Visit 2-NB,this 
information about potential GBS invasive disease in the first 90 days of life will be 
solicited during LRTI active surveillance contacts (described in Section 8.5.5). 
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During the initial months of LRTI surveillance, supplemental questions related to 
invasive GBS disease.Data includes living environment and household 
composition, breastfeeding, passive smoking and hospitalization will be included 
with the LRTI script.   
• 
In case of suspected neonatal sepsis, pneumonia or meningitis, the outcome of blood 
or cerebrospinal fluid test results for GBS should be documented in the infant’s 
eCRF if performed by a local healthcare provider day-care attendance. 
Surveillance for Neonatal events of interest (Section 8.6.3) 
• 
Investigators should make at least 3 documented attempts (through telephone call(s) 
or any other convenient procedure) to contact the child’s parents/ LAR(s) (or their 
designates) if they do not return for scheduled visits or follow-up. Additional details 
can be found in the SPM.    
Surveillance for episodes of potential Lower Respiratory Tract Infection (LRTI) 
(Section 8.6.4) 
Definitions (Section 8.6.4.1) 
• 
Symptoms of Respiratory Tract Infection (RTI) include: 
− 
regular bursts of cough,  
− 
nasal discharge running freely out of the infant’s nose (runny nose), or  
− 
breathing through the mouth because the infant’s nose is blocked (blocked 
nose).  
• 
An episode of potential lower respiratory tract infection (LRTI) is one in which the 
infant has one or more of the RTI symptoms listed above AND at least one of the 
following: 
− 
Difficulty in breathing (fast breathing, poor feeding, working hard to breathe, 
or making unusual sounds when breathing); 
− 
Wheezing (a whistling sound when the infant breathes out); 
− 
Parental concern (the parent(s)/LAR(s) or their designate(s) are concerned 
about the infant’s respiratory tract illness or general health and intend to seek 
medical care). 
− 
An RTI episode starts on the day when (per parental report) the first RTI 
symptom started.  
− 
An RTI episode ends on the day when (per parental report) the last RTI 
symptom resolved. 
− 
There must be at least 7 symptom-free days between 2 consecutive RTI 
episodes.  
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Overview (Section 8.6.4.2) 
It will be accomplished via two types of contact.  Both may be made with/ by either the 
Parent(s)/ LAR(s), or a person designated by the parent(s)/LAR(s), such as 
grandparents or a nanny (as long as the parent(s)/LAR(s) have given approval).  
• 
In an Active, wherein contact, site personnel contact the subject’s parent(s) / 
LAR(s) or their designate(s).  Active contacts will occur at regular intervals and will 
be scripted.  
• 
In a Passive, wherein contact, the subject’s parent(s) / LAR(s) or their designate(s) 
notify site personnel.  Site personnel will use a script to guide data collection once 
a passive contact has been made. 
Active and passive surveillance contacts can also be made with/by a person designated by 
the parent(s)/LAR(s) (e.g. grandparents, nanny) as long as the parent(s)/LAR(s) have 
given approval.  
Site staff will use information gathered during each active or passive surveillance 
contact to determine whether a visit to assess a potential LRTI …..should be scheduled. 
For all interactions between parent(s)/LAR(s)/designates and study staff, the safety 
of the infant is paramount. For any reported illness, the investigator/study staff 
should assess the need for any intervention and provide this as part of regular 
healthcare or instruct/advise the parent(s) / LAR(s) where to obtain thisseek care as 
necessary.  This study is not intended to replace local standards of care. 
Figure 2 
Two footnotes have been deleted, and 4 footnotes have been added to the figure.  
Revisions to the footnotes are presented on this page.  The figure itself is presented on the 
next page.  In the figure, the phrase “Perform assessment visit within 3 days” has been 
changed to read “Perform assessment visit ideally within 3 days.” 
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RR: Respiratory rate: SpO2: Blood oxygen saturation by pulse oximetry.. 
Refer to the GLOSSARY OF TERMS for a definition of RTI with parental concern. 
1 Refer to the Study Procedures Manual (SPM) for signs and symwardhanptoms to be collected. 
1Details regarding Active and Passive Surveillance are provided in Sections 8.6.4.3, 8.6.4.4, and the SPM. 
2Cough, runny nose, blocked nose, difficulty in breathing, wheezing and parental concern are defined in 
Section 8.6.4.1. 
3Details regarding the assessment visit to evaluate a potential LRTI are provided in Section 8.6.5and the SPM. 
4 Post-visit follow up is described in Section 8.6.6 and in the SPM. 
5If a follow-up assessment visit is conducted, collection of additional nasal swabs are at the Investigator’s 
discretion.  
Active or Passive surveillance 
contact 1
Yes
Yes
No
Yes
No
No
Perform assessment visit 3, 4 ideally
within 3 days:
•
Document signs and symptoms
•
Record RR and SpO2 
•
Record health care utilization
•
Nasal swab 5
OR
•
Document details from medical records
Difficulty in breathing OR 
wheezing OR parental 
concern? 2
Cough OR runny nose OR 
blocked nose OR difficulty in 
breathing OR wheezing? 2
Remind to report any worsening 
of symptoms
Remind to report any future 
symptoms
Worsening of 
symptoms? 4
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Active surveillance (Section 8.6.4.3) 
The purpose of the contact is to check with the infant’s parent(s)/LAR(s) or their 
designate(s) if, as defined in Section 8.6.4.1:  
• 
the infant has developed (new RTI symptoms (cough, runny nose or blocked nose),  
• 
the infant has developed new) symptoms of RTI, difficulty in breathing, or 
wheezing  
the parent(s)/LAR(s) (or their designate(s)) are concerned about the infant’s RTI signs 
and/or symptoms (there is parental concernDuring active surveillance contacts, Parent(s) 
/LAR(s) (or their designates) will be reminded to record RTI symptoms, their start and 
stop dates, and any medications taken, on the RTI episode card.  
Passive Surveillance (Section 8.6.4.4) 
Infants’ parents/LAR(s) or their designate(s) will be instructed to contact the site 
whenever: 
• 
theirthe infant has developed (new) symptoms of RTI, difficulty in breathing, or 
wheezing  as defined in Section 8.6.4.1,  
• 
 they (the parent(s) / LAR(s) or their designate(s)) are concerned about the infant’s 
RTI signs and/or symptoms worsen 
• 
there is parental concern as defined in Section 8.6.4.1. 
• 
During passive surveillance contacts, Parent(s) /LAR(s) (or their designates) will be 
reminded to record RTI symptoms, their start and stop dates, and any medications 
taken, on the RTI episode card.  
Decision to conduct a visit to assess a potential LRTI (Section 8.6.4.5) 
If there is NO suspicion of difficulty in breathing, nor wheezing, nor parental concern: 
• 
No LRTI assessment visit will be conducted. 
If there IS difficulty in breathing, or wheezing (both based on parental assessment), or 
there is parental concern:  
• 
The parent(s)/LAR(s) will be informed that their infant potentially has a(n) (new) 
LRTI,  
• 
AnLRTI assessment visit will be conducted as soon as possible, ideally within 3 
calendar days after learning of the potential LRTI case (Section 8.6.5).  
If it is not possible to perform the clinical evaluation and collect a nasal swab during an 
assessment visit (for example, if the child develops a potential LRTI while the family is 
travelling), then the LRTI assessment visit page of the eCRF should be filled in as 
completely as possible using available medical records. 
Visit to assess a potential LRTI (Section 8.6.5) 
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Overview (Section 8.6.5.1) 
The visit may take place in the subject’s home (if allowed per standard of care), the 
investigator’s clinical facility or another medical facility, as appropriate to the 
circumstances inper the judgment of the investigator. 
Note that if the reported symptoms are of a level of severity that warrantssevere 
enough to warrant urgent care, the parent(s)/LAR(s)/designates should be advised 
to seek urgent such care (e.g. Emergency Room).  
Clinical evaluation (Section 8.6.5.2) 
The investigator/study staff will evaluate the clinical signs and symptoms of the RTI. 
Signs and symptoms Data to be collected and recorded in the eCRF will be listed in the 
Study Procedures Manual (SPM).include (but are not limited to): 
• 
Temperature 
• 
Respiratory rate 
• 
Blood oxygen saturation (measured by pulse oximetry in room air, if feasible) 
• 
Signs of difficulty in breathing (including wheezing,  tachypnoea, nasal flaring, 
chest in-drawing and apnoea)  
Refer to the Study Procedures Manual (SPM) for additional details. 
Nasal Swab (Section 8.6.5.3) 
Follow up assessment 
A nasal swab will be collected using sponsor-provided supplies and sent to the sponsor 
laboratory for detection of RSV-A/B using quantitative RT-qPCR.  
If an LRTI more than one assessment visit is conducted to evaluate a nasal swab is 
collected, and the parents return for a follow-up LRTI assessment visit at which 
symptoms have diminished / resolved, nopotential LRTI episode, additional nasal swab 
need be collected. 
If an LRTI assessment visit is conducted, a nasal swab is collected, and the parents return 
for a follow-up LRTI assessment visit because symptoms have worsened, an additional 
nasal swabswabs may be collected at the discretion of the investigatorInvestigator. 
Note: If other nasal swabs are collected and tested locally as per routine standard of 
care, results will be entered into the eCRF. However, only the sponsor laboratory 
results will be used when applying the case definitions for data analysis in Table 3. 
Missed assessment visit (Section 8.6.5.4) 
Note that the visit may be conducted, and a nasal swab collected, as long as symptoms 
are ongoing. 
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If it is truly not possible to perform an assessment visit (for example, if the child 
develops a potential LRTI while the family is travelling, and all symptoms have 
resolved by the time the family returns), then the LRTI assessment visit page of the 
eCRF should be filled in as completely as possible using available medical records.   
Follow-up after an assessment visit to evaluate a potential LRTI (Section 8.6.6) 
After an assessment visit (Section 8.6.5) the infant will be followed with at least weekly 
active surveillance contacts, until the RTI/LRTI episode has resolved. During these 
active contacts, worsening of symptoms will be assessed. Parent(s) / LAR(s) / 
designate(s) will be reminded to call/contact/visit the site if symptoms worsen.  
If parent(s)/LAR(s)/designates report during an active or passive contact that 
symptoms have worsened, the site should perform a follow-up  visit. 
During the follow-up visit, collection of a nasal swab is at the Investigator’s discretion.  
Additional details can be found in the SPM.   
RSV Hospitalization (Section 8.6.7) 
• 
Study staff will collect If possible, a nasal swab will be collected from any subject 
who has beenis hospitalized with a RTI (or soon after release, as long as symptoms 
are ongoing, per SPM specifications). The nasal swab should be collected using 
sponsor-provided supplies, for transmission to and testing by the sponsor laboratory.   
• 
In order to establish a fast and accurate diagnosis, collection (using locally 
providedlocal supplies) of an additional nasal swab for testing at a local laboratory is 
recommended.  
• 
If other specimens are collected and tested locally as per routine standard of care, 
results will be entered into the eCRF. However, only the sponsor laboratory results 
will be used when applying the case definitions for data analysis in Table 3. 
Baseline Screening failures (Section 8.9) 
BaselineScreening failures are defined as subjects who withdraw or are withdrawn from 
the study after giving informed consent, but before study eligibility (presence of all 
inclusion and absence of all exclusion criteria) is confirmed.  The Day 1 
discoveryDiscovery during screening of any pregnancy related-event of interest or other 
condition that violates the requirements for study enrolmenteligibility should be 
considered to be a baselinescreening failure. Discovery during Visit 1 of any condition 
that violates the requirements for study eligibility should also be considered a 
screening failure.  
The subsequent development of such conditions (after DayVisit 1) aredoes not baseline 
failuresconstitute screening failure and should be captured on the eCRF, as applicable.  
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Limited data for screening failures will be reported to the eCRF.  This limited data set is 
specified in the eCRF. for screening failures will be limited to: 
• 
ICF information 
• 
Demographic data 
• 
Inclusion/Exclusion criteria 
• 
Level II /Fetal Morphology Ultrasound 
• 
Screening conclusion data 
• 
Study conclusion data. 
Medical history and OB/GYN physical assessment data (including height, weight and 
vital signs) do not need to be reported to the eCRF. 
Table 7 Biological samples 
Sample Type† 
Quantity 
Unit 
Timepoint 
Group 
Samples collected by Investigator / site staff 
Maternal Blood for antibody titers 
 5 
ml 
Visit 1 (Day 1)15 (Delivery) 
All mothers in 
selected countries 
 
 5 
ml 
Visit 3 (Day 56)1 
 
 5 
ml 
Visit 5 (Delivery) 
All pregnant 
women (mothers) 
Vaginal swab 
- 
- 
Visit 1 (Day 1)1 
All mothers in 
selected countries 
- 
- 
Visit 3 (Day 56)1 
- 
- 
Visit 5 (Delivery) 2 
All mothers 
Nasal swab 
- 
- 
LRTI Assessment visit 
All infants, event-
driven 
Urine (dipstick)1 
- 
- 
Visit 1 (Day 1) 
All  
 
 
 
 
Visit 2 (Day 28) 
pregnant women  
 
 
 
 
Visit 3 (Day 56) 
(mothers) 
 
 
 
 
Visit 4 (Day 84) 
 
Cord blood 
 5 up to 
10 
ml 
Visit 5 (Delivery) 
All pregnant 
women (mothers) 
(provides infant 
antibody levels) 
Nasal swab 
- 
- 
LRTI Assessment visit 
All infants, event-
driven 
Samples preferentially collected by local health care provider per local practice1 
Maternal Blood for haematology/ 
biochemistry 
Up to 10 
ml 
Visit 1 (Day 1) 
All pregnant 
women (mothers) 
 
Up to 10 
ml 
Visit 3 (Day 56)2 
Urine (dipstick) 
 
- 
- 
Visit 1 (Day 1) 
All  
 
 
 
 
Visit 2 (Day 28) 
(mothers) 
 
 
 
 
Visit 3 (Day 56) 
 
 
 
 
 
Visit 4 (Day 84) 
 
 
 
 
Visit 5 (Delivery) 
 
1 Only in countries where routine implementation of risk based intrapartum antibiotic prophylaxis for GBS is the 
standard of care 
2Vaginal swab at delivery will only be collected prior to rupture of membranes. 
3Performed 1 To be performed preferentially by local healthcare providers, as per local practice. To be performed by 
the investigator/study staff ONLY if not done by the local healthcare provider within 2 weeks before the study 
visit. 
2 Hemoglobin only 
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Antibody determination (Section 8.10.3.1) 
• 
Testing for GBS antibody concentrations will be performed upon availability of 
assay. 
Table 8 Humoral immunity (Antibody determination) 
System 
Component 
Method** 
Kit / 
Manufacturer 
Unit 
Cut-off* 
Laboratory** 
SERUM 
Respiratory 
Syncytial 
Virus A Ab 
NEUTRALISATION 
In house 
ED60 
To be 
defined 
GSK Biologicals or GSK 
designated lab*** 
SERUM 
GBS 
antibody 
To be defined 
To be defined 
To be 
defined 
To be 
defined 
GSK Biologicals or GSK 
designated lab*** 
GBS assessment of vaginal swabs 
GBS vaginal colonization will be assessed by culture and/or molecular biology 
methodologies (GSK Biologicals or GSK designated laboratory) upon assay availability. 
If available, local laboratory results on GBS colonization will also be recorded in the 
eCRF. 
The method that will be used to perform GBS serotyping remains to be determined (will 
be done at GSK Biologicals or by a GSK designated laboratory). 
Table 10 GSB assessment of vaginal swabs* 
Vaginal swab sampling timepoint 
Component 
Method 
Scale 
Laboratory 
Type of contact (timepoint) 
Visit 1 (Day 1)*** 
Visit 3 (Day 56)*** 
Visit 5 (Delivery)** 
GBS  
To be determined 
To be 
determined 
GSK Biologicals 
or GSK 
designated lab** 
* Laboratory assays for GBS assessment of vaginal swabs to be confirmed (may be assessed by culture and/or 
molecular biology). 
** Vaginal swab at delivery will only be collected prior to rupture of membranes. 
*** Only in countries where routine implementation of risk based intrapartum antibiotic prophylaxis for GBS is the 
standard of care 
Haematology, biochemistry and urinalysis (Section 8.10.3.3) 
Haematology and biochemistry and urinalysis will tests are to be performed 
preferentially requested by local health carehealthcare providers. Information will, as 
per local practice. They are to be collected and recorded in the eCRF. If performed by 
the investigator/study staff ONLY if not done by the local healthcare provider as per 
local practicewithin 2 weeks before the investigator study staff visit. 
The investigators will perform a urine dipstick test to detect for the tests specified in 
Table 10 presence of proteins, glucose, RBC and/or WBC.  
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Table 10 
Hematology, biochemistry, urine tests  
System 
Discipline 
Component 
Time 
point 
Method 
Scale 
Laboratory 
Whole 
blood 
Hematology 
Hemoglobin 
Visit 1 
As per 
local 
practice 
Quantitative 
Local 
laboratory 
 
 
 
Visit 3 
 
 
Leukocytes (White 
Blood Cells) 
Visit 1 
 
 
Platelets  
Visit 1 
Serum 
Biochemistry 
Alanine 
Aminotransferase 
(ALT)  
Visit 1 
As per 
local 
practice 
Quantitative 
Local 
laboratory 
 
 
Aspartate 
Aminotransferase 
(AST) 
Visit 1 
 
 
Creatinine  
Visit 1 
 
 
Urea Nitrogen  
Visit 1 
Urine 
- 
Protein  
Visit 1 
As per 
local 
practice, 
dipsticks 
provided 
by GSK 
Biologicals 
Ordinal 
Local 
laboratory 
 
 
 
Visit 2 
 
 
 
Visit 3 
 
 
 
Visit 4 
 
 
Glucose  
Visit 1 
 
 
 
Visit 2 
 
 
 
Visit 3 
 
 
 
Visit 4 
 
 
Hemoglobin  
Visit 1 
 
 
(RBC) 
Visit 2 
 
 
 
Visit 3 
 
 
 
Visit 4 
 
 
Leukocyte esterase 
Visit 1 
 
 
(WBC) 
Visit 2 
 
 
 
Visit 3 
 
 
 
Visit 4 
1 When available, urine dipstick results for RBC and WBC will also be collected.  
2 Culture results will be obtained, if performed 
Table 11 
Immunological read-outs 
Blood sampling 
timepoint 
Group 
No. subjects 
Component 
Component 
priority rank 
Type of contact and time 
point 
Maternal Blood 
Visit 1 (Day 1)** 
All mothers in selected 
countries 
400 maximum by country 
GBS* 
1 
Visit 3 (Day 56)** 
All mothers in selected 
countries 
400 maximum by country 
GBS* 
1 
Visit 5 (Delivery) 
 
 
GBS* 
2 
Cord Blood 
Visit 5 (Delivery) 
 
 
GBS* 
2 
GBS = group B streptococcus; RSV-A/B = Respiratory syncytial virus subtype A/B. 
* Testing for GBS antibody concentrations will be performed upon availability of assay. 
** Only in countries where routine implementation of risk based intrapartum antibiotic prophylaxis for GBS is the 
standard of care 
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In case of insufficient blood sample volume to perform assays for all antibodies, the 
samples will be analysed according to the priority ranking provided in Table 11.  
Table 12 Molecular biology for nasal swab specimen analysis 
Nasal swab sampling timepoint 
Group 
No. subjects 
Type of contact (timepoint) 
Sampling timepoint 
Visit to assess potential LRTI 
Assessment visit 
Unscheduled 
All infants* 
Event-driven** 
Footnotes  
* For each RTI with suspicion of difficulty in breathing, wheezing or parental concern reported during an active or 
passive surveillance contact a nasal swab will be collected. A nasal swab will also be collected at the examination visit 
performed in case parents/ LAR(s) come to the study site without previous surveillance contact (if RTI with suspicion of 
difficulty in breathing, wheezing or parental concern, and visit within 3 days after the start of symptoms). 
* Refer to Section 8.6.5. 
Table 13 Hematology/blood chemistry tests (footnotes only) 
* Number of subjects depending on country. Prenatal screening willTests to be performed preferentially by local 
healthcare providers and information will be collected and recorded in the eCRF. The investigator/study staff will 
collect biological samples for prenatal screeningthe specified testing if not done by the local healthcare provider 
as per local practice.  
GBS assessment of vaginal swabs (Deleted Section) 
Table 15 GSB assessment of vaginal swabs* 
Vaginal swab sampling timepoint 
Group 
No. subjects 
Component 
Type of contact (timepoint) 
Visit 1 (Day 1)*** 
All mothers, selected 
countries*** 
400 maximum by country  
GBS* 
Visit 3 (Day 56)*** 
All mothers, selected 
countries*** 
400 maximum by country 
GBS* 
Visit 5 (Delivery)** 
All mothers 
400 maximum by country 
GBS* 
* Laboratory assays for GBS assessment of vaginal swabs to be confirmed (may be assessed by culture and/or 
molecular biology). 
** Vaginal swab at delivery will only be collected prior to rupture of membranes. 
*** Only in countries where routine implementation of risk based intrapartum antibiotic prophylaxis for GBS is the 
standard of care 
Event Identification (Section 9.2) 
Blood, urine and vaginal swaburine samples will be collected from pregnant women 
enrolled in the study.  Nasal 
Subject withdrawal (Section 10.2) 
Investigators will make an attemptat least 3 attempts to contact those subjects asubject 
who dodoes not return for a scheduled visitsvisit or follow-up as described in Section 8.4 
and in the SPM.  
A subject will be defined as lost to follow-up if there is no contact with the subject 
/subject’s parent(s) / LAR(s) over a period of at least 3 months after a planned visit (see 
SPM for details). Efforts to contact the subject/subject’s parents should be recorded in the 
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source documents.  The subject’s data will be censored at the time of last contact once 
this definition is met. 
Information relative relevant to the withdrawal will be documented in the eCRF. 
………….as well as which of the following possible reasons was responsible for 
withdrawal: 
• 
Study procedure participation related SAE. 
• 
Neonatal event of interest (specify). Note: includes death in infants from birth – 28 
days old 
• 
Death in infants > 28 days old (specify cause). Note that death in neonates from birth 
– 28 days old is captured as a neonatal event of interest).   
Subjects who are withdrawn from the study because of study participation 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 result of ana 
study participation related SAE until resolution of the event (see Section 9.6.2). 
Primary endpoints (Section 11.1.1), Primary Objectives Analysis (Section 11.6) and 
Synopsis 
− 
Hypertensive disorders of pregnancy:  
o 
gestational hypertension, and  
o 
Pre-eclampsia, and 
o 
Pre-eclampsia with severe features (including eclampsia), 
− 
Neonatal Acute neonatal encephalopathy  
Secondary endpoints (Section 11.1.2), Secondary Objectives Analysis (Section 11.7) 
and Synopsis 
− 
Occurrence of nneonatal events of interest from birth through Day 28 days of 
age (as defined in primary endpoints) for each GAIA level of diagnostic 
certainty (where applicable and feasible) 
Tertiary endpoints (Section 11.1.3), Tertiary Objectives Analysis (Section 11.8) and 
Synopsis 
− 
Human respiratory syncytial virus A (RSV A)  
− 
Human respiratory syncytial virus B (RSV B)  
Exposed Set (ES) – pregnant women (mothers) (Section 11.3.1.1) 
The ES will include all pregnant women (mothers) with a valid informed consentform 
who were enrolled in the study. 
Per Protocol Sets (PPS) – pregnant women (mothers) and Neonates/Infants 
(Sections 11.3.2) 
The maternal PPS will include all pregnant women (mothers) 
The infant PPS will include all enrolled neonates / infants 
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Derived and transformed data (Section 11.4) 
Age of the infant 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. 
Analysis of demographic and baseline characteristics (Section 11.5) 
• 
For the ES and maternal PPS cohorts, the cohort, analyses of demographic analyses 
for pregnant women and baseline characteristics at Visit 1 will describe be 
described.  
• 
For the infant PPS cohort, analyses of demographic characteristics of women at 
visit 1 at Visit 1-NB will be described.  Analyses of lifestyle characteristics will be 
described at Visit 2 NB. 
• 
For the ES and PPS cohorts, the overall demographic analyses for neonate / infants 
will describe the demographic characteristics of the neonate / infants at visit 1-NB. 
• 
For Screening Failures, reasons for non-eligibility will be described. 
Analysis of primary objectives (Section 11.6) 
The primary objectives analyses will be performed on the PPS cohorts by country, and 
possibly by region or other relevant groupingIn case more than 5% of the subjects are 
excluded from the PPS cohort then the analyses may be performed on the ES cohort. 
Analysis of secondary objectives (Section 11.7) 
The secondary objectives analyses will be performed on the PPS cohorts (maternal or 
infant as applicable) overall by country and possibly by region or other relevant 
grouping. In case more than 5% of the subjects are excluded from the PPS cohort then 
the analyses may be performed on the ES cohort. 
Analysis of tertiary objectives (Section 11.8) 
The following tertiary objectives analyses will be performed on infants within the PPS 
cohort overall by country, region, or other relevant grouping. In case more than 5% of 
the subjects are excluded from the PPS cohort then the analyses may be performed on the 
ES cohort: 
The following tertiary objectives analyses will be performed on the PPS cohorts 
(maternal or infant as applicable) by country, region, or other relevant grouping. In case 
more than 5% of the subjects are excluded from the PPS cohort then the analyses may be 
performed on the ES cohort: 
To describe GBS serotype specific antibody concentrations in cord blood (if 
possible). 
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− 
Geometric mean titers (GMTs) will be tabulated with 95% CI.  
− 
Percentage of subjects above thresholds will be tabulated. 
The following tertiary objectives analyses will be performed on pregnant women 
(mothers) within the PPS cohort overall by country, region, and/or other relevant 
grouping: 
• 
To describe the prevalence of GBS vaginal colonization and serotypes 
distribution  in pregnant women in the 2nd and 3rd trimester and at delivery (if 
possible).  
− 
The proportion of women colonized with GBS by serotype at each timepoint 
will be calculated. The proportion of colonized women will be calculated as the 
number of women having a positive result for GBS divided by the number of 
women for whom a vaginal swab has been taken. This will be presented overall 
and by serotype. 
• 
To describe GBS serotype specific antibody concentrations in pregnant women 
in the 2nd and 3rd trimester and at delivery (if possible). 
− 
For each serotype-specific GBS Concentration in serum of mothers and in cord 
blood the following analysis will be performed:  
− 
The proportion of women with serotype specific antibody concentrations 
above various thresholds will be calculated overall and by colonization 
status. 
− 
GMCs for each serotype will be calculated overall and by colonization 
status  
− 
Variation in colonization status and antibody titers will be calculate for each 
timepoint, when feasible. 
The following tertiary objectives analyses will be performed on neonates / infants within 
the PPS cohort overall by country, region, or other relevant grouping: 
• 
To describe the occurrence of GBS invasive disease in infants (if possible). 
− 
Incidence proportions will be calculated as the number of new invasive GBS 
disease cases occurring from birth up to 90 days of life (if feasible) divided by 
the number of infants included in the study. 
− 
Incidence proportions will be categorized as follows: early onset disease ( 
during days 1-7) and  late onset disease (during days 8-90) (if data available; 
i.e., depending on whether GBS blood and / or CSF testing is done as per local 
practice).  
• 
To describe occurrences of hospitalization and death due to GBS invasive 
disease (if possible). 
− 
Incidence proportions will be calculated as the number of new hospitalizations 
due to GBS disease cases occurring from birth up to 1 year of life (if feasible) 
divided by the number of infants included in the study. 
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− 
Incidence proportions will be calculated as the number of new deaths due to 
GBS disease cases occurring from birth up to 1 year of life (if feasible) divided 
by the number of infants included in the study. 
− 
Incidence proportion will categorized as follows: early onset disease ( during 
days 1-7),  late onset disease (during days 8-90), and post-late onset disease 
(≥91 days) (if data available; i.e., depending on whether GBS blood and / or 
CSF testing is done as per local practice).  
Conduct of analyses (Section 11.11) 
Analyses will be performed in a stepwise manner after each country / group of countries / 
countries in a region have completed all study visits in Epoch 001 002 and again after 
completion of all study visits in Epoch 002 003.   
Analyses of pregnancy outcomes, pregnancy related events of interest, and neonatal 
events of interest will be performed when all data up to 42 days post-delivery are 
available (Epoch 001002). 
Final analyses will be performed when all data up to study end are available (Epoch 
001002 and Epoch 002003). 
Interim Additional analyses may be performed if deemed necessary to inform the design 
or implementation of future clinical trials  
References (Section 14) 
Barbas CF, Crowe JE, Cababa D, et al. Human monoclonal Fab fragments derived 
from a combinatorial library bind to respiratory syncytial virus F glycoprotein and 
neutralize infectivity. Proc Natl Acad Sci U S A. 1992;89(21):10164-8. 
Bates JT, Keefer CJ, Slaughter JC, et al. Escape from neutralization by the respiratory 
syncytial virus-specific neutralizing monoclonal antibody palivizumab is driven by 
changes in on-rate of binding to the fusion protein. Virology. 2014; 454-455:139-144. 
Bauwens J, Bonhoeffer J, Chen RT, editors. Harmonising Immunisation Safety 
Assessment in Pregnancy. Vaccine. 2016. 34 (49): 5991 – 6110. 
DaSilva FT, Gonik B, McMillan M, et al. Stillbirth: Case definition and guidelines for 
data collection, analysis, and presentation of maternal immunization safety data. Vaccine. 
2016;34(49):6057-6068. 
DeSilva M, Munoz FM, Mcmillan M, et al. Congenital anomalies: Case definition and 
guidelines for data collection, analysis, and presentation of immunization safety data. 
Vaccine. 2016;34(49):6015-6026.  
Gravett C, Eckert LO, Gravett MG, et al. Non-reassuring fetal status: Case definition & 
guidelines for data collection, analysis, and presentation of immunization safety data. 
Vaccine. 2016;34(49):6084-6092. 
Harrison MS, Eckert LO, Cutland C, et al. Pathways to preterm birth: Case definition and 
guidelines for data collection, analysis, and presentation of immunization safety data. 
Vaccine. 2016;34(49):6093-6101. 
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Kochhar S, Bauwens J, Bonhoeffer J, editors. Harmonising Immunization Safety 
Assessment in Pregnancy – Part II. Vaccine. 2017. 35 (48): 6469-6582. 
Kerr R, Eckert LO, Winikoff B, et al. Postpartum haemorrhage: Case definition and 
guidelines for data collection, analysis, and presentation of immunization safety data. 
Vaccine. 2016;34(49):6102-6109. 
Pathirana J, Muñoz FM, Abbing-Karahagopian V, et al. Neonatal death: Case definition 
& guidelines for data collection, analysis, and presentation of immunization safety data. 
Vaccine. 2016;34(49):6027-6037. 
Patwardhan M, Eckert LO, Spiegel H, et al. Maternal death: Case definition and 
guidelines for data collection, analysis, and presentation of immunization safety data. 
Vaccine. 2016;34(49):6077-6083. 
Quinn JA, Munoz FM, Gonik B, et al. Preterm birth: Case definition &amp; guidelines 
for data collection, analysis, and presentation of immunisation safety data. Vaccine. 
2016;34(49):6047-6056. 
Rouse CE, Eckert LO, Wylie BJ, et al. Hypertensive disorders of pregnancy: Case 
definitions &amp; guidelines for data collection, analysis, and presentation of 
immunization safety data. Vaccine. 2016;34(49):6069-6076 
Vergnano S, Buttery J, Cailes B, et al. Neonatal infections: Case definition and guidelines 
for data collection, analysis, and presentation of immunisation safety data. Vaccine. 
2016;34(49):6038-6046 
World Health Organization (WHO) WHO recommendations for prevention and treatment 
of maternal peripartum infections. Published in September 2015. Last accessed on 21 
March 2017. 
APPENDIX D: Definitions Of Maternal, Fetal And Neonatal Events Of Interest As 
Per Gaia D 
The 2 tables presented in the original protocol have been replaced with 21 separate tables 
(one for each of the 19 events of interest defined per GAIA, and two for events of interest 
– maternal and neonatal – not defined as such per GAIA).  Definitions and levels of 
diagnostic certainty have been updated (where applicable) per the reference cited 
(beneath each table) for each event of interest.  
The 2 tables in the original protocol, for reference, follow.  
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Maternal events of interest – TABLE FROM PROTOCOL VERSION 01 
Event of interest 
Description 
Levels of diagnostic certainty 
Reference 
Maternal death 
The death of a woman while pregnant or 
within 42 days of termination of 
pregnancy, irrespective of the duration 
and site of the pregnancy, from any 
cause related to or aggravated by the 
pregnancy or its management but not 
from accidental or incidental causes. 
(As ICD-10 terminology).  
In the context of immunization:  
“Death of a woman during pregnancy, 
childbirth and the puerperium that is 
closely related temporally to an 
immunization event of the mother which 
is likely the single or contributory cause” 
Level 1 
Diagnosis of pregnancy established by any of the following documented criteria: 
a. Ultrasound examination 
b. Fetal heart tones 
c. Positive serum or urine human chorionic gonadotropin pregnancy test 
d. Delivery of a neonate or other products of conception (abortus, stillborn) And 
Death of the mother while pregnant or within 42 days of termination of pregnancy, irrespective 
of the duration and site of the pregnancy And 
Documentation of Cause of death as: 
a. Direct: abortive outcome, hypertensive disorder, obstetric hemorrhage, pregnancy related 
infection, other obstetric com-plications, unanticipated complications  
b. Indirect: non obstetric complications  
c. Death during pregnancy, childbirth and the puerperium: other or coincidental 
Level 2 
Diagnosis of pregnancy established by any of the following criteria in the absence of Level 1 
criteria: 
a. LMP date 
b. Serial Symphysio Fundal Height examinations And Death of the mother while pregnant or 
within 42 days of termination of pregnancy, irrespective of the duration and site of the 
pregnancy And  
Documentation of Cause of death as: 
a. Direct: abortive outcome, hypertensive disorder, obstetric hemorrhage, pregnancy related 
infection, other obstetric complications, unanticipated complications 
b. Indirect: non-obstetric complications  
c. Death during pregnancy, childbirth and the puerperium: other or coincidental 
d. Unspecified: unknown or undetermined 
Level 3 
Absence of Level 1 or 2 criteria for establishing diagnosis of pregnancy and: 
a. Unsure LMP 
b. No clinical examination documented And 
Death of the mother temporal to pregnancy, childbirth or the postpartum period when exact 
timing of death is unknown, And 
Documentation of cause of death as: 
[Patwardhan, 
2016] 
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Event of interest 
Description 
Levels of diagnostic certainty 
Reference 
a. Direct: abortive outcome, hypertensive disorder, obstetric hemorrhage, pregnancy related 
infection, other obstetric com-plications, unanticipated complications 
b. Indirect: non-obstetric complications 
c. Death during pregnancy, childbirth and the puerperium: other or coincidental 
d. Unspecified: unknown or undetermined. 
Hypertensive 
disorders of 
pregnancy 
Gestational 
hypertension / 
Preeclampsia / 
Eclampsia 
Gestational Hypertension is a clinical 
syndrome characterized by pregnancy 
≥20 weeks AND new onset 
hypertension (systolic blood pressure 
≥140 mmHg and/or diastolic blood 
pressure ≥90 mmHg) sustained on two 
measurements over a minimum of 1 h 
WITHOUT severe features (see 
preeclampsia with severe features 
category) and WITHOUT proteinuria  
Preeclampsia has conventionally been 
defined as the development of 
gestational hypertension and proteinuria 
after 20 weeks gestation. 
Proteinuria can be quantified by 24 h 
urine collection, a spot protein: 
creatinine ratio, or with urinary dipstick. 
Proteinuria of≥300 mg in a 24 h urine 
specimen (the gold standard for 
measurement of proteinuria), or ≥0.30 
on a spot protein: creatinine ratio, or 
≥1+ on a dipstick meets the criteria for 
preeclampsia. 
Preeclampsia diagnose with severe 
features 
•Vascular: 
◦ Severely elevated blood pressures, 
with systolic blood pressure≥160 mmHg 
and/or diastolic blood pressure ≥110 
mmHg, which is confirmed after only 
Preeclampsia 
For All Levels of Diagnostic Certainty  
Clinical syndrome characterized by pregnancy ≥20 weeks AND new onset hypertension 
(systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg) sustained on 
two measurements over a minimum of 1 h AND new onset proteinuria  
Level 1  
proteinuria diagnosed with ≥300 mg of protein on 24 h urine collection OR≥0.3 on spot protein: 
creatinine ratio  
Level 2  
proteinuria diagnosed with ≥1+ protein on urine dipstick 
Insufficient evidence blood pressure cannot be measured OR no proteinuria evaluation is 
available (note diagnosis of preeclampsia with severe features does not require proteinuria, 
see definition below) 
Preeclampsia with severe features 
For All Levels of Diagnostic Certainty  
Clinical syndrome characterized by pregnancy ≥20 weeks AND new onset hypertension 
(systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg) sustained on 
two measurements over a minimum of 1 h AND At least one of the criteria for severe disease:  
Level 1  
At least one of the following:  
Systolic blood pressure ≥160 mmHg and/or diastolic blood pressure ≥110mmHg, which is 
confirmed after only minutes OR  
Development of severe, persistent headache OR 
Development of visual changes OR  
Eclampsia OR  
New onset thrombocytopenia (platelets <100,000/L) OR 
New onset unremitting epigastric pain ORAST and ALT elevated to twice upper limit of normal 
OR 
[Rouse, 2016] 
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Event of interest 
Description 
Levels of diagnostic certainty 
Reference 
minutes (to facilitate timely anti-
hypertensive treatment) 
•Neurologic: 
◦ Development of a severe headache 
(which can be diffuse, frontal, temporal 
or occipital) that generally does not 
improve with over the counter pain 
medications (such as 
acetaminophen/paracetamol) 
◦ Development of visual changes 
(including photopsia, scotomata,cortical 
blindness)  
◦ Eclampsia, or new-onset grand mal 
seizures in a patient with pre-eclampsia, 
without other provoking factors (such as 
evidence of cerebral malaria or 
preexisting seizure disorder). Seizures 
are often preceded by headaches, 
visual changes or altered mental status  
•Hematologic: 
◦ New onset thrombocytopenia, with 
platelet count <100,000/L 
•Gastrointestinal: 
◦ New onset of nausea, vomiting, 
epigastric pain 
◦ Transaminitis (AST and ALT elevated 
to twice the upper limit of normal) 
◦ Liver capsular hemorrhage or liver 
rupture 
•Renal: 
◦ Worsening renal function, as 
evidenced by serum creatinine level 
greater than 1.1 mg/dL or a doubling of 
the serum creatinine(absent other renal 
disease) 
◦ Oliguria (urine output <500 mL/24 h) 
 Evidence of liver capsular hematoma or liver rupture (diagnosed on clinical exam or with 
imaging) OR 
Worsening renal function, as evidenced by serum creatinine level greater than 1.1 mg/dL or a 
doubling of the serum creatinine (absent other renal disease) or oliguria (<500 cc/24 h) OR 
Pulmonary edema (confirmed on imaging with chest X-ray, or on clinical exam) 
Level 2 new onset nausea and vomiting  
Insufficient evidence blood pressure cannot be measured 
Gestational Hypertension 
For All Levels of Diagnostic Certainty  
Clinical syndrome characterized by pregnancy ≥20 weeks AND new onset hypertension 
(systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg) sustained on 
two measurements over a minimum of 1 h WITHOUT severe features (see preeclampsia with 
severe features category) and WITHOUT proteinuria 
Level 1 of diagnostic certainty no proteinuria (as defined by 24 h urine collection < 300 mg, 
spot protein: creatinine ratio <0.3)  
Level 2 of diagnostic certainty no proteinuria (as defined by urine dipstick negative or trace)  
Insufficient evidence blood pressure cannot be measured OR no proteinuria evaluation is 
available 
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Event of interest 
Description 
Levels of diagnostic certainty 
Reference 
•Respiratory: 
◦ Pulmonary edema (confirmed on 
clinical exam or imaging) 
Antenatal Bleeding 
Antenatal bleeding is a clinical 
syndrome characterized by bleeding in 
the second or third trimester of 
pregnancy. Pathologic etiologies 
attributable to the pregnant state include 
placenta previa, morbidly adherent 
placenta, vasa previa, placental 
abruption, cesarean scar pregnancy, 
intra-abdominal pregnancy, and uterine 
rupture. 
For both levels of diagnostic certainty 
for each etiology of antenatal bleeding: 
Bleeding is either documented vaginally 
or suspected to be occurring 
intrauterine, intraperitoneally, or (rarely) 
retroperitoneally, based on clinical signs 
and symptoms. 
In the case of ultrasound-based 
diagnosis, transvaginal ultrasound is 
more specific than transabdominal 
ultrasound, and transvaginal ultrasound 
is recommended where available. 
Placenta Previa 
Level 1  
Second or third trimester ultrasound (and/or MRI) evidence of placental tissue overlying or 
abutting the internal cervical os. 
Level 2  
Painless vaginal bleeding in the second or third trimester, 
AND a high presenting part or abnormal fetal lie. 
AND pelvic exam with fullness palpable in the fornices (avoiding digital cervical exam). 
Morbidly Adherent Placentation 
Level 1  
Second- or third-trimester ultrasound or MRI evidence of placenta previa, 
AND one of the following ultrasound features:  
Greyscale: loss of the retroplacental sonolucent zone, irregular retroplacental sonolucent zone, 
thinning or disruption of the hyperechoic serosa–bladder interface, presence of focal exophytic 
masses invading the urinary bladder, abnormal placental lacunae  
Color Doppler: diffuse or focal lacunar flow, vascular lakes with turbulent flow (peak systolic 
velocity over 15 cm/s), hypervascularity of serosa–bladder interface, markedly dilated vessels 
over peripheral subplacental zone 
3D Power Doppler: numerous coherent vessels involving the whole uterine serosa–bladder 
junction (basal view), hypervascularity (lateral view), inseparable cotyledonal and intervillous 
circulations, chaotic branching, detour vessels (lateral view) 
AND one of the risk factors: prior cesarean delivery, prior uterine surgery (including 
endometrial ablation) or cesarean scar pregnancy 
OR 
Morbidly adherent placentation found on histology in a hysterectomy or partial wedge resection 
specimen. 
Level 2 
Ultrasound evidence of placenta previa, 
AND hypervascularity of the lower uterine segment, diagnosed at laparotomy. 
OR 
Difficulty with placental separation after delivery of the infant, at either a vaginal or cesarean 
delivery with resultant hemorrhage due to partial separation. 
Prabhu M, 
Eckert LO, 
Belfort M, et al. 
Antenatal 
Bleeding: Case 
Definition & 
Guidelines for 
Data Collection, 
Analysis, and 
Presentation of 
Immunization 
Safety Data. 
Unpublished 
manuscript. 
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Event of interest 
Description 
Levels of diagnostic certainty 
Reference 
Vasa Previa 
Level 1  
Second trimester ultrasound evidence of fetal vessels (vessel with fetal heart rate identified by 
color flow Doppler) running through the membranes and overlying the internal cervical os, 
AND post-delivery examination of the placental specimen with unsupported fetal vessels within 
the membranes. 
Level 2 
Vaginal bleeding in the second or third trimester at the time of ruptured amniotic membranes, 
AND fetal heart rate changes ultimately resulting in sinusoidal rhythm/terminal bradycardia, 
AND delivery of a pale, anemic infant or recent stillbirth or neonatal death, 
AND post-delivery examination of the placental specimen with unsupported fetal vessels within 
the membranes. 
Placental Abruption 
Level 1  
In the absence of placenta previa on ultrasound, vaginal bleeding in the second or third 
trimester, 
AND uterine irritability or labor, 
AND clinical signs of hypovolemic shock or coagulopathy. 
OR 
Placental pathology with histologic findings of a chronic abruption. 
Level 2  
Vaginal bleeding in the second or third trimester, 
AND uterine irritability or labor, without clinical signs of hypovolemic shock or coagulopathy, 
OR 
Vaginal bleeding in the second or third trimester, 
AND clinical evidence of retroplacental clot or visually evident placental infarcts at the time of 
delivery. 
Cesarean Scar Pregnancy 
Level 1  
Transvaginal ultrasound with the following characteristics: empty uterine cavity, AND empty 
cervical canal, without contact with the gestational sac, AND presence of gestational sac, +/- 
fetal pole, +/- cardiac activity, in the anterior uterine segment adjacent to the cesarean scar, 
AND absence or defect in myometrium between bladder and gestational sac, AND gestational 
sac well perfused on Doppler ultrasound (to differentiate from an expulsing, avascular 
gestational sac). 
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Event of interest 
Description 
Levels of diagnostic certainty 
Reference 
OR 
Hysterectomy specimen with evidence of pregnancy implanted into the cesarean scar. 
There is no Level 2 definition for this event. 
Intra-abdominal Pregnancy 
Level 1  
At laparotomy, a fetus found within the abdominal cavity, without evidence of uterine rupture, 
and with placentation not within the uterine cavity. 
There is no Level 2 definition for this event. 
Uterine Rupture 
Level 1  
Complete uterine disruption at the time of laparotomy in the context of vaginal or intra-
abdominal bleeding. 
There is no Level 2 definition for this event. 
Postpartum 
haemorrhage 
Genital tract bleeding after delivery (up 
to 42 days) of a foetus or infant that 
leads to an adverse clinical outcome. 
Such as hypovolemia or anaemia e.g. 
exertional dyspnoea, postural 
presyncope, tiredness or reduced 
consciousness. At the furthest extreme 
uncorrected hypovolaemic shock can 
lead to organ-dysfunction and maternal 
death. 
ICD-10 definition: “heamorrhage after 
delivery of a foetus or infant” 
Level 1  
Genital bleeding after delivery leading to severe maternal out-come (maternal death or 
maternal near miss) as defined by WHO28.  
Level 2  
Genital bleeding after delivery with at least one of the following: measured abnormal bleeding 
(1000 ml or more), or any bleeding leading to hypotension or blood transfusion. 
Level 3  
Genital bleeding after delivery estimated at 1000 ml or more 
[Kerr, 2016] 
Fetal Growth 
Restriction 
A fetus with a sonographic estimation of 
fetal weight below the tenth percentile 
for a given gestational age with 
increasing specificity for adverse 
perinatal outcomes below the third 
percentile. 
Level 1a 
Level 1 evidence of pregnancy dating AND 
Estimated fetal weight below 3% using locally-accepted growth curve OR 
Estimated fetal weight below 10% using locally-accepted growth curve AND 
Absent or reversed end-diastolic flow of the umbilical artery Doppler OR 
Oligohydramnios as defined by amniotic fluid index (AFI) < 8 or deepest vertical pocket (DVP) 
< 2. 
Level 1b 
Level 1 evidence of pregnancy dating AND 
Estimated fetal weight below 10%ile using locally-accepted growth curve AND 
Easter SR, 
Eckert OL, 
Boghossian N, 
et al. Fetal 
Growth 
Restriction: 
Case Definition 
& Guidelines for 
Data Collection, 
Analysis, and 
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Event of interest 
Description 
Levels of diagnostic certainty 
Reference 
Lack of absent or reversed end-diastolic flow of the umbilical artery OR oligohydramnios as 
defined by AFI <8 or DVP <2. 
Level 2a 
Level 2 evidence of pregnancy dating AND 
Estimated fetal weight below 3% using locally-accepted growth curve OR 
Estimated fetal below 10% using locally-accepted growth curve AND 
Absent or reversed end-diastolic flow of the umbilical artery Doppler. OR 
Oligohydramnios as defined by AFI < 8 or DVP < 2. 
Level 2b 
Level 2 evidence of pregnancy dating AND 
Estimated fetal weight below 10%ile using locally-accepted growth curve AND 
No findings of absent or reversed end-diastolic flow of the umbilical artery or oligohydramnios 
as defined by AFI <8 or DVP <2. OR 
Level 1 evidence of pregnancy dating AND 
Estimated fetal weight below 10% using locally-accepted growth curve with no findings of 
oligohydramnios as defined by AFI <8 or DVP <2 with inability to assess umbilical artery 
Doppler. 
Insufficient Evidence 
Absence of ultrasound for use in assessment of estimated fetal weight. 
Presentation of 
Immunization 
Safety Data. 
Unpublished 
manuscript. 
Dysfunctional 
Labor 
Prolonged labor at or after 37 weeks 
and before 42 weeks of gestational age  
First Stage of Labor 
For both levels of diagnostic the woman is in established labor defined by regular contractions 
and cervical dilation of at least 4cm. 
Level 1  
Progress of less than 0.5 cm cervical dilation per hour, for at least 4 hours, in women in 
established labor (i.e. have regular contractions and cervical dilation of at least 4cm) and with 
confirmed ruptured membranes. 
Level 2  
Progress of less than 0.5cm cervical dilation per hour in women, for at least 4 hours, with 
established labor, (i.e. that is, regular contractions and cervical dilation of at least 4cm) without 
certainty of ruptured membranes. 
Second Stage of Labor 
The definitions below are applicable in cases with or without regional analgesia. 
Level 1  
Full dilation of the cervix AND 
onset of the active stage (active maternal effort (i.e. pushing) OR visible baby) AND 
Boatin AA, 
Eckert LO, 
Boulvain M, et 
al. Dysfunctional 
Labor: Case 
Definition & 
Guidelines for 
Data Collection, 
Analysis, and 
Presentation of 
Immunization 
Safety Data. 
Unpublished 
manuscript. 
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Event of interest 
Description 
Levels of diagnostic certainty 
Reference 
greater than 2 hours of pushing in nulliparous women OR 
greater than 1 hour of pushing in multiparous women OR use of instrument OR  
caesarean delivery for the indication of dystocia. 
Level 2  
Full dilation of the cervix in any phase of the second stage 
AND 
no delivery within 3 hours of full dilation in the nulliparous woman OR  
within 2 hours in multiparous women OR 
use of instrument OR 
caesarean delivery for the indication of dystocia. 
Gestational 
Diabetes Mellitus 
Pregnancy induced hyperglycemia 
For All Levels of Diagnostic Certainty 
Gestational diabetes mellitus (GDM) is a clinical syndrome characterized by 
the absence of pre-gestational diabetes diagnosis defined by 
Previous diagnosis of diabetes while not pregnant OR 
First trimester hemoglobin A1c level of ≥ 6.5% (47.5 mmol/mol) OR 
First trimester fasting blood glucose 126 mg/dL / ≥ 7mmol/L AND 
Identification of sustained hyperglycemia during pregnancy not due to other known causes (i.e. 
corticosteroids, beta-mimetics, etc.) 
Level 1  
Absence of pre gestational diabetes mellitus diagnosis in the first trimester as defined above 
with level 1-2 certainty for gestational age using GAIA definition for gestational age AND 
Diagnosis of gestational diabetes based on a positive internationally recognized oral glucose 
tolerance test (see below “major criteria”) using venous blood sample/samples 
Level 2  
Absence of pre gestational diabetes mellitus diagnosis in the first trimester as defined above 
with at least level 3 certainty for gestational age using GAIA definition for gestational age AND 
Diagnosis of gestational diabetes based on positive internationally recognized oral glucose 
tolerance test (see below “major criteria”) using capillary blood sample/samples 
Level 3  
Absence of pregestational diabetes mellitus diagnosis in the first trimester as defined above 
with at least level 3 certainty for gestational age using GAIA definition for gestational age AND 
Diagnosis of gestational diabetes based on fasting plasma glucose of 5.1-6.9 mmol/l (92-125 
mg/dL) using venous or capillary blood samples. 
Insufficient evidence for diagnosis  
Blood glucose cannot be measured OR 
Kachikis A, 
Eckert LO, 
Walker C, et al. 
Gestational 
Diabetes 
Mellitus: Case 
Definition & 
Guidelines for 
Data Collection, 
Analysis, and 
Presentation of 
Immunization 
Safety Data. 
Unpublished 
manuscript. 
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Event of interest 
Description 
Levels of diagnostic certainty 
Reference 
Use of Hemoglobin A1c alone for the diagnosis of GDM without a diagnostic oral glucose 
tolerance test (OGTT) or elevated fasting plasma glucose level. OR 
Clinical and laboratory findings such as glucosuria, fundal height greater than dates, obesity, 
prior history of GDM or family history for the diagnosis of gestational diabetes mellitus without 
a diagnostic test. 
Non-reassuring 
fetal status 
Indicator of underlying event resulting in 
temporary or permanent oxygen 
deprivation to the fetus which may lead 
to fetal hypoxia and metabolic acidosis  
Level 1  
Category III fetal heart rate tracings detected via continuous cardiotocography as defined by 
NICHD  
Absent baseline fetal heart rate variability AND any of the following: 
- recurrent late decelerations 
- recurrent variable deceleration 
- bradycardia (<110 bpm) OR 
Sinusoidal pattern AND 
Umbilical cord blood analysis consistent with metabolic acidosis (pH < 7.0 and Base deficit >12 
mmol/L) 
Level 2 
Category III fetal heart rate tracings detected via continuous cardiotocography as defined by 
NICHD  
Absent baseline fetal heart rate variability AND any of the following: 
- recurrent late decelerations 
- recurrent variable deceleration 
- bradycardia (<110 bpm)OR◦ Sinusoidal pattern 
Level 3  
Fetal heart pattern detected via intermittent auscultation suggestive of fetal hypoxia  
Baseline FHR <110 bpm or >160 bpm 
Presence of repetitive or prolonged (>3 min) decelerations 
More than 5 contractions in a 10 min period 
[Gravett, 2016] 
Pathways to 
preterm birth 
Premature preterm rupture of 
membranes 
Preterm labor 
Insufficient cervix 
Provider-initiated preterm birth 
Premature preterm rupture of membranes 
All levels of certainty 
Patient is determined to be preterm as defined by GAIA  
On presentation, patient is determined to not be in preterm labor, having ≤4 contractions per 
hour documented clinically or on tocodynometer, with <2 cm cervical dilation (greater than 4 
contractions per hour would qualify the patient as having preterm labor)  
Fluid can be noted to be clear, blood-tinged, meconium-tinged (fetal stool), purulent-tinged 
(yellowish, suggesting infection) 
Level 1 
[Harrison, 2016] 
 
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Event of interest 
Description 
Levels of diagnostic certainty 
Reference 
Clinical history of rupture of membranes AND 
Visible leakage of fluid on vaginal speculum exam AND 
Visible arborization (ferning) on microscopy of amniotic fluid OR 
Ultrasound with oligohydramnios (AFI <5 or MVP <2) AND 
Documented membrane rupture by a diagnostic test (one of the below options): 
Positive intra-amniotic dye-injection method 
Positive result on amniotic fluid alpha-fetoprotein test kit  
Amniotic fluid pH measurement (nitrazine paper test) 
Amniotic fluid placental alpha macroglobulin-1 protein assay (PAMG-1) test (AmniSure test)  
Amniotic fluid insulin-like growth factor binding protein(IGFBP-1) test (Actim PROM test) 
Level 2 
Clinical history of rupture of membranes AND 
Visible leakage of fluid on vaginal speculum examination AND 
Visible arborization (ferning) on microscopy of amniotic fluid OR 
document membrane rupture by a diagnostic test (one of those listed above) OR Ultrasound 
with oligohydramnios (AFI <5 or MVP <2) 
Level 3 
Clinical history of rupture of membranes AND 
Visible leakage of presumed amniotic fluid; this may be on vaginal speculum examination 
(pooling in vagina), on inspection of the perineum (wet perineum due to leakage of fluid from 
the vagina), or fluid soaked cloth/clothes/sanitary pad. 
Preterm labor 
For all levels of diagnostic certainty 
Patient is determined to be have delivered preterm as defined by the Brighton Collaboration 
definition 
Level 1  
On presentation, >4 documented uterine contractions per hour as determined by a 
tocodynometer AND 
Documented change in length or dilation of cervix by physical examination or transvaginal 
ultrasound over a two hour period, with clinical criteria for documenting cervical change by 
exam including: 
a. Cervical dilation 2 cm or greater at the internal os by digital examination  
b. Cervical length of 1 cm or less by digital examination 
c. 50% or greater effacement by digital examination 
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Event of interest 
Description 
Levels of diagnostic certainty 
Reference 
Level 2  
Greater than 4 uterine contractions per hour as determined by a tocodynometer or clinical 
assessment AND 
Documented change in length or dilation of cervix by physical examination, with clinical criteria 
including:  
a. Cervical dilation 2 cm or greater at the internal os by digital examination 
b. Cervical length of 1 cm or less by digital examination 
c. 50% or greater effacement by digital examination 
Level 3  
1. Greater than 4 documented uterine contractions per hour determined by clinical assessment 
AND 
2. Documented change in cervical examination (change in dilation or effacement) over a two 
hour period 
Insufficient cervix 
For all levels of diagnostic certainty 
Patient is determined to be ≥16 weeks and <24 weeks gestation as defined by the Brighton 
Collaboration definitions of gestational age  
Patient is determined to have advanced cervical dilation (>2 cm) resulting in either treatment 
with a cerclage (cervical stitch) or preterm delivery 
Patient is determined to not be in preterm labor, having ≤4 con-tractions per hour documented 
clinically or on tocodynometer (with anything >4 contractions per hour falling into the category 
of preterm labor) 
Level 1  
Internal cervical os dilation (>2 cm) with ≤4 contractions/h, as determined by transvaginal 
ultrasound AND 
digital examination  
Level 2  
Internal cervical os dilation (>2 cm) with ≤4 contractions/h, as determined by digital 
examination  
Level 3  
Patient reports fetal delivery without any painful contractions 
History excludes other causes of mid-trimester delivery 
Provider-initiated preterm birth 
For all levels of diagnostic certainty 
Patient is determined to be preterm as defined by the Brighton Collaboration definition  
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Event of interest 
Description 
Levels of diagnostic certainty 
Reference 
Level 1  
Documentation in the healthcare record by a patient’s delivering provider that there were no 
signs or symptoms of the spontaneous onset of preterm labor AND 
Documentation in the healthcare record by a patient’s delivering provider that the patient 
needed to undergo induction of labor or cesarean delivery which led to the preterm delivery  
Level 2 
From recall, delivering provider confirms that there was an absence of any signs or symptoms 
of the spontaneous onset of preterm labor AND 
Delivering provider reports from recall that he or she decided that the patient needed to 
undergo induction of labor or cesarean delivery 
Level 3  
From recall, patient confirms that there was an absence of any signs or symptoms of the 
spontaneous onset of preterm labor AND 
Patient reports from recall that the healthcare provider indicated that she needed to undergo 
induction of labor or cesarean delivery 
 
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Neonatal events of interest - –TABLE FROM PROTOCOL VERSION 01 
Event of interest 
Description 
Levels of diagnostic certainty  
(1 highest level to 4 lowest level of certainty) 
Reference 
Small for 
gestational age  
Weight below 10th percentile for 
gestational age as assessed against a 
validated global, regional or local 
standard. 
Level 1  
Weight below 10th percentile for gestational age AND 
The following used in assessment of weight: 
Newborn weighed within 24 hours of birth 
Weight assessed using a calibrated electronic scale with 10 g resolution 
AND 
The following for assessment of gestational age: 
Certain LMP or IUI or embryo transfer date AND confirmatory ultrasound in first trimester OR 
The following for assessment of gestational age: 
First trimester ultrasound 
Level 2A  
Weight below 10th percentile for gestational age AND 
The following used in assessment of weight: Newborn weighed within 24 hours of birth on any 
scale with a < 50 g resolution, tared to zero and calibrated AND 
The following for assessment of gestational age: 
Certain LMP with first or second trimester ultrasound OR 
Certain LMP with first trimester physical exam2 
Level 2B  
Weight below 10th percentile for gestational age AND 
The following used in assessment of weight: Newborn weighed within 24 hours of birth on any 
scale with a < 50 g resolution, tared to zero and calibrated AND 
The following assessment of gestational age: Uncertain LMP with second trimester ultrasound 
Level 3A 
Weight below 10th percentile for gestational age AND 
The following used in assessment of weight: Infant weighed within the first 48 hours of life, 
Newborn weighed on any scale with a < 50 g resolution, tared to zero and calibrated AND 
The following assessment of gestational age: 
Certain LMP with third trimester ultrasound OR 
Certain LMP with confirmatory 2nd trimester fundal height OR 
Certain LMP with birthweight OR 
Uncertain LMP with first trimester physical exam 
Level 3B 
Weight below 10th percentile for gestational age AND 
Schlaudecker 
EP, Munoz FM, 
Bardají A, et al. 
Small for 
Gestational Age: 
Case Definition & 
Guidelines for 
Data Collection, 
Analysis, and 
Presentation of 
Maternal 
Immunisation 
Safety Data. 
unpublished 
manuscript. 
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Event of interest 
Description 
Levels of diagnostic certainty  
(1 highest level to 4 lowest level of certainty) 
Reference 
The following used in assessment of weight: Infant weighed within the first 48 hours of life, 
Newborn weight assessed by measuring the difference between an adult holding the infant 
and the adult being weighed alone on any scale AND 
The following assessment of gestational age: 
Uncertain LMP with fundal height OR 
Uncertain LMP with newborn physical assessment OR 
Uncertain LMP with birthweight 
Level 4 
Baby noted to be small, but no actual weight 
Baby with GA assessed only by infant examination 
Diagnosis extracted from billing codes or chart, with no documentation of actual birth weight 
or GA 
Low birth weight 
(LBW) 
LBW <2500 grams. Very low birth 
weight (VLBW) <1500 grams and 
extremely low birth weight (ELBW) is 
<1000grams. 
Level 1  
1. Newborn infant weighed within 24 hours of birth AND 
2. Use electronic scale which is graduated to 10 grams AND 
3. Scale is calibrated at least once a year AND 
4. Scale placed on level, hard surface AND 
5. Scale tared to zero grams AND 
6. Weight recorded as <2500 grams OR 
7. Birth weight recorded as <2500 grams AND 
8. Birth weight assessed as per health care facility’s standard operating procedure, which 
fulfills criteria 1 to 5  
Level 2  
1. Newborn infant weighed within 24 hours of birth AND 
2. Scale (electronic/spring) is graduated to at least 50 grams AND 
3. Scale is calibrated at least once a year, or more often if moved AND 
4. Scale tared to zero grams or 0.00kg AND 
5. Weight recorded as <2500 grams OR 
6. Birth weight recorded as <2500 grams AND 
7. Birth weight assessed as per health care facility’s standard operating procedure, which 
fulfills criteria 1 to 4 
(Scale used could be electronic or spring scale, including colour-coded scale) 
Level 3  
1. Newborn infant weighed on day 1 or 2 of life (first 48 hours of life) AND 
2. Weight measured using dial/spring/colour-coded scale AND 
Cutland CL, 
Lackritz E, 
Alonso AB, et al. 
Low Birth 
Weight: Case 
Definition & 
Guidelines for 
Data Collection, 
Analysis, and 
Presentation of 
Maternal 
Immunisation 
Safety Data. 
Unpublished 
manuscript. 
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Event of interest 
Description 
Levels of diagnostic certainty  
(1 highest level to 4 lowest level of certainty) 
Reference 
3. Weight assessed as <2500 grams 
Level 4  
1. Newborn weight assessed between 3 and 7 days of age AND 
2. Weight assessed using dial/ spring/ colour-coded scale OR 
3. Proxy measure (Table 1 of reference) of birth weight used AND 
4. Weight CATEGORY assessed as <2500 grams 
Acute Neonatal 
Encephalopathy 
Is a clinical syndrome presenting with 
abnormal functioning of the central 
nervous system, in the earliest days of 
life in an infant born at or beyond 35 
weeks of gestation, manifested by an 
abnormal level of alertness or seizures, 
and often accompanied by difficulty 
with initiating and maintaining 
respiration and depression of tone that 
may be due to a variety of etiologies 
including hypoxia/ischemia, metabolic 
disturbance, or infection. 
Level 1  
Abnormal level of alertness AND 
Clinical Seizures with electroencephalographic correlation AND 
Difficulty with initiating and maintaining respiration AND 
Depression of tone 
Level 2  
Abnormal level of alertness AND 
Clinical Seizures with or without electroencephalographic correlation AND 
Difficulty with initiating and maintaining respiration OR 
Depression of tone 
Level 3  
Abnormal level of alertness AND 
Clinical Seizures OR 
Difficulty with initiating and maintaining respiration OR 
Depression of tone 
Sell E, Munoz 
FM, Soe A, et al. 
Acute Neonatal 
Encephalopathy: 
Case Definition & 
Guidelines for 
Data Collection, 
Analysis, and 
Presentation of 
Maternal 
Immunization 
Safety Data. 
Unpublished 
manuscript. 
Congenital 
Microcephaly 
Congenital microcephaly, also referred 
to as primary microcephaly due to its 
presence in utero or at birth, is a 
descriptive term for a structural defect 
in which a fetus or infant’s head 
(cranium) circumference is smaller than 
expected when compared to other 
fetuses or infants of the same 
gestational age, sex and ethnic 
background. 
Postnatally diagnosed Congenital Microcephaly Case Definition  
Level 1  
Live birth, stillbirth, or spontaneous or therapeutic abortion of at least 24 weeks of Gestational 
Age (GA) AND  
HC 2 SD below mean or <3% according to GA and gender, using appropriate standardized 
reference charts for the population (e.g., WHO growth reference charts if GA ≥37 weeks and 
Intergrowth-21st reference charts for GA 24–36 weeks) AND  
Measured between 24–36 hours after birth or end of pregnancy.  
Level 2A  
Live birth, stillbirth, or spontaneous or therapeutic abortion of at least 24 weeks of GA AND  
HC 2 SD below mean or <3% according to GA and gender, using appropriate standardized 
reference charts for the population (e.g., WHO growth reference charts if GA ≥37 weeks and 
Intergrowth-21st reference charts for GA 24–36 weeks) AND  
Measured within the first 24 hours OR  
DeSilva M, 
Munoz FM, Sell 
E, et al. 
Congenital 
Microcephaly: 
Case Definition & 
Guidelines for 
Data Collection, 
Analysis, and 
Presentation of 
Safety Data after 
Maternal 
Immunisation. 
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Event of interest 
Description 
Levels of diagnostic certainty  
(1 highest level to 4 lowest level of certainty) 
Reference 
Measured >36 hours and up to 6 weeks after birth or end of pregnancy with no apparent post-
natal insult resulting in microcephaly  
Level 2B  
Live birth, stillbirth, or spontaneous or therapeutic abortion of at least 24 weeks of GA AND  
HC 2 SD below mean or <3% according to GA and gender, using appropriate standardized 
reference charts for the population (e.g., WHO growth reference charts if GA ≥37 weeks and 
Intergrowth-21st reference charts for GA 24–36 weeks) AND  
Measured within the first 24 hours OR  
Measured >36 hours and up to 6 weeks after birth or end of pregnancy with no apparent post-
natal insult resulting in microcephaly  
Level 3  
Live birth, stillbirth, or spontaneous or therapeutic abortion AND  
Case meets criteria for microcephaly using a validated algorithm: 1 inpatient diagnosis OR 2 
outpatient diagnoses OR 1 outpatient diagnosis AND death in first year using the following 
diagnostic codes ICD-9-CM code 742.1 or ICD-10-CM code Q02  
Level 4  
Live birth, stillbirth, or spontaneous or therapeutic abortion AND  
Diagnosis of congenital microcephaly based on physical inspection without HC measurement 
OR  
Diagnosis of congenital microcephaly based on ICD-9-CM or ICD-10-CM code that does not 
meet validated algorithm criteria above.  
B. Prenatally diagnosed Congenital Microcephaly Case Definition  
Level 1A  
Fetus of at least 24 weeks GA based on certain LMP with confirmatory 1st trimester (<14 
weeks) or 2nd trimester US scan IUI, or embryo transfer date AND  
HC 2 SD below mean or <3% according to fetal ultrasound (US) examination using 
appropriate standardized reference charts according to GA and gender for the population (eg. 
WHO growth reference charts if GA ≥37 weeks and Intergrowth-21st reference charts for GA 
24–36 weeks) AND  
Confirmation of microcephaly (i.e., HC 2 SD below mean or <3%) in fetus by at least one 
additional US after 24 weeks and at least one week after first US OR  
Confirmation of microcephaly by HC measurement with standard tape measure at birth or 
autopsy  
Unpublished 
manuscript. 
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Event of interest 
Description 
Levels of diagnostic certainty  
(1 highest level to 4 lowest level of certainty) 
Reference 
Level 1B  
1. Fetus of at least 24 weeks GA based on uncertain LMP with 2nd trimester US AND  
2. HC 2 SD below mean or <3% according to fetal ultrasound (US) examination using 
appropriate standardized reference charts according to GA and gender for the population (eg. 
WHO growth reference charts if GA ≥37 weeks and Intergrowth-21st reference charts for GA 
24–36 weeks) AND  
Confirmation of microcephaly (i.e., HC 2 SD below mean or <3%) in fetus by at least one 
additional US after 24 weeks and at least one week after first US OR  
Confirmation of microcephaly by HC measurement with standard tape measure at birth or 
autopsy 
Level 2 
Fetus of at least 24 weeks GA based on LMP with fundal height and no confirmatory US scan 
AND  
HC 2 SD below mean or <3% according to fetal US examination using appropriate 
standardized reference charts according to GA and gender for the population (eg. WHO 
growth reference charts if GA ≥37 weeks and Intergrowth-21st reference charts for GA 24–36 
weeks) AND  
Confirmation of microcephaly (i.e., HC 2 SD below mean or <3%) in fetus with at least one 
additional US after 24 weeks and at least one week after first US OR  
Confirmation of microcephaly by HC measurement with standard tape measure at birth or 
autopsy  
Level 3  
Fetus of at least 24 weeks GA AND  
HC 2 SD below mean or <3% according to fetal US examination using appropriate 
standardized reference charts according to GA and gender for the population (eg. WHO 
growth reference charts if GA ≥37 weeks and Intergrowth-21st reference charts for GA 24–36 
weeks) AND  
No confirmation of microcephaly with any additional US or by HC measurement at birth or 
autopsy  
Level 4  
Fetus of at least 24 weeks GA AND  
No available measurement of HC in utero by US, but documentation on medical record review 
suggesting microcephaly based on US imaging AND  
No confirmation of microcephaly with any additional US or by HC measurement at birth or 
autopsy  
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Event of interest 
Description 
Levels of diagnostic certainty  
(1 highest level to 4 lowest level of certainty) 
Reference 
Level 5  
Fetus of at least 24 weeks GA AND  
HC 2 SD below mean or <3% according to fetal US examination using appropriate 
standardized reference charts according to GA and gender for the population (eg. WHO 
growth reference charts if GA ≥37 weeks and Intergrowth-21st reference charts for GA 24–36 
weeks) AND  
HC at birth or autopsy is in the normal range using appropriate standardized reference charts 
according to GA and gender for the population, which means that this is NOT a case of 
prenatally diagnosed congenital microcephaly 
Congenital 
anomalies 
Congenital anomalies, also commonly 
referred to as birth defects, congenital 
disorders, congenital malformations, or 
con-genital abnormalities, are events of 
prenatal origin that a represent at birth, 
potentially impacting an infant’s health, 
development and/or survival.  
For all levels of diagnostic certainty 
A major congenital anomaly is a structural or functional defect with the following three 
characteristics: 
1. Of prenatal origin 
2. Present at the time of live birth or fetal demise, or in utero 
3. Affecting (or has the propensity to affect) the health, survival, or physical or cognitive 
functioning of the individual 
Major External Structural Defects  
Level 1  
•Alterations in external anatomy visible at the time of live birth and persistent beyond the 
immediate peripartum period unless surgically repaired OR 
•Alterations in external anatomy visible in a stillbirth or in the products of conception of a 
spontaneous or therapeutic abortion AND 
•Confirmed by documentation of a diagnosis made by a clinician experienced in diagnosing 
congenital anomalies and with the highest level of morphology training for the specific setting 
Level 2  
•Alterations in external anatomy visible at the time of live birth and persistent beyond the 
immediate peripartum period unless surgically repaired OR 
•Alterations in external anatomy visible in a stillbirth or in the products of conception of a 
spontaneous or therapeutic abortion AND 
•Confirmed by documentation of a diagnosis made by a clinician with some experience 
diagnosing congenital anomalies 
Level 3  
•Alterations in external anatomy visible at the time of live birth and persistent beyond the 
immediate peripartum period unless surgically repaired OR 
[DaSilva, 2016] 
 
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Event of interest 
Description 
Levels of diagnostic certainty  
(1 highest level to 4 lowest level of certainty) 
Reference 
•Alterations in external anatomy visible in a stillbirth or in the products of conception of a 
spontaneous or therapeutic abortion AND 
•Confirmed by documentation of a diagnosis made by a trained maternal or child health care 
provider with at least minimal experience diagnosing congenital anomalies OR 
•For live births, confirmed using individual (ICD-9/ICD-10) codes or as part of an ICD-9/ICD-
10 code based algorithm, where the outcome (individual code or algorithm) has been 
validated 
Level 4 (insufficient evidence to confirm)  
•Alterations in external anatomy visible at the time of live birth and persistent beyond the 
immediate peripartum period unless surgically repaired OR 
•Alterations in external anatomy visible in a stillbirth or in the products of conception of a 
spontaneous or therapeutic abortion AND  
•Confirmed by medical record review OR 
•Confirmed in claims data (ICD-9/ICD-10 diagnoses)  
Internal Structural Defects 
Level 1 
•Alterations in internal anatomy present at the time of live birth and persistent beyond the 
immediate peripartum period unless surgically repaired AND 
•Confirmed by definitive imaging study or intraoperative diagnosis OR  
•Alterations in internal anatomy detected during autopsy for a stillbirth, spontaneous or 
therapeutic abortion confirmed by documentation by a pathologist or other relevant 
subspecialist  
Level 2  
•Alterations in internal anatomy present at the time of live birth and persistent beyond the 
immediate peripartum period unless surgically repaired AND 
•Confirmed by documentation of a diagnosis made by a clinician experienced in diagnosing 
congenital anomalies and with the highest level of morphology training for the specific setting 
without definitive imaging or intraoperative evaluation OR  
•For stillbirth, spontaneous or therapeutic abortion, internal structural defect is visible by 
ultrasound or other imaging modality prenatally 
Level 3  
•Alterations in internal anatomy present at the time of live birth and persistent beyond the 
immediate peripartum period unless surgically repaired AND 
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Event of interest 
Description 
Levels of diagnostic certainty  
(1 highest level to 4 lowest level of certainty) 
Reference 
•Confirmed by documentation of a diagnosis made by a clinician with some experience 
diagnosing congenital anomalies OR 
•Confirmed using individual (ICD-9/ICD-10) codes or as part of an ICD-9/ICD-10 code based 
algorithm, where the outcome (individual code or algorithm) has been validated 
Level 4 insufficient evidence to confirm 
•Alterations in internal anatomy present at the time of live birth and persistent beyond the 
immediate peripartum period unless surgically repaired OR 
•Alterations in internal anatomy present at time of stillbirth, spontaneous abortion, or induced 
abortion AND 
•Confirmed through medical record review, with the medical record demonstrating that the 
anomaly was present at the time of live birth or time of fetal demise, and that the anomaly was 
diagnosed by a trained maternal or child health care provider with minimal experience 
diagnosing congenital anomalies OR 
•Confirmed by claims data (ICD-9/ICD-10 diagnoses) 
Functional Defects 
Level 1  
•For live births, alterations in functioning of one or more organs or body parts not due to a 
structural defect, present at the time of birth (or propensity to develop alteration present at live 
birth), and persistent beyond the immediate peripartum period, unless treated through gene 
therapy or stem cell transplantation OR  
•For stillbirths, spontaneous or therapeutic abortions, alterations in functioning of one or more 
organs or body parts, not due to a structural defect AND  
•Confirmed by definitive diagnostic study 
Level 2  
•For live births, alterations in functioning of one or more organs or body parts not due to a 
structural defect, present at livebirth (or propensity to develop alteration present at live 
birth),and persistent beyond the immediate peripartum period, unless treated through gene 
therapy or stem cell transplantation OR  
•For stillbirths, spontaneous or therapeutic abortions, alterations in functioning of one or more 
organs or body parts, not due to a structural defect AND  
•Confirmed by documentation of a diagnosis made by a clinician experienced in diagnosing 
congenital anomalies and with the highest level of training in the diagnosis of functional 
defects for the specific setting 
Level 3  
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Event of interest 
Description 
Levels of diagnostic certainty  
(1 highest level to 4 lowest level of certainty) 
Reference 
•For live births, alterations in functioning of one or more organs or body parts not due to a 
structural defect, present at livebirth (or propensity to develop alteration present at live 
birth),and persistent beyond the immediate peripartum period, unless treated through gene 
therapy or stem cell transplantation OR  
•For stillbirths, spontaneous or therapeutic abortions, alterations in functioning of one or more 
organs or body parts, not due to a structural defect AND 
•Confirmed by documentation of a diagnosis made by a clinician with some experience 
diagnosing functional defects OR  
•Confirmed using individual (ICD-9/ICD-10) codes or as part of an ICD-9/ICD-10 code based 
algorithm, where the outcome(individual code or algorithm) has been validated 
Level 4 (insufficient evidence to confirm)  
•For live births, alterations in functioning of one or more organs or body parts not due to a 
structural defect, present at the time of live birth (or propensity to develop alteration present at 
livebirth), and persistent beyond the immediate peripartum period, unless treated through 
gene therapy or stem cell transplantation OR 
•For stillbirths, spontaneous or therapeutic abortions, alterations in functioning of one or more 
organs or body parts, not due to a structural defect AND 
•Confirmed through medical record review, with the medical record demonstrating that the 
anomaly was present at the time of live birth or time of fetal demise, and that the anomaly was 
diagnosed by a trained maternal or child healthcare provider who is not a qualified geneticist, 
neonatologist, pathologist, subspecialist, pediatrician, obstetrician, or family medicine 
practitioner OR  
•Confirmed by claims data (ICD-9/ICD-10 diagnoses) 
Neonatal death 
Death of a live born infant regardless of 
gestational age at birth, within the first 
28 completed days of life. 
Neonatal death in a non-viable live birth 
Level 1  
1. Live born infant AND 
2. Gestational age <22 weeks (GA level of certainty = 1) OR 
3. Birth weight <500 g AND 
4. Death of infant in first 28 days of life AND 
5. Medically-confirmed death 
Level 2  
1. Live born infant AND 
2. Gestational age/size of newborn assessed as at least one of: 
a. Gestational age <22 weeks (GA Level of Certainty = 1 OR 2) 
b. Birth weight <500 g AND 
[Pathirana, 2016] 
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Event of interest 
Description 
Levels of diagnostic certainty  
(1 highest level to 4 lowest level of certainty) 
Reference 
3. Death of infant in first 28 days of life AND 
4. Medically-confirmed death OR non-medically-confirmed death 
Level 3  
1. Live born infant AND 
2. Gestational age <5 months according to parent/family member/delivery attendant (GA 
Level of Certainty = 2 OR 3) AND 
3. Death of infant in first 28 days of life AND 
4. Medically-confirmed death OR non-medically-confirmed death 
Neonatal death in an extremely preterm live birth 
Level 1  
1. Live born infant AND 
2. Gestational age ≥22 and <28 weeks (GA Level of Certainty = 1) OR 
3. Birth weight ≥500 g but <1000 g AND 
4. Death of infant in first 28 days of life AND 
5. Medically-confirmed death 
Level 2  
1. Live born infant AND 
2. Gestational age/size of newborn assesses as one or more of: 
a. Gestational age ≥22 and <28 weeks (GA Level of Certainty = 1 OR 2)  
b. Birth weight ≥500 g but <1000 g AND 
3. Death of infant in first 28 days of life AND 
4. Medically-confirmed death OR non-medically-confirmed death 
Level 3  
1. Live born infant AND  
2. Gestational age ≥5 months but <7 months according to neonate’s parent 
(mother/father)/family member/delivery attendant (GA Level of Certainty = 2 OR 3) AND 
3. Death of infant in first 28 days of life AND 
4. Medically-confirmed death OR non-medically-confirmed death 
Neonatal death in a preterm live birth (gestational age ≥28to <37 weeks) 
Level 1  
1. Live born infant AND 
2. Gestational age ≥28 and <37 weeks (Level of Certainty = 1)OR 
3. Birth weight ≥1000 g but <2500 g AND 
4. Death of infant in first 28 days of life AND 
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Event of interest 
Description 
Levels of diagnostic certainty  
(1 highest level to 4 lowest level of certainty) 
Reference 
5. Medically-confirmed death 
Level 2  
1. Live born infant AND  
2. Gestational age/size of newborn assesses as one or more of: 
a. Gestational age ≥28 and <37 weeks (GA Level of Certainty = 1 OR 2)  
b. Birth weight ≥1000 g but <2500 g AND 
3. Death of infant in first 28 days of life AND 
4. Medically-confirmed death OR non-medically-confirmed death 
Level 3  
(MAY apply to LMIC- or may be non-viable in LMIC) 
1. Live born infant AND 
2. Gestational age ≥7 months but <9 months according to parent/family member/delivery 
attendant (GA Level of Certainty = 2 OR 3) AND 
3. Death of infant in first 28 days of life AND 
4. Medically-confirmed death OR non-medically-confirmed death 
Neonatal death in a term live birth 
Level 1  
1. Live born infant AND 
2. Gestational age ≥37 weeks (GA Level of Certainty = 1) AND 
3. Birth weight >2500 g OR  
4. Documented intra-uterine growth retardation if ≤2500 g AND 
5. Death of infant in first 28 days of life AND 
6. Medically-confirmed death 
Level 2 
1. Live born infant AND 
2. Gestational age/size of newborn assesses as one or more of: 
a. Gestational age ≥37 weeks (GA Level of Certainty = 1 OR 2) 
b. Birth weight ≥2500 g AND 
3. Death of infant in first 28 days of life AND 
4. Medically-confirmed death OR non-medically-confirmed death which is confirmed by 
examination by (by at least) non-medically-trained attendant (e.g. undertaker, community 
member) 
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Event of interest 
Description 
Levels of diagnostic certainty  
(1 highest level to 4 lowest level of certainty) 
Reference 
Level 3 (apply to LMIC) 
1. Live born infant AND 2. Gestational age ≥9 months according to parent/family 
member/delivery attendant (GA Level of Certainty = 2 OR 3) AND 
3. Death of infant in first 28 days of life AND 
4. Medically-confirmed death OR non-medically-confirmed death 
Neonatal infections 
Neonatal bacteraemia and sepsis (of 
early or late onset), meningitis, 
pneumonia and other respiratory 
infections such as bronchiolitis, caused 
by bacteria, parasites, viruses or fungi. 
Localised eye and ear infections, 
encephalitis, urinary tract infections and 
intestinal infections were excluded from 
these guidelines.  
Neonatal invasive blood stream infections: bacterial/fungal/viral 
Level 1 
Recognised pathogen identified using a validated method and from a normally sterile site. 
Level 2 
Not meeting Level 1 of evidence AND  
3 or more criteria: 
• Temperature ≥37.5 ◦C or <35.5 ◦C 
• Tachycardia or new or more frequent episodes of bradycardia 
•New or more frequent episodes of apnea or increased oxygen requirement or increased 
requirement for ventilatory support 
• Lethargy or moving only when stimulated or hypotonia or irritability 
• Difficulty in feeding or abdominal distention 
• Pallor or poor perfusion or hypotension 
•Abnormal White Cell Count or I/T ratio >0.2 
• Abnormal platelet count  
•Increased inflammatory markers (CRP, procalcitonin) 
• Metabolic acidosis as defined by a base excess 
Level 3 
Not meeting Level 1 or 2 of evidence AND 
2 or more of the following criteria: 
• Temperature ≥37.5 ◦C or <35.5 ◦C 
• Tachypnea or severe chest in drawing or grunting or cyanosis 
• Change in level of activity 
• History of feeding difficulty 
• History of convulsions 
Bacterial/fungal/viral meningitis 
Level 1 
Recognised pathogen identified using a validated method from cerebrospinal fluid (CSF) 
[Vergnano, 2016] 
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Event of interest 
Description 
Levels of diagnostic certainty  
(1 highest level to 4 lowest level of certainty) 
Reference 
Level 2 
CSF pleocytosis OR  
positive IgM antibodies to a specific pathogen in the CSF AND 
Recognised pathogen identified using a validated method from a normally 
sterile site (other than CSF) AND 
Temperature ≥37.5 ◦C or <35.5 ◦C AND 
1 or more criteria: 
• History of convulsions 
•Lethargy or irritability 
•Coma 
•Apnea 
•Bulging fontanel 
•Neck stiffness 
Level 3a 
CSF pleocytosis AND 
No pathogen identified using a validated method from a normally sterile site AND 
Temperature ≥37.5 ◦C or <35.5 ◦C AND 
3 or more criteria: 
• History of convulsions 
• Lethargy or irritability 
• Coma 
• Apnea 
• Bulging fontanel 
• Neck stiffness 
Level 3b 
No lumbar puncture done or no sample available AND 
Temperature ≥37.5 ◦C or <35.5 ◦C AND 
4 or more criteria: 
• History of convulsions 
• Lethargy or irritability 
• Coma 
• Apnea 
• Bulging fontanel 
• Neck stiffness 
Respiratory bacterial/fungal/viral infection 
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Event of interest 
Description 
Levels of diagnostic certainty  
(1 highest level to 4 lowest level of certainty) 
Reference 
Level 1 
New or progressive or persistent infiltrate or shadowing or fluid in the intrapleural cavity or 
interlobar fissure on chest X-ray AND 
Recognised virus identified using a validated assay from an upper respiratory sample OR 
Recognised pathogen identified using a validated method and from a normally sterile site 
AND  
3 or more criteria: 
• Temperature ≥37.5 ◦C or <35.5 ◦C 
• Tachypnea or Nasal flaring or Chest in-drawing or Grunting 
• Desaturations or increased oxygen requirements or increased ventilator requirements or 
oxygen saturation <95% 
• Apneas 
• Increased respiratory secretions or Increased suctioning requirements 
• Cough or wheeze or crepitations 
• Increased CRP or procalcitonin 
Level 2 
New or progressive or persistent infiltrate or shadowing or fluid in the intrapleural cavity or 
interlobar fissure on chest X-ray AND  
4 or more criteria: 
• Temperature ≥37.5 ◦C or <35.5 ◦C 
• Tachypnea or Nasal flaring or Chest in-drawing or Grunting 
• Desaturations or increased oxygen requirements or increased ventilator 
requirements or oxygen saturation <95% 
• Apneas 
• Increased respiratory secretions or Increased suctioning requirements 
• Cough or wheeze or crepitations 
• Increased CRP or procalcitonin 
Level 3 
2 or more criteria: 
• Difficulty in breathing/Tachypnea 
• Severe chest in-drawing 
• Nasal flaring 
• Grunting 
• Wheezing 
• Stridor 
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Event of interest 
Description 
Levels of diagnostic certainty  
(1 highest level to 4 lowest level of certainty) 
Reference 
• Fever 
Respiratory distress 
in the neonate 
Constellation of clinical findings that 
support the presence of breathing 
difficulty in the neonate. 
Level 1 
Newborn 0 to 28 days of life AND 
Abnormal respiratory rate: 
Measurement of number of breaths per minute consistent with: 
Tachypnea = respiratory rate of more than 60 breaths per minute OR 
Bradypnea = respiratory rate of less than 30 breaths per minute OR 
Apnea = cessation of respiratory effort (no breaths) for at least 20 seconds 
AND 
Clinical symptoms consistent with labored breathing 
Nasal flaring (dilatation of alae nasi) OR 
Noisy respirations in the form of expiratory grunting, stridor, or wheeze OR 
Retractions or increased chest in-drawings on respiration (subcostal, intercostal, sternal, 
suprasternal notch) OR 
Central cyanosis (whole body, including lips and tongue) on room air OR 
Low Apgar Score (< 7 points) at 10 min, with respiration score <2 AND 
Examination and documentation by qualified, trained, health care provider appropriate for the 
clinical setting. 
Level 2 
Newborn 0 to 28 days of life AND 
Abnormal respiratory rate: 
Not measured, but reported as “rapid breathing”, “slow breathing”, having periods of “no 
breathing”, or “abnormal breathing” AND 
Clinical symptoms consistent with labored breathing 
Nasal flaring (dilatation of alae nasi) OR 
Noisy respirations in the form of expiratory grunting, stridor, or wheeze OR 
Retractions or increased chest in-drawings on respiration (subcostal, intercostal, sternal, 
suprasternal notch) or seesaw respirations OR 
Central cyanosis (whole body, including lips and tongue) on room air OR 
Low Apgar Score (< 7 points) at 10 min, with respiration score <2 AND 
No medical record documentation, but reporting through either a non-medical observer (e.g. 
mother, father, community worker) or via standard census mechanisms (e.g. Demographic 
and Health Surveillance System) OR 
Collection of information from medical record review or billing codes. 
Sweet LR, Keech 
C, Klein NP, et 
al. Respiratory 
Distress in the 
Neonate: Case 
Definition & 
Guidelines for 
Data Collection, 
Analysis, and 
Presentation of 
Maternal 
Immunization 
Safety Data. 
Unpublished 
manuscript. 
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Event of interest 
Description 
Levels of diagnostic certainty  
(1 highest level to 4 lowest level of certainty) 
Reference 
Level 3 
No need for a level 3 per working group. 
Level 4 
Not enough information to ascertain case of respiratory distress. 
Stillbirth 
Fetal death occurring before birth after 
a 20 to 28 weeks of gestation (variation 
due to country definitions). 
Antepartum Stillbirth 
Fetal death occurs prior to the evidence of labor. 
Level 1 
•Delivery of an infant with no of signs of life at birth (No spontaneous movements, no umbilical 
cord pulse, no heartbeat, no respirations, Apgar score of 0 at 1 and 5 min) determined by 
physical examination after delivery (with or without electronic monitoring of heart rate, 
respiratory rate, and pulse oximetry). AND  
•Prenatal ultrasound examination documenting lack of fetal cardiac activity or movement 
before the onset of labor. OR 
•Auscultation for fetal heart tones (using electronic devices or non-electronic devices) 
documenting lack of fetal heartbeat. AND 
•Maternal report of lack of fetal movement for 24 h or more. OR 
•Maternal physical examination confirming lack of fetal movement. OR 
•Radiology findings consistent with intrauterine fetal death. AND 
•Attended delivery followed by fetal physical examination afterbirth consistent with antepartum 
death, by obstetrician, neonatologist, pediatrician, maternal-fetal medicine specialist, or 
pathologist. In the setting where access to a specialist is not feasible, diagnosis by a health 
care provider trained or experienced to make the diagnosis is acceptable (e.g. general 
practice physician, mid-wife, nurse practitioner, a physician’s assistant or other qualified 
trained practitioner). OR 
•Fetal/placental pathology report consistent with antepartum death. AND 
•Gestational age within pre-defined range for selected stillbirth definition as assessed by 
maternal and/or fetal parameters (Level1 or 2 in GA assessment algorithm). 
Level 2 
•Delivery of an infant with no of signs of life at birth (No spontaneous movements, no umbilical 
cord pulse, no heartbeat, no respirations, Apgar score of 0 at 1 and 5 min) determined 
physical examination after delivery. AND 
•Maternal report of lack of fetal movement for 24 h or more. OR 
•Maternal physical examination confirming lack of fetal movement. OR 
•Auscultation for fetal heart tones (using electronic or non-electronic devices) documenting 
lack of fetal heartbeat. AND 
[DaSilva, 2016] 
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Event of interest 
Description 
Levels of diagnostic certainty  
(1 highest level to 4 lowest level of certainty) 
Reference 
•Attended delivery followed by physical examination after birth consistent with antepartum 
death, by specialist or qualified trained practitioner appropriate to the health care setting. OR 
•Fetal/placental pathology report consistent with antepartum death. AND 
•Gestational age within pre-defined range for selected stillbirth definition as assessed by 
maternal and/or fetal parameters (Level1–2 in GA assessment algorithm). 
Level 3 
•Delivery of an infant reported to have no of signs of life at birth(No spontaneous movements, 
no umbilical cord pulse, no heart-beat, no cry or spontaneous respirations, no chest 
movement, and whole body cyanosis). AND 
•Maternal report of lack of fetal movement for 24 h or more prior to delivery. OR 
•Report of auscultation for fetal heart tones (using electronic or non-electronic devices) 
documenting lack of fetal heartbeat. AND 
•Non-attended delivery followed by physical examination of the fetus after birth consistent with 
antepartum death by a healthcare professional appropriate to the level of standard of care in 
the health care setting. OR 
•Verbal history by a trained health care provider, non-medical witness or the mother of a fetus 
born with no signs of life or unresponsive to resuscitation efforts immediately after birth and 
with physical features consistent with antepartum death. AND 
•Gestational age within pre-defined range for selected stillbirth definition as assessed by 
maternal and/or fetal parameters (Level2–3 in GA assessment algorithm).Level 4•Report of 
stillbirth but fetus is not available for physical examination after birth (no objective assessment 
can be made) 
•Maternal information insufficient to assess gestational age 
Intrapartum stillbirth 
Fetal death occurs during labor and before delivery 
Level 1 
•Delivery of an infant with no of signs of life at birth, including: No spontaneous movements, 
no umbilical cord pulse, no heartbeat, no respirations, and Apgar score of 0 at 1 and 5 min 
.•Determination of the absence of signs of life is made by physical examination after delivery, 
with or without electronic monitoring of heart rate, respiratory rate, and pulse oximetry. AND 
•Evidence of live fetus prior to onset of labor (documentation of fetal movement and of fetal 
heart tones by ultrasound prior to onset of labor) (Note: in the absence of evidence of a live 
fetus prior to the onset of labor, the fetal death should be reported as a stillbirth or an 
antepartum stillbirth).AND 
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Event of interest 
Description 
Levels of diagnostic certainty  
(1 highest level to 4 lowest level of certainty) 
Reference 
•Attended delivery followed by physical examination afterbirth consistent with intrapartum 
death by obstetrician, neonatologist, pediatrician, maternal-fetal medicine specialist, 
pathologist. In the setting where access to a specialist is not feasible, diagnosis by a health 
care provider trained or experienced to make the diagnosis is acceptable (e.g. general 
practice physician, midwife, or other qualified trained practitioner).AND 
•Gestational age within pre-defined range for selected stillbirth definition as assessed by 
maternal and/or fetal-neonatal parameters (Level 1 in GA assessment algorithm) 
Level 2 
•Delivery of an infant with no of signs of life at birth, including: No spontaneous movements, 
no umbilical cord pulse, no heartbeat, no respirations, and Apgar score of 0 at 1 and 5 min. 
•Determination of the absence of signs of life is made by physical examination after delivery, 
with or without electronic monitoring of heart rate, respiratory rate, and pulse oximetry OR 
documentation of lack of response to resuscitation efforts. AND 
•Evidence of live fetus prior to onset of labor (maternal report of fetal movement prior to onset 
of labor and documentation of fetal heart tones by auscultation or hand held Doppler) (Note: 
in the absence of evidence of a live fetus prior to the onset of labor, the fetal death should be 
reported as a stillbirth or an antepartum stillbirth). AND 
•Attended delivery followed by physical examination after birth consistent with intrapartum 
death by a health care professional appropriate to the level of standard of care in the health 
care setting. AND 
•Gestational age within pre-defined range for selected stillbirth definition as assessed by 
maternal and/or fetal parameters (Level1–2 in GA assessment algorithm). 
Level 3 
•Delivery of an infant reported to have no of signs of life at birth, including: No spontaneous 
movements, no umbilical cord pulse, no heartbeat, no cry, no spontaneous respirations or 
chest movement, and whole body cyanosis. AND 
•Evidence of live fetus prior to onset of labor (maternal report of fetal movement prior to onset 
of labor OR auscultation of fetal heart tones) (Note: in the absence of evidence of a live fetus 
prior to the onset of labor, the fetal death should be reported as a stillbirth or an antepartum 
stillbirth). AND 
•Non-attended delivery followed by physical examination of the fetus after birth consistent with 
intrapartum death by a healthcare professional appropriate to the level of standard of care in 
the health care setting OR verbal history by a trained health care provider, non-medical 
witness or the mother of a fetus born with no signs of life or unresponsive to resuscitation 
efforts immediately after birth. AND 
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Event of interest 
Description 
Levels of diagnostic certainty  
(1 highest level to 4 lowest level of certainty) 
Reference 
•Gestational age within pre-defined range for selected stillbirth definition as assessed by 
maternal and/or fetal parameters (Level2–3 in GA assessment algorithm). 
Level 4 
•Report of stillbirth but fetus is not available for physical examination after birth (no objective 
assessment can be made). 
•Maternal information insufficient to assess gestational age. 
Preterm birth 
Birth in less than 37 gestation 
completed weeks (less than 259 days).  
 
Prematurity and assessment of gestational age  
Level 1 
Certain LMP or intrauterine insemination (IUI) date or embryo transfer (ET) date with 
confirmatory 1st trimester scan (≤13 6/7 weeks). OR 
1st trimester scan (≤13 6/7 weeks) 
Level 2A 
Certain LMP* with 2nd trimester scan (14 0/7 weeks to 27 6/7weeks). If LMP and U/S do not 
correlate, default to U/S GAassessment.OR2. Certain LMP* with 1st trimester physical 
examination. 
Level 2B 
Uncertain LMP with 2nd trimester scan (14 0/7 weeks to 276/7 weeks). 
Level 3A 
Certain LMP with 3rd trimester scan – 28 0/7 weeks + OR 
Certain LMP with confirmatory 2nd trimester FH OR 
Certain LMP with birth weight OR 
Uncertain LMP with 1st trimester physical examination. 
Level 3B 
Uncertain LMP with FH. OR 
Uncertain LMP with newborn physical assessment. OR 
Uncertain LMP with Birth weight 
Definitions of LMP, birth weight and physical assessment in article.  
[Quinn, 2016] 
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GlaxoSmithKline Biologicals 
Vaccines R & D 
Protocol Amendment 2  
eTrack study number and Abbreviated Title 
207636 (EPI-RSV-008 BOD) 
Amendment number: 
Amendment 2 
Amendment date: 
03-JUL-2018 
Co-ordinating author: 
, Lead Science Writer 
Rationale/background for changes:  
The protocol has been amended to reflect the following changes and provide the 
following clarifications / corrections. 
• 
The title and detailed title have been re-phrased in an effort to improve their 
clarity. 
• 
The Glossary of terms has been updated. 
• 
Objectives and endpoints have been re-phrased for improved consistency with 
epidemiological terminology. 
• 
In the inclusion criteria for pregnant women, language regarding informed consent 
has been clarified. 
• 
Language describing inclusion criteria for infants has been clarified. 
• 
For infants, a Month 6 visit has been added. 
• 
Memory aids have been replaced with Diary cards. 
• 
Subject cards have been added. 
• 
An interim analysis has been added. 
• 
Laboratory assays described in Appendix B have been updated. 
• 
Laboratory addresses in Appendix B have been updated. 
• 
Additional editorial changes have been made to ensure consistency with the 
modifications noted above, and typographical errors have been corrected. 
Text that has been moved or added is presented in bold italics and deleted text in 
strikethrough in the following sections. 
Global changes: 
Global additions/replacements are displayed in boldface italics in the document but are 
not enumerated word by word here. 
US spellings replace UK spellings of terms such as hospitaliszation, paediatric, 
haematology, enrollment, labour, and titere. 
“Maternal/fetal” has been replaced throughout with the term “maternal.” 
“Difficulty breathing” has been replaced with “Difficulty in breathing.” 
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Where reference is made to specifically to the first 28 days of life, the term 
“neonate/infant” has been replaced with the term “neonate.” 
Title: 
A Prospective Epidemiological prospective epidemiological study of Outcomes 
pregnancy outcomes and of events of interest in pregnant women, Neonates neonates and 
Infants  infants (PEPNI)  
Detailed Title: 
A prospective epidemiological study of women as of between 24-27 weeks of 
pregnancyand their infants up to 1 year of age, to describe maternal, fetal and neonatal 
pregnancy outcomes, pregnancy-related and /infant  and events of interest and in the 
occurrence mother and neonate, as well as determine incidence in neonates infants of 
RSV LRTI and RSV hospitalization. 
Contributing Authors: 
Two lists are now provided. The first is a list of authors who contributed to Amendment 
2.  The second is a list of authors who contributed to previous versions of the document. 
Persons who appear as contributing authors for the first time are: 
• 
, Clinical Research and Development Lead 
• 
, Expert Epidemiology Biostatistician 
• 
, Clinical Trial Supply manager 
• 
, Clinical Read-Out Team Leader  
• 
, Safety Physician 
• 
, Study Delivery Lead 
 replaces 
 as the CEPL. 
Glossary 
Child 
A young human being below the legal age of majority 
(generally ≤ < 18 years of age). 
Enrollment 
Pregnant woman who meet all eligibility criteria at the 
Screening visit and return to the study site for Visit 1 
are considered enrolled.  Live born neonates who meet 
all eligibility criteria and complete Visit 1-NB are 
considered enrolled. 
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GAIA 
Global Alignment of Immunization Safety Assessment 
in pregnancy. A project that aims to improve the quality 
of outcome data from clinical vaccine trials in pregnant 
women with a specific focus on the needs and 
requirements for safety monitoring in low to middle 
income countries .  
 
Local healthcare provider 
A healthcare provider who provides subjects with 
medical care per local standards. This individual may or 
may not be a member of the study staff.  
Neonatal events of interest 
Events as described in  Clinically significant events that 
occur from birth through 28 days of age and may be 
considered adverse events if they occur after 
vaccination.  They are listed in Section 11.1 that occur 
from birth through 28 days of age.and described in detail 
in APPENDIX D. 
Parental concern 
The parent(s) / Legally Acceptable Representative(s) or 
their designates are concerned about the infant’s 
respiratory tract illness or general health and intend to 
seek medical care 
Pregnancy related events 
of interest 
Events as described in Section 11.1 that occur from Visit 
1 through Visit 6 (Day 42).Clinically significant events 
that occur up to 42 days after delivery and may be 
considered adverse events if they occur after 
vaccination.  They are listed in Section 11.1 and 
described in detail in APPENDIX D. 
Synopsis: 
Rationale for the study: 
This multi-country study will enroll pregnant women ≥ 240/7 weeks and <280/7 weeks 
gestational age (GA).  Study procedures in this protocol are defined to ensure that 
maternal and neonatal events of interest are captured. They are not intended to replace 
procedures performed by local healthcare providers as part of standard care. Prenatal 
screening and care will be provided by local healthcare providers as much as possible and 
information will be collected and recorded in this study’s electronic case report form 
(eCRF(in accordance with local standards). 
• 
End of Study (EoS): … samples collected up to Visit 3 4-NB... 
• 
Epoch 003: … ending at Visit 3 4-NB (1 year post-birth). 
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Background and Rationale (Section 1.1 and Synopsis “Rationale for the Study and 
Study Design”) 
…Several marketed vaccines are already recommended for and routinely administered to 
pregnant women, including influenza, tetanus and Tdap vaccines (MMWR 2013, ACIP 
2012).CDC 2013a, CDC 2013b). There are also a number of maternal vaccines in 
development that aim to protect neonates and infants from additional pathogensincluding 
in addition to respiratory syncytial virus (RSV). GlaxoSmithKline (GSK) is developing 
an investigational vaccine for use in pregnant women, against RSV disease. Of note these 
vaccines are this vaccine is developed solely for immunization in pregnancy.  
Maternal immunization is implemented worldwide and has the potential to make a major 
contribution to reducing RSV lower respiratory tract infections (LRTI) and other disease 
the burden of other diseases in infants globally.… GSK is proactively addressing 
potential challenges of conducting clinical trials in pregnant women in low- and middle 
income countries (LMIC). 
Understanding Before conducting clinical trials it is important to understand the 
frequency of pregnancy outcomes and the maternal , fetal, and neonatal outcomes and 
events of interest (i.e. clinically significant events that may be considered adverse events 
if they occur after vaccination) in each setting prior to conducting where clinical trials 
is critical may be conducted for better interpretation of safety data. Also, to ensure safety 
of the participating women, and to characterize the safety profile of the product, adverse 
events (AEs) in pregnancy should be appropriately detected and managed. This study 
addresses gaps in understanding of anticipated rates of pregnancy outcomes and as well 
as events of interestFurtherin pregnant women and neonates. Furthermore, this study 
will be conducted at potential sites for future maternal immunization trials and will help 
assure the capacity of sites to detect and manage clinically significant events of interest in 
pregnant women and their neonates. It will also establish surveillance mechanisms for 
infections and events of interest. 
Secondarily, the study will establish surveillance mechanisms for RSV infections in the 
neonate/infant(through the first 12 months of life. Whilst there is good documentation 
of the global burden of RSV disease, incidence of RSV-LRTI according to the World 
Health Organization (WHO) 2015 case definitions [Modjarrad , 2016] is lacking limited 
in the literature, particularly in many LMIC settings. Hence, this study will also estimate 
the incidence of infant RSV-LRTI using WHO case definitions across geographically 
distinct locations to support incidence rate assumptions for planning of future efficacy 
trials.  
Section 1.1 only: Standardization of surveillance methodology and case definitions 
(applicable to maternal immunization AEs) may support comparison of data across 
different countries [Jones , 2016]. 
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Rationale for the Study Population (Section 1.1.1 and Synopsis) 
The intention of this trial epidemiological study is to obtain an estimate of the 
background rate of adverse pregnancy outcomes and events that will may be seen in 
future vaccine trial populations and, separately, to assess whether sites are suitable for 
Phase II/III vaccine trials. 
Rationale for the Surveillance System for the detection of pregnancy related events 
of interest (Section 1.3) 
There are particular challenges in conducting clinical trials in pregnant women, among 
them limited data on background rates of pregnancy outcomes as well as what may be 
observed in clinical trials as maternal and neonatal outcomes and adverse events.  
This study is not intended to provide comprehensive antenatal care or to replace local 
antenatal standard of care, but rather to leverage the data (e.g., clinical findings, 
diagnoses, laboratory results) captured in local antenatal standard of care. Information 
obtained from study-specific procedures and laboratory tests (e.g. blood sampling, urine 
dipstick) is not to be relied upon for clinical management of study subjects.  
To achieve these goals, GSK will be guided by the WHO recommendations on 
antenatal care for a positive pregnancy experience [WHO, 2016] and the Global 
Alignment of Immunization Safety Assessment in pregnancy (GAIA) case definitions 
[Bonhoeffer , 2016; Bauwens , 2016; Kochhar , 2017]. Standardization of surveillance 
methodology and case definitions (applicable to maternal immunization AEs) may 
support comparison of data across different countries [Jones , 2016]. 
The number and timing of study visits was informed by WHO recommendations on 
antenatal care [WHO, 2016]. However, local standards of care differ from country-by-to 
country. Women should follow the local standard of care. Study visits data will be used 
to collect and record collected, in part, from records of the data obtained during the 
locally recommended antenatal care visits. 
In this study, best efforts will be made to work with local healthcare providers to collect 
the key data on maternal, fetal and, neonatal and infant health from routine health 
records to avoid duplication and an undue burden on the trial subjects.  
Rationale for the use of Global Alignment of Immunization safety Assessment in 
pregnancy (GAIA) case definitions (Section 1.4) 
GAIA, a Brighton collaboration project, aims to develop standardized case definitions 
and criteria for diagnostic certainty of maternal outcomes and events of interest and 
neonatal outcomes events of interest in the context of immunization trials [Bauwens 
2016, Bonhoeffer 2016, Kochhar 2017]. 
Rationale for the active and passive surveillance for RSV associated respiratory 
tract infections (RTI) with suspicion of difficulty in breathing/wheezing or with 
parental concern in neonates/ infants (Section 1.5) 
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As part The implementation of the RSV maternal program, this study aims to set up the 
surveillance will also assist in establishing robust infrastructure and processes for 
RSV-LRTI and RSV hospitalization detection, for site preparedness  in future vaccine 
trials.  
Benefit Assessment (Section 2.2) 
Study procedures aim to ensure adequate surveillance for maternal and neonatal 
outcomes of pregnancy and events of interest and neonatal events of interest. The 
attention to adequate surveillance of these events may enhance the ability to detect these 
safety events and to refer subjects for management according to local standard of care. 
The protocol also includes procedures that may enhance surveillance for RSV, and 
possibly other lower respiratory tract infections, in neonates and infants. Thus, the 
procedures described in this protocol may enhance the ability to detect these events or 
infections and to refer subjects for management according to local standard of care.   
Data collected during the study may enhance understanding of the incidence frequency of 
maternal events of interest in women with low risk pregnancies, neonatal events of 
interest, and RSV-associated lower respiratory tract infections associated with RSV 
infection in neonates and infants.   
Overall Benefit:Risk Conclusion (Section 2.3) 
…….and by the knowledge gained about the incidence frequency of medical events of 
interest. 
Primary Objectives (Section 3.1 and Synopsis) 
• 
To determine the frequencies of Visit 1: To detect and describe pregnancy 
outcomes.  
• 
To detect and describe determine the frequencies of pregnancy related events of 
interest.  
from enrollment (Visit 1) through 42 days after delivery (Visit 6). 
(Although pregnancy  related events of interest occur within the first 42 days after 
delivery they may only be detected later, and are to be reported throughout the 
study.) 
• 
To detect and describe determine the frequencies of neonatal events of interest. 
Neonatal AEs of interest occur within the first 28 days after birth, but may only be 
detected later and are to be reported throughout the study.  
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Secondary Objectives (Section 3.2 and Synopsis) 
In healthy pregnant women with uncomplicated pregnancies as of Visit 1 at enrollment: 
• 
To detect and describe determine frequencies of pregnancy related events of interest 
according (where these are specified) to GAIA levels of diagnostic certainty (where 
these are specified) (APPENDIX D) from enrollment (Visit 1) through 42 days 
after delivery (Visit 6). (Although pregnancy  related events of interest occur 
within the first 42 days after delivery they may only be detected later, and are to be 
reported throughout the study.) 
• 
To describe the distribution of RSV-A antibody titers in maternal blood at delivery 
• 
To detect and describe determine frequencies of neonatal events of interest 
according (where these are specified) to GAIA levels of diagnostic certainty (where 
these are specified).(APPENDIX D). 
Neonatal AEs of interest occur within the first 28 days after birth, but may only be 
detected later and are to be reported throughout the study. 
• 
To describe the distribution of RSV-A antibody titers in cord blood at delivery.  
• 
To describe occurrences of determine the incidence of all, of severe, and of very 
severe RSV-lower respiratory tract infections (LRTIs).  
• 
To describe occurrences determine the incidence of RSV hospitalization.  
• 
Refer to the GLOSSARY OF TERMS for the definition of enrollment. 
Tertiary Objectives (Section 3.3 and Synopsis) 
• 
To describe the association co-infections of RSV-LRTI with other respiratory 
viruses with the occurrence of RSV-LRTI in infants.  
• 
To describe estimate the association between of RSV-LRTI in neonates/infants and 
the level of RSV neutralizing antibodies in cord blood.  
• 
To describe determine risk factors for pregnancy-related and neonatal events of 
interest  
• 
If deemed necessary, to further characterize the immune responses to the diseases 
under study RSV and other infections in pregnant women/mothers and infants, and / 
or to explore further parameters in pregnant women (mothers) or their infants.(based 
on maternal serum and cord blood).  
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Study Design Figure 1 and accompanying footnotes (Section 4.0) 
The design figure has been adjusted to add a 6-month visit in infants and to indicate that 
an interim analysis will be performed.  The entire figure is reproduced below. 
 
Study Design Footnotes  
Refer to Section 11.11 for additional information about the analyses indicated above. 
4 Blood Allowed interval for blood sample should be collected within collection begins with start of labor (e.g. 
when the mother arrives at the hospital to deliver and an intravenous line is inserted) and ends 72 hours 
after delivery. 
6Neonatal conditions events of interest occur (by definition) between 0 and 28 days after birth.  They will be reported 
once site staff become aware of them (whether this occurs during the first 28 days after birth, or at a later time).  
Study population (Section 4.0 and Synopsis) 
• 
Study population: The study will be conducted in multiple countries, in pregnant 
women and their neonatesinfants.  
V2 (D28)1
GA: 28 0/7
- 31 6/7w
Screening
GA: 24 0/7
- 27 6/7w
V5 
Delivery
V6
Day 42
BS:
• H/B
US :
• Glucose
• Proteins
• RBC
• WBC
Up to (approximately) 400 pregnant women (≥ Week 24 of gestation) per country
Up to (approximately) 4,000 pregnant women in total   
Pregnant women (mothers)
BS:
• H 3
US :
• Glucose
• Proteins
• RBC
• WBC
V3 (D56) 1
GA: 32 0/7 -
35 6/7w
BS 4
• Imm 2
Cord blood 5
• Imm
Epoch 002
Mother: V1 through V6
Child: V1-NB through V2-NB
V4 (D84) 1
GA: 36 0/7 -
39 6/7w
Analysis 1
Neonates/Infants
V1-NB
Birth
V2-NB
Day 42
V4-NB
Year 1
Final Analysis 
Epoch 003
Child: V3-NB
Neonatal events of interest 6
LRTI Surveillance in Neonates / Infants
Pregnancy outcomes and maternal/fetal events of interest 
Study Procedure Related Serious Adverse Event Follow-up
US :
• Glucose
• Proteins
• RBC
• WBC
US :
• Glucose
• Proteins
• RBC
• WBC
V1 (D1)
GA: 24 0/7 -
27 6/7w
Epoch 001
Screening
Mother only
Informed 
consent
Inclusion, 
Exclusion 
Criteria
V3-NB
Month 6
Interim 
Analysis
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Sampling schedule for pregnant women/mothers, Table 1 and Synopsis Table 1, 
footnote 5:   
5This sample may be collected as from start of labour  (e.g. when the mother arrives at 
the hospital to deliver and an intravenous line is inserted)  ) through 72 hours after 
delivery.   
• 
Sampling schedule for neonates/infants: Surveillance for RSV LRTI will be 
conducted in infants through the 12 month study period. During the this 1-year 
post-birth surveillance period, for each RTI with suspicion of difficulty in breathing, 
or wheezing, or with parental concern, a nasal swab will be collected at a visit to 
assess potential RSV associated RTIs/LRTIs. 
• 
Epoch 003: Follow-up of infants starting 43 days post-delivery/birth and ending at 
Visit 3 4-NB (1 year post-birth). 
• 
Surveillance for pregnancy outcomes and pregnancy-related events of interest 
(Section 8.5.8) that occur from Visit 1 up to 42 days after delivery (Visit 6). 
Footnotes to Table 3: 
2 For blood oxygen saturation (SpO2), the lowest value monitored will be used. In high altitudes (>2500m), SpO2 
<92% for LRTI, <90% for severe LRTI, <87% for very severe LRTI.   
5 RSV sampling and testing is based on medical judgment of medical practitioner or driven by algorithm.  
6 Hospitalization is defined as a medical decision that the child requires admission for observation or treatment 
based on the judgement of a health care provider. 
Pregnancy related events of interest (Section 5.1) 
Pregnancy related events of interest are briefly defined in the GLOSSARY OF TERMS 
…….  
Neonatal events of interest (Section 5.2) 
Neonatal events of interest are briefly defined in the GLOSSARY OF TERMS…  
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Inclusion Criteria for Enrolment (Section 6.2) 
Pregnant Women (Section 6.2.1) 
• 
Individuals who gave give written or witnessed/thumb printed informed consent 
after the study had has been explained according to local regulatory requirements. 
Informed 
− 
The informed consent given at screening should either include consent for 
study both the mother’s participation and participation of the mother should be 
obtained from the mother or infant after the infant’s birth (if consistent with 
local regulations/guidelines), or consent for the mother’s participation and 
expressed willingness to consider permitting the infant to take part after the 
infant has been born (if local regulations/guidelines require parent(s) to 
provide an additional informed consent after the infant’s birth).  
− 
Both mother and father, as applicable by local law, prior to performance of any 
study specific procedures; should consent if local regulations/guidelines 
require it. 
• 
Individuals (mother or mother and father) who, at the time of their informed 
consent, express willingness to enroll their infant in the study at the time of birth.  
Infants (Section 6.2.2): 
• 
Infants live-born to enrolled women that resulted from the enrolled pregnancyInfants 
who were in utero at the time maternal (and paternal, if required) informed 
consent was given, and who are live-born. 
• 
If local law requires it:Written or witnessed/thumb printed informed consent for 
study participation of the infant obtained from the infant’s mother and/or father, as 
applicable by local law, or parent(s)/LAR(s) within 10 days of birth.  
General Study Aspects (Section 8.2) 
Supplementary Critical study conduct information not mandated to be present in this 
protocol is provided in the Study Procedures Manual (SPM). As such, the SPM should 
be viewed as a companion document that should be read carefully to fully understand 
the study protocol. The SPM provides the investigator and the site personnel with 
administrative and detailed technicaloperational information that is essential for correct 
study execution and does not impact the safety of the subjects. 
Study visits and procedures in this protocol are defined to ensure that maternal, fetal and 
neonatal events of interest, as well as RSV-associated LRTIs and RSV hospitalization in 
infants, are captured. Prenatal screening and care will be provided by local healthcare 
providers and information will be collected and recorded in the eCRF.(in accordance 
with local standards). 
Study visits are not intended to replace local standard of care antenatal visits. If local 
standard of care recommends additional visits/medical evaluations during pregnancy, 
women participating in this study should comply with their regular antenatal care visit 
schedules, per local recommendations. 
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Study procedures are not intended to replace procedures performed by local healthcare 
providers as part of standard care.  
Outline of Study Procedures (Section 8.3) 
Table 4, List of Study Procedures.  
No columns were added with this amendment.  Only rows where changes were made 
have been presented.  Only footnotes where changes were made have been presented. 
Gestational age 
≥ 24 0/7  -  
27 6/7 
24 
0/7 –   
27 
6/7 
28 0/7 
- 
31 6/7 
32 0/7 
- 
35 6/7 
36 0/7 - 
delivery 
 
 
 
Epoch 
Epoch 
001  
Epoch 002  
Type of contact 
Screening 
Visit 
1  
Visit 
2 2   
Visit 
3 2  
Visit 4 2 
Visit 5  
Visit 6 
3, 4 
Additional 
antenatal/medical 
evaluations 
(external to study 
visits/procedures)4 
5  
Timepoints 
 
Day 
1 
Day 
28 
Day 
56 
Day 84 
At 
Delivery 
Post-
Delivery 
Day 42 
 
Eligibility Review 
and Confirmation 
 
 
 
 
 
 
 
 
Informed consent 1  
●  
 
 
 
 
 
 
 
Inform study 
paediatrician 
and/or staff of 
subject’s 
participation 
Ensure that site 
study physicians 
(both 
obstetrician(s) 
and 
pediatrician(s)) 
are informed 
 
O  
 
 
 
O   
 
 
Medical History / 
Examinations 
 
 
 
 
 
 
 
 
Distribute 
Maternal Subject 
Card  
 
O  
 
 
 
 
 
 
Distribute maternal 
health memory 
aid diary card  
 
O 
O 
O 
O  
O   
O 
 
Review and 
collect maternal 
diary card  
 
 
O 
O 
O 
O  
O 
 
Transcribe 
applicable diary 
card data to the 
eCRF  
 
 
● 
● 
● 
● 
● 
 
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Gestational age 
≥ 24 0/7  -  
27 6/7 
24 
0/7 –   
27 
6/7 
28 0/7 
- 
31 6/7 
32 0/7 
- 
35 6/7 
36 0/7 - 
delivery 
 
 
 
Epoch 
Epoch 
001  
Epoch 002  
Type of contact 
Screening 
Visit 
1  
Visit 
2 2   
Visit 
3 2  
Visit 4 2 
Visit 5  
Visit 6 
3, 4 
Additional 
antenatal/medical 
evaluations 
(external to study 
visits/procedures)4 
5  
Timepoints 
 
Day 
1 
Day 
28 
Day 
56 
Day 84 
At 
Delivery 
Post-
Delivery 
Day 42 
 
Travel history to, 
or living in, Zika 
virus endemic 
countries/regions 
with Zika virus 
transmission  
O  
● 
 
 
 
 
 
 
Record results of 
General and 
Obstetric 
examination 10  
●  
●   
●  
●   
●   
 
●  
● 13  
Check and record 
prescription 
medications, 
vaccinations, 
folate and/or iron 
(independently or 
included in a 
multivitamin)  12   
●  
●  
●  
● 
● 
● 
● 
●  
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Gestational age 
≥ 24 0/7  -  
27 6/7 
24 
0/7 –   
27 
6/7 
28 0/7 
- 
31 6/7 
32 0/7 
- 
35 6/7 
36 0/7 - 
delivery 
 
 
 
Epoch 
Epoch 
001  
Epoch 002  
Type of contact 
Screening 
Visit 
1  
Visit 
2 2   
Visit 
3 2  
Visit 4 2 
Visit 5  
Visit 6 
3, 4 
Additional 
antenatal/medical 
evaluations 
(external to study 
visits/procedures)4 
5  
Timepoints 
 
Day 
1 
Day 
28 
Day 
56 
Day 84 
At 
Delivery 
Post-
Delivery 
Day 42 
 
Biological 
Specimens / 
Laboratory Test 
Results 
 
 
 
 
 
 
 
 
Record results of  
local hematology/ 
biochemical 
analysis (up to 10 
Visit 15.5 ml; 
Visit 32 ml – 
hemoglobin only) 
6  
 
●  
 
●  
 
 
 
●13   
Record results of 
urine dipstick to 
check for 
presence of 
proteins, glucose, 
RBC, WBC 7 
 
● 
● 
● 
● 
 
 
●13 
Record results of 
any clinically 
significant 
abnormal 
laboratory tests 
(including positive 
urine culture) if 
performed by local 
healthcare 
provider and 
available 5  
 
O  
O  
O 
O 
O 
O 
● 
Outcomes and 
Events of Interest 
 
 
 
 
 
 
 
 
Record 
pregnancy-related 
events of interest 
and other clinically 
significant events 
or diagnoses that 
could impact the 
pregnancy 
 
●  
●   
● 
● 
● 
● 
● 
1 Refer to Section 6.2.1, fifth bullet.  
8 At Visit 3, only hemoglobin testing.  
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13 Beginning the month before the estimated date of conception and while on study.  (Routine concomitant medications 
administered during labor and delivery need not be collected.) 
14 Record If clinically significant abnormal results    
Table 5, List of Study Procedures  
One column was added to account for the 6 month visit. Because a column was added, 
the amended table has been presented in its entirety.  All footnotes (since only 1 was 
unchanged) have also been provided. 
Epoch 
Epoch 002  
Epoch 003  
Epoch 002 and Epoch 003  
Age 
0-10 
days  
42 
Days 
6 
Months 
12 
months 
0-12 months 
Type of contact 
Visit 
1-NB  
Visit 2-
NB b   
Visit 3-
NB b  
Visit 4-
NB b  
Contact for 
active/ 
passive 
surveillance  
Visit to assess 
potential LRTI 
a   
Timepoints 
Birth  Day 42 
 
Y1  
 
 
Check inclusion/exclusion criteria  
● 
 
 
 
 
 
Obtain post-delivery informed 
consent of from parent(s)/LAR(s) if 
required per local regulations  
● a  
 
 
 
 
 
Record infant’s subject number  
● 
 
 
 
 
 
Record Apgar assessment  
● 
 
 
 
 
 
Record demographic data  
● 
 
 
 
 
 
Record lifestyle characteristics  
 
● 
 
 
 
 
Distribute Infant's Subject Card  
O 
 
 
 
 
 
Distribute infant health and RTI 
memory aiddiary card d  
O 
O  
O 
 
 
O 
Review infant diary card  
 
O  
O 
O 
 
O 
Collect infant diary card e f  
 
O  
O  
O  
 
O  
Transcribe applicable infant diary 
card data to eCRF  
 
●  
● 
● 
 
● 
Weight, length, head circumference, 
results of targeted medical history, 
and results of physical examination  
● 
● 
● 
● 
 
 
Record prescription medications / 
vaccinations  
● 
● 
● 
● 
●  
● 
Record neonatal events of interest  
● 
● 
● 
● 
 
 
Clinical evaluation of potential LRTI  
 
 
 
 
 
● 
Nasal swab b  
 
 
 
 
 
● c  
Record all hospitalizations and 
clinically significant events  
● 
● 
● 
● 
● 
● 
Record SAEs related to study 
participation  
● 
● 
● 
● 
● 
● 
Study conclusion  
 
 
 
●  
 
 
Investigator sign-off on eCRF before 
analysis  
 
● 
●  g  
● 
 
 
a  If local regulations require that confirmation of consent for the infant’s participation be obtained at birth. 
b  Visits 2-, 3-,  and 4-NB Visit 2-NB (Day 42), Visit 3-NB (Year 1)  and LRTI assessment visits may take place in 
the subject’s home (if the standard of care allows for home visits), at the investigator’s clinical facility or 
at another facility per the investigator’s judgment.  
c  If more than one assessment visit is conducted to evaluate a potential LRTI episode, additional nasal swabs may be 
collected at the discretion of the Investigator. 
d Distribute at V1-NB:  Distribute additional diary cards at subsequent visits as needed.  
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e Collect diary cards that are fully filled out and / or document (L)RTI episodes that have ended (as defined in 
Section 8.6.5.1).  Provide new diary cards as needed.  
f Collect all diary cards for potential RTIs that are considered resolved. Collect the diary card for the current 
potential LRTI once the episode has ended (as defined in Section 8.6.5.1). 
g After at least 50% of infants have completed Visit 3-NB, an interim analysis on data that is as clean as 
possible will be performed. 
Table 6: Intervals between study visits/contacts/observations 
Interval 
Optimal interval*** 
Allowed interval** 
Birth → Visit 3-NB  
180 days  
166 -194 days  
Birth → Visit 3 4-NB  
365 days  
351 – 407- 379 days  
Eligibility Review and Confirmation (Section 8.5.1) 
• 
Obtain informed consent as The signed/witnessed/thumb printed informed consent of 
the subject must be obtained before study participation. Refer to Section 7.1 for the 
requirements on how to obtain informed consent, as appropriate. The father of the 
unborn child should also sign the mother’s ICF, if required by the local 
regulations/guidelinesdescribed in Sections 6.2.1 and 7.1.  
• 
Inform For eligible pregnant women who complete visit 1 (are enrolled): ensure 
that site study paediatrician physicians (both obstetrician(s) and pediatrician(s)) are 
informed.  In particular, the study pediatrician and/or staff of the pregnant woman’s 
participationA copy of the informed consent should be forwarded to the study 
paediatrician and/or staff notified as soon as possible after a pregnant woman’s 
enrolment to ensure the study pediatrician is informed in a timely manner of the 
approximate date of delivery and potential enrolment of the neonate. 
History and Examinations for pregnant women/mothers (Section 8.5.2) 
• 
Distribute the Maternal Health Memory Aid.  It is intended to serve as a reference 
during study visits/contacts, to help the subject provide the investigator/ study staff 
with protocol-specified data (and contact information for other healthcare 
providers, so medical records may be requested if required).  (Refer to the SPM for 
details). 
• 
Distribute the Maternal Subject Card (Section 9.3). 
• 
Distribute the Maternal Diary Card to the subject (Section 8.5.4).   
• 
Record demographic data, which may include (but is not limited to) information such 
as race, month and year of birth, and ethnicityand geographic location. 
• 
Record information about whether the subject has travelled to / is living in Zika virus 
endemiccountries / regions with Zika virus transmission. 
Maternal Diary Card (Section 8.5.3) 
A maternal diary card will be provided to each subject at visit 1, then collected and 
replenished throughout the study as needed. It will document any prescription 
medications, folate and/or iron (independently or included in a multivitamin) taken, 
any vaccinations received during pregnancy and after delivery, and any additional 
visits the subject may make to a healthcare provider not affiliated with the study.  
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The diary card will be reviewed with the subject during study visits.  If review indicates 
that the subject visited a healthcare provider not affiliated with the study, study staff 
should (if permitted by local regulation) contact that healthcare provider to obtain the 
medical record(s) for the visit.   
Refer to the SPM for additional details. 
Biological Specimens / Laboratory Data for pregnant women/mothers (Section 
8.5.4) 
• 
If performed by local healthcare provider and results are available, the 
investigator/site staff will also…………. 
Labor and Delivery (Section 8.5.4) 
 
• 
Medications Any medications administered during labor and delivery as per 
standard of care if not considered routine 
Concomitant medications Medications, vaccinations, and supplements for administered 
to pregnant women/mothers as per standard of care (Section 8.5.6) 
See Section 8.5.6 for medications administered during labor and delivery 
Outcomes and Events of Interest in pregnant women/mothers (Section 8.5.7) 
− 
If there is no live birth, all study visits and procedures related to the maternal 
subject should still be followed up to study end.  
− 
Maternal events of interest (including, but not limited to, those described in 
Section 11.1.1) occurring up to Visit 6 (Post-delivery Month 1.5Day 42) should 
be recorded in the eCRF 
Additional Antenatal / medical evaluations external to study visits / procedures 
(Section 8.6.8) 
For any additional antenatal / medical evaluations at which a pregnancy related event of 
interest is identified, record information that supports the diagnosis of the event, if 
available. 
Eligibility Review and Confirmation for Neonates (Section 8.6.1) 
• 
Check all applicable inclusion and exclusion criteria as described in Sections 6.2.2 
and 6.3.2. A neonate who does not meet the eligibility criteria should be considered 
ineligible. 
• 
Obtain informed consent from parent(s) / LAR(s) at Visit 1-NB, as per local 
requirements. 
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History and Examinations for Neonates / Infants (Section 8.6.2) 
• 
Record lifestyle characteristics. Data may include (but are not limited to) passive 
smoking and day-care attendance contact with young children under 6 years of 
age. 
• 
Distribute the Infant Health and RTI Memory Aid Subject Card to the 
parent(s)/LAR(s)/designate(s). The memory aid is intended to serve as a reference 
during study visits/contacts, to help (Section 9.3). 
• 
Distribute the Infant Diary Card to the parent(s)/LAR(s)/designate(s) provide the 
investigator/ study staff with protocol-specified data (and contact information for 
other healthcare providers, so medical records may be requested if 
required). (Section 8.6.3). 
Infant Diary Cards (Section 8.6.3) 
[Note that numbering for all subsections that follow this new section was incremented, 
and the adjustments are reflected in updated cross references].  
Infant diary cards will be provided at the infant Visit 1 NB.  They should be completed 
by the Parent(s)/LAR(s)/designate(s) of the infant subject.   
The infant diary cards will be used to document: 
− 
RTI symptoms experienced by the infant, including start and end dates for 
those symptoms, and 
− 
Additional visits to a pediatric healthcare provider not affiliated with the study, 
as well as prescription medications (including those taken to treat an RTI) and 
vaccinations administered to the infant. (If the infant subject was taken to a 
healthcare provider not affiliated with the study, the study staff should (if 
permitted by local regulation) contact that healthcare provider to obtain the 
medical record(s) for the visit.)   
Documentation of RTI episodes (Section 8.6.3.1): 
One diary card should be completed for each RTI episode whether or not an 
Assessment Visit (Section 8.6.6) takes place. An RTI episode has “ended” if it satisfies 
the criteria in Section 8.6.5.1.   
At each study visit (including any assessment visits), RTI episode(s) may have ended or 
may be ongoing.  
For any RTI episode(s) that has/have ended by the time of a study visit: 
• 
Study staff should collect the Diary card(s), and replenish the 
parent(s)/LAR(s)/designate(s) supply of blank cards as needed.  
For any RTI episode that is ongoing at the time of a study visit (including any 
assessment visit): 
• 
Study staff should review the diary card, make a photocopy of it, and return it to 
the parent(s)/LAR(s)/designate(s) so information can continue to be collected until 
the episode has ended.  
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• 
 Once the episode has ended, study staff must collect the completed diary card by a 
site visit, home visit., or postal mail, whichever is most effective based on local 
practice.  The site should make every effort to collect completed diary cards as 
soon after the end of an episode as possible. If diary card collection occurs during 
a visit to the study site or to the subject’s home, a brief clinical evaluation may be 
performed to confirm that the episode has ended. 
Refer to the SPM for additional details. 
Surveillance for Neonatal events of interest (Section 8.6.4) 
In addition, the investigator or study staff will perform (if not performed by local 
healthcare provider) a minimum of 2 clinical examinations: one at birth (or up to 72 
hours after birth), and another at approximately 42 days of age.   
Surveillance for episodes of potential Lower Respiratory Tract Infection (Section 
8.6.5) 
Definitions (Section 8.6.5.1) 
− 
snot nasal discharge running freely out of the infant’s nose (runny nose), or  
− 
An RTI episode starts on the day when (per parental report, as written in the 
Diary Card and/or provided verbally during an assessment visit) the first RTI 
symptom started.   
− 
An RTI episode ends on the day when (per parental report, as written in the last 
RTI symptom Diary Card and/or provided verbally during an assessment visit) 
either cough or difficulty in breathing has resolved, whichever resolves later. 
− 
There must be at least 7 symptom-free days between 2 consecutive RTI 
episodes; the only exception is runny nose, which is a symptom that can 
persist during that minimum 7-day period that would distinguish one episode 
from a new episode.  
Active surveillance (Section 8.6.5.3) 
Three attempts should be made to contact the infant’s parents/ LAR(s) (or their 
designates) within the week of a scheduled contact before it is abandoned.  If these 
attempts are unsuccessful,  that active contact is considered a missed contact. The next 
active contact will be made according to schedule. 
Decision to conduct a visit to assess a potential LRTI (Section 8.6.6) 
An assessment visit will be conducted as soon as possible, ideally within 3 calendar days 
after learning of the potential LRTI case. Note that the visit may be conducted, and a 
nasal swab collected, even if beyond the ideal 3-day window as long as symptoms are 
ongoing. 
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Nasal Swab (Section 8.6.7.3) 
A nasal swab will be collected using sponsor-provided supplies and sent to the sponsor 
(or sponsor-designated) laboratory for detection of RSV-A/B using quantitative RT-
qPCR.  
If more than one assessment visit is conducted to evaluate a potential LRTI episode, 
additional nasal swabs may be collected (using sponsor-provided supplies and sent to 
the sponsor laboratory) at the discretion of the Investigator. 
Note: Only the results generated by the sponsor (or sponsor-designated) laboratory 
(analyzing nasal swabs collected using sponsor-provided supplies) will be used when 
applying the case definitions for data analysis in Table 3.  If other nasal swabs are 
collected and tested locally as per routine standard of care, results will be required to be 
entered into the eCRF. However, only the sponsor laboratory results however this will be 
used when applying thenot form part of the sponsor’s application of case definitions for 
data analysis in Table 3...  
Therefore where mandated by the protocol every effort should please be made to obtain 
samples for analysis by the sponsor (or sponsor-designated) laboratory.  
Missed assessment visit (Section 8.6.7.4) 
Note that If the criteria for an assessment visit may be conducted, and a nasal swab 
collected, as long ashave been met, but the visit cannot take place while symptoms are 
ongoing, it is a missed assessment visit. 
If it is truly not possible to perform an assessment visit (for example, if the child develops 
a potential LRTI while the family is travelling, and all symptoms have resolved by the 
time the family returns), then the LRTI assessment visit page of the eCRF should be 
filled in as completely as possible using available medical history and medical records.   
Follow-up after an assessment visit to evaluate a potential LRTI (Section 8.6.8) 
Additional After an RTI episode that resulted in one or more assessment visits has 
ended (Section 8.6.5.1), site staff will ensure that the diary card for that episode is 
returned to the site via site visit, home visit, or postal mail (depending on the most 
effective  local best practice for prompt retrieval of the completed infant diary card 
following the end of an RTI episode).  
Important details can be found are provided in the SPM.   
Biological sample handling and analysis (Section 8.10) 
• 
….. to allow GSK or a contracted partner use of the samples for future research ….. 
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Table 7 Biological Samples 
Sample Type† 
Quantity 
Unit 
Timepoint 
Group 
Samples preferentially collected by local health care provider per local practice1 
Maternal Blood for hematology/ 
biochemistry 1 
Up to 
105.5 
ml 
Visit 1 (Day 1) 
All Pregnant women 
(mothers)  
Maternal Blood for hemoglobin  
Up to 10 2  
ml 
Visit 3 (Day 56)2 
2 Hemoglobin only 
Table 8 Humoral immunity (Antibody determination 
System 
Component 
Method**** 
Kit / 
Manufacturer 
Unit 
Cut-off 
Laboratory*** 
SERUM 
Respiratory 
Syncytial 
Virus A Ab 
NEUTRALISATION 
In house 
ED60 
To be 
defined 
GSK Biologicals***** 
or GSK designated 
lab******* 
Ab = antibody; ED60 = serum dilution inducing 60% inhibition in plaque forming units. 
* Assay cut-off and unit might be subject to change during the course of the study (e.g. in case of requalification, 
revalidation or standardization). In this case, this will be documented in the study report. 
*** Refer to APPENDIX B for the laboratory addresses. 
***** GSK Biologicals laboratory refers to the Clinical Laboratory Sciences (CLS) in Rixensart, Belgium; Wavre, 
Belgium. 
******* Testing may possibly be outsourced to a laboratory designated by GSK. In this case, the method and unit may 
be different than the one indicated in this table. 
Table 9 Molecular Biology 
For Multiplex real time PCR of nasal swabs, AllplexTM Respiratory Panel (Seegene) or 
equivalent** * has been added as the kit manufacturer 
Haematology, biochemistry and urinalysis (Section 8.10.3.3) 
The investigators will perform a urine dipstick tests to detect for  the presence of proteins, 
glucose, RBCs and/or WBCs. These tests do not replace those performed by local 
healthcare practitioners, per local practice, for clinical management of study subjects.  
Table 10 Hematology, biochemistry, urine tests: neutrophils, lymphocytes, 
monocytes, basophils, and eosinophils have been added as components. 
Additional tests (Section 8.10.3.4) 
Additional exploratory testing on the disease under study and/or other respiratory tract 
infections or infections of relevance to pregnant women and their newborns may be 
…... 
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Table 11 Immunological read-outs 
Blood sampling 
timepoint 
Group 
No. subjects 
Component 
Component 
priority 
rank 
Type of contact 
and time point 
Maternal Blood 
Visit 5 (Delivery) 
All pregnant women 
(mothers) 
400 maximum 
by country 
Respiratory Syncytial Virus A Ab 
(RSV-A neutralising antibody) 
1 
Cord Blood 
Visit 5 (Delivery) 
All pregnant women 
(mothers) (provides 
infant antibody levels) 
400 maximum 
by country 
Respiratory Syncytial Virus A Ab 
(RSV-A neutralising antibody) 
1 
RSV-A/B = Respiratory syncytial virus subtype A/B. 
Table 13 Hematology/blood chemistry 
Blood sampling timepoint 
Group 
No. subjects 
Component 
Type of contact (timepoint) 
Visit 1 (Day 1) 
All pregnant 
women (mothers) 
400 maximum by 
country* 
Hematology (Leukocytes, Hemoglobin, 
Platelets) 
Biochemistry (ALT, AST, Creatinine, 
blood urea nitrogen) 
Visit 3 (Day 56) 
All pregnant 
women (mothers) 
400 maximum by 
country* 
Hematology (Hemoglobin) 
Subject Cards (Section 9.3) 
Study subjects/parents/LARs must be provided with the address and telephone number 
of the main contact for information about the clinical study. The investigator (or 
designate) must therefore provide subjects/parents/LARs with a “subject card.”   
For this study, a subject card will be provided to each pregnant woman who enrolls.  A 
second subject card will be provided for each infant who is enrolled.  
In an emergency situation these cards serve to inform the responsible attending 
physician(s) that the subject is in a clinical study and that relevant information may be 
obtained by contacting the investigator.  
In a non-emergency situation, if subjects visit a local healthcare provider not affiliated 
with the study, these cards serve to inform the responsible local healthcare provider 
that the subject is in a clinical study and that relevant information may be obtained by 
contacting the investigator. Further, subject will have information on the card to 
contact the study site at any time.  
Subjects/parents/LARs must be instructed to keep the subject cards in their possession 
at all times during the study.  
GSK Contact information, GSK Reporting Timeframes, and Regulatory reporting 
requirements (Section 9.4) 
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GSK Biologicals has a legal responsibility to promptly notify, as appropriate, both the 
local regulatory authority and other regulatory agencies (as applicable, per country) 
about the event.  
Primary endpoints (Section 11.1.1), Primary Objectives Analysis (Section 11.6) and 
Synopsis 
• 
Pregnancy Occurrence of pregnancy related events of interest from Visit 1 through 
Visit 6.  (Although pregnancy  related events of interest occur within the first 42 
days after delivery they may only be detected later, and are to be reported 
throughout the study.) TheyThese 
• 
Neonatal Occurrence of neonatal events of interest from birth through 28 days of 
age.. Neonatal AEs of interest occur within the first 28 days after birth, but may 
only be detected later and are to be reported throughout the study.  They. These 
include… 
Secondary endpoints (Section 11.1.2), Secondary Objectives Analysis (Section 11.7) 
and Synopsis 
• 
PregnancyOccurrence of pregnancy related events of interest from Visit 1 through 
Visit 6 (as defined in primary endpoints) for each GAIA level of diagnostic certainty 
(where applicable and feasible) 
• 
NeonatalOccurrence of neonatal events of interest from birth through 28 days of age 
(as defined in primary endpoints) for each GAIA level of diagnostic certainty (where 
applicable and feasible) 
• 
Maternal RSV-A neutralizing antibody titertiters in maternal blood at delivery  
• 
Titers of RSV-A neutralizing antibodiesantibody titers in cord blood at delivery. 
• 
Episode(s)Occurrence of RSV-LRTI from birth up to 1 year of age.  
• 
Episode(s) ofOccurrence RSV hospitalization from birth up to 1 year of age.  
Tertiary endpoints (Section 11.1.3), Tertiary Objectives Analysis (Section 11.8) and 
Synopsis 
• 
Co-infectionsOccurrence of RSV-LRTI associated with other respiratory viruses in 
infants, confirmed by PCR of nasal swabs in infants from birth up to 1 year of age: 
• 
PotentialOccurrence of potential risk factors for maternal, fetal pregnancy related 
and neonatal events of interest.  
• 
Any further exploratory immunology to detect disease-related characterization of 
immune responses, such as but not limited to RSV B neutralizing antibody 
titers.and/or other respiratory tract infections or infections of relevance to 
pregnant women and their newborns (based on maternal serum and cord blood).  
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Derived and transformed data (Section 11.4) 
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 / 
subject’s parent[s]/LAR[s]). 
Analysis of primary objectives (Section 11.6) 
• 
To detect and describe determine the frequencies of pregnancy outcomes.  
The number and percentage (with exact 95% CI) of women presenting the following 
events of interest outcomes: live birth, fetal death/still birth, and elective/therapeutic 
termination will be reported for each event by presence or absence of congenital 
anomalies.  
• 
To detect and describe determine the frequencies of pregnancy related events of 
interest. 
• 
To detect and describe determine the frequencies of neonatal related events of 
interest.  
Analysis of secondary objectives (Section 11.7) 
• 
To detect and describe determine frequencies of pregnancy related events of interest 
according (where these are specified) to GAIA levels of diagnostic certainty (where 
these are specified) (APPENDIX D) 
• 
To describe the distribution of RSV-A antibody titers in maternal blood collected at 
delivery.  
• 
To detect and describe determine frequencies of neonatal events of interest 
according (where these are specified) to GAIA levels of diagnostic certainty 
(where these are specified). (APPENDIX D) 
• 
To describe the distribution of RSV-A antibody titers in cord blood at delivery.  
• 
To describe occurrences of determine the incidence of all, of severe, and of very 
severe RSV-lower respiratory tract infections (LRTIs).  
− 
….. from visit 1-NB to visit 3 4-NB…….. 
− 
Incidence rates of LRTI infections will be calculated, with exact 95% CI, taking 
into account all LRTI events reported in the study during the first year of life. 
The period at risk would be the whole follow-up time of the subjects during the 
study. 
• 
To describe occurrences determine the incidence of RSV hospitalization.  
− 
… from visit 1-NB to visit 3 4-NB… 
− 
Incidence rates of RSV hospitalizations will be calculated, with exact 95% CI, 
taking into account all RSV hospitalisations reported in the study during the first 
year of life. The period at risk would be the whole follow-up time of the subjects 
during the study. 
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Analysis of tertiary objectives (Section 11.8) 
• 
To explore the association of describe co-infections of RSV-LRTI with other 
respiratory viruses with the occurrence of RSV-LRTI in infants.  
− 
… from visit 1-NB to visit 34-NB………. 
• 
To evaluate estimate the association between of RSV-LRTI in neonates/infants and 
the level of RSV neutralizing antibodies in cord blood.  
• 
To describe determine risk factors for maternal, fetal and neonatal pregnancy-related 
and neonatal events of interest.  
− 
… (such as multiple logistic regression for binary outcomes and multiple 
Poisson/negative binomial and/or other appropriate models for count 
outcomes) …. 
• 
If deemed necessary, to further characterize the immune responses to the disease 
under study in mothers/infants, or to explore RSV and other parameters infections in 
pregnant women/mothers or their and infants (based on maternal serum and cord 
blood).  
Statistical considerations for interim analyses (Section 11.11.1) 
All analyses are descriptive. Therefore, the conduct of interim analyses has no impact on 
interpretation of study results. 
Interim analysis for RSV LRTIs 
An interim analysis will be performed on RSV surveillance data as part of the 
secondary objective of determining incidence of RSV LRTI. This interim analysis will 
be performed to obtain preliminary information on the performance of the case 
definitions used for RSV LRTI, severe LRTI, and very severe LRTI (Table 3). The 
interim analysis will occur after the database freeze at the time point when at least 50% 
of infants will have completed 6 months of follow up during the surveillance period 
following birth. Data cleaning plans will be scheduled as needed to supply data for 
interim analyses in a timely manner. This interim analysis will be performed on data 
that is as clean as possible. Preliminary results will be made available in a timely 
manner for use in the potential adjustment of the RSV LRTI case definitions to be used 
in pivotal clinical trials scheduled to begin shortly thereafter. The results pertaining to 
this analysis will be purely descriptive, with no adjustment of type I error, and will be 
reported in an interim statistical report. 
References (Section 14) 
Centers for Disease Control and Prevention (CDC). Updated recommendations for use 
of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine (Tdap) in 
pregnant women. Advisory Committee on Immunization Practices (ACIP) - 2012.  
MMWR. 2013a ; 62 (7) :131 -135. 
Centers for Disease Control and Prevention (CDC). Influenza Vaccination Coerage 
Among Pregnant Women — United States, 2012–13 Influenza Season. MMWR.  
2013b; 62 (38): 787–792. 
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Appendix A Laboratory Assays 
Neutralization assay 
First, virus Virus neutralization is performed by incubating a fixed amount of RSV-A 
long strain (Long, ATCC No. VR-26) or RSV-B strain (18537, ATCC No. VR-1580) 
with serial dilutions of the test serum. Then, the The serum-virus mixture is then 
transferred onto a monolayer of Vero cells (African Green Monkey, kidney, Cercopitheus 
aethiops, ATCC CCL-81) and incubated for three days to allow infection of the Vero 
cells by non-neutralized viruses virus and the formation of plaques in the cell monolayer. 
Following the a fixation period step, RSV-infected cells are detected using a primary 
antibody directed against RSV (anti-RSV IgG) and a secondary antibody conjugated with 
fluorescein isothiocyanateto horse-radish peroxidase (HRP), allowing the visualization 
of plaques by immunofluorescence after coloration with TrueBlueTM peroxidase 
substrate.  
• 
Quantitative RT-PCR able to discriminate RSV-A and RSV-B subtypes: 
• 
Qualitative multiplex RT-PCR for detection of a panel of viruses. 
A qualitative RT-PCR multiplex assay is used …: 
Table 18 
Outsourced laboratories 
Laboratory 
Address 
DDL Diagnostic Laboratory 
B.V. 
Fonteijnenburghlaan 7 
Voorburg 
Netherland 
Headquarters 
Visseringlaan, 25 
2288 ER Rijswijk - NL 
 
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GlaxoSmithKline Biologicals 
Vaccines R & D 
Protocol Amendment 3  
eTrack study number and Abbreviated Title 
207636 (EPI-RSV-008 BOD) 
Amendment number: 
Amendment 3 
Amendment date: 
18-FEB-2019 
Co-ordinating author: 
, Lead Science Writer 
The protocol has been amended to reflect the following changes and provide the 
following clarifications / corrections. 
• 
The overall sample size has been reduced from 4,000 to 2,300, as the original 
number of subjects will no longer be required to move the RSV Maternal 
immunization program to the next stage of development.  
• 
The terms respiratory tract infection and lower respiratory tract infection have been 
replaced with the terms respiratory tract illness and lower respiratory tract illness to 
improve consistency with World Health Organization terminology.   
• 
The phrase “pregnant women (mothers)” has been replaced with the term “maternal 
subjects.” 
• 
The List of Abbreviations and Glossary of terms have been updated. 
• 
Language describing mitigation of the risks associated with venipuncture has been 
clarified. 
• 
The reference to nasal obstruction in Footnote 1 of Table 3 has been removed.  
• 
Eligible maternal subjects may now be up to 45 years of age and must now have a 
pre-pregnancy body mass index within the range specified in the inclusion criteria.   
• 
 “Geographic ancestry (race)” replaces the word “race.” 
• 
A footnote has been added to Table 4 to indicate that if results of an oral glucose 
challenge / tolerance test are not available, then fasting blood glucose or 
haemoglobin A1C test results may be used as described in Table 26. 
• 
Language has been added to clarify that “parental concern” as described in Sections 
8.6.4 through 8.6.8 occurs in the context of a respiratory tract illness. 
• 
Instructions for infant diary completion and for collection of RTI/LRTI symptom 
start and stop dates have been re-written in an effort to improve clarity. 
• 
A definition for respiratory tract illness/lower respiratory tract illness symptom 
“worsening” has been added. 
• 
Objectives, endpoints and the text of Appendix D have been adjusted to improve 
consistency with GAIA criteria. 
• 
References to country and/or region-specific analyses have been removed from 
Section 11.10. 
• 
Assessment of blood oxygen saturation (by pulse oximetry) in maternal subjects has 
been added. 
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• 
Text has been added to clarify that levels of RSV-A neutralising antibody in 
maternal and cord blood at delivery will be assessed during the interim analysis. 
• 
Text that addresses study / site closure has been added. 
• 
Laboratory addresses in Appendix B have been updated. 
Additional editorial changes have been made to ensure consistency with the 
modifications noted above, and typographical errors have been corrected 
Text that has been moved or added is presented in bold italics and deleted text in 
strikethrough in the following sections. 
Global changes: 
• 
“Pregnant women (mothers)” has been replaced with maternal subjects 
• 
Age 18 – 40 has been replaced with 18-45 
• 
<280/7 has been replaced with ≤276/7 weeks gestational age (GA) 
• 
Number of subjects enrolled has changed from 4000 to 2300 (“up to 400” to “200-
300” per country) 
• 
“Respiratory tract infections” has been replaced with respiratory tract illnesses 
• 
“Race” has been replaced with “geographic ancestry (race)”  
List of contributing authors: 
• 
, Lead 
 Epidemiologist 
• 
, Clinical Research and Development Lead 
• 
, Expert Epidemiology Biostatistician, 
, Lead Epi 
Statistician  
• 
, 
, Study Delivery 
Leads 
• 
, Clinical Trial Supply manager 
• 
, Clinical Read-Out Team Leader  
• 
, Safety Physician 
• 
, Oversight Data Manager 
• 
 Study Data Manager (Tata Consultancy Services for GSK Biologicals) 
• 
, Regulatory Affairs Representative 
Authors who contributed to previous versions of the protocol 
• 
, Study Delivery Leads 
• 
, Safety Physician 
Synopsis and Secondary Objectives 
Neonatal events AEs of interest occur within the first 28 days after birth, but may only be 
detected later and are to be reported throughout the study 
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Synopsis and Introduction 
4th pargraph: Secondarily, the study will establish surveillance mechanisms for RSV 
associated illnesses infections 
7th paragraph: Pregnant women 240/7 up to and but not including 276280/7 weeks of 
gestation 
Section 1.5, Introduction: 
RSV infects 50-70% of infants in their first year of life, and practically all children have 
experienced RSV infection and / or illness 
Synopsis Table 2 and Table 2 
Study groups and epochs foreseen in the study  
Study Groups 
Number of 
subjects enrolled 
Age (Min/Max) 
Epochs 
Epoch 001  
Epoch 002  
Epoch 003  
Maternal subjects 
Pregnant women 
(mothers) 
Up to  2300 400 
(per country) 
18 years – 45 40 
years  
x  
x  
 
Infants 
Up to  2300 400 
per country) 
NA  
 
x  
x  
Approximately 200 to 300 subjects per country. To achieve the enrollment targets noted above, the number of 
pregnant women SCREENED in each country may exceed the country-specific enrolment target. 400 
Synopsis and Section 11.1, Primary Endpoints 
• 
Pregnancy outcomes.  Of note, fetal death/stillbirth has multiple subcategories. For 
example, fetal death/stillbirth with no congenital anomalies is an outcome with two 
subcategories that include: 1) antepartum stillbirth; 2) intrapartum stillbirth. For 
each outcome, the investigator should select the applicable sub-category. 
− 
Fetal death/stillbirth (loss at or after 22 weeks of gestation) with no congenital 
anomalies: 
o 
Antepartum stillbirth  
o 
Intrapartum stillbirth  
− 
Fetal death/stillbirth (loss at or after 22 weeks of gestation) with congenital 
anomalies: 
o 
Antepartum stillbirth 
o 
Intrapartum stillbirth  
− 
Pregnancy related events of interest from Visit 1 through Visit 6…… They are 
listed below. Of note, some events of interest fall under a single category but 
have multiple subcategories. For example, hypertensive disorders of 
pregnancy is an event with three subcategories that include: 1) gestational 
hypertension; 2) pre-eclampsia; and 3) pre-eclampsia with severe features 
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(including eclampsia). For each event, the investigator should identify the 
event and select the applicable sub-category. 
− 
Antenatal bleeding:  
o 
Morbidly adherent placenta 
o 
Placental abruption 
o 
Cesarean Scar Pregnancy 
o 
Uterine rupture 
− 
Dysfunctional labor  
o 
first stage of labor 
o 
second stage of labor 
− 
Gestational Liver Disease: 
o 
Intrahepatic Cholestasis of Pregnancy (ICP)   
o 
Acute Fatty Liver of Pregnancy 
− 
Maternal Sepsis 
Neonatal events of interest from birth through 28 days of age. Neonatal events AEs of 
interest……… 
− 
Congenital microcephaly,  
o 
Postnatally diagnosed 
o 
Prenatally diagnosed 
− 
Congenital anomalies 
o 
Major external structural defects 
o 
Internal structural defects 
o 
Functional defects 
− 
Neonatal death, 
o 
Neonatal death in a preterm live birth (gestational age>=28 to < 37 weeks) 
o 
Neonatal death in a term live birth 
− 
Neonatal infections, 
o 
Blood stream infections 
o 
Meningitis 
o 
Respiratory infection 
− 
Failure to thrive, 
Any other neonatal event considered by the investigator to be of concern (specify, e.g. 
neurodevelopment delay). 
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Section 11.1.1 (Primary Endpoints – pregnancy outcomes and pregnancy related 
events of interest; text does not appear in Synopsis): 
Section 11.1.1.2: For events of interest that include subcategories, the frequency of the 
main event of interest and of each event subcategory will be included in the analysis. 
The overall frequency will include mothers who present at least one of the subcategory 
events.  
Section 11.1.1.3: For events of interest that include subcategories, the frequency of the 
main event of interest and of each event subcategory will be included in the analysis. 
The overall frequency will include infants who present at least one of the subcategory 
events.  
Synopsis and Secondary Endpoints 
Of note, some events of interest fall under a single category but have multiple 
subcategories. For each event, the investigator should identify the event and select the 
applicable sub-category and the GAIA level of diagnostic certainty. 
List of Abbreviations 
BMI 
Body mass index 
LRTI 
Lower Respiratory Tract Illness Infection 
RTI 
Respiratory Tract Illness Infection 
Glossary of Terms 
Body Mass Index 
A key index for relating weight to height. Calculated as 
follows: Weight (kg) / (Height (m))2 
Parental concern 
The parent(s) / Legally Acceptable Representative(s) or 
their designates are concerned about the infant’s 
respiratory tract illness, or general health in the context 
of the respiratory tract illness, and intend to seek medical 
care 
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Section 2.1, Risk Assessment 
Important Potential/Identified Risk 
Data/Rationale for Risk 
Mitigation Strategy 
Study Procedures 
Blood sample collection- While giving 
blood the subject may feel faint, or 
locally experience mild pain, bruising, 
irritation or redness. 
Spontaneous data 
Sample collection will only be performed by 
appropriately trained study personnel. 
All Subjects will remain under observation, 
post venipuncture, through completion of 
the applicable study visit be observed for 
at least 30 minutes after blood sample 
collection. 
Subjects will be notified of this risk in the 
informed consent form. 
 
Section 4, Study Design Overview 
Figure 1 has been replaced. The current Figure, followed by the Figure as presented in 
Amendment 2, follow. 
 
V2 (D28)1
GA: 28 0/7
- 31 6/7w
Screening
GA: 24 0/7
- 27 6/7w
V5 
Delivery
V6
Day 42
BS:
• H/B
US :
• Glucose
• Proteins
• RBC
• WBC
Up to (approximately) 2,300 maternal subjects (≥ Week 24 of gestation) 
Maternal subjects
BS:
• H 3
US:
• Glucose
• Proteins
• RBC
• WBC
V3 (D56) 1
GA: 32 0/7 -
35 6/7w
BS 4
• Imm 2
Cord blood 5
• Imm
Epoch 002
Mother: V1 through V6
Child: V1-NB through V2-NB
V4 (D84) 1
GA: 36 0/7 -
39 6/7w
Analysis 1
Neonates/Infants
V1-NB
Birth
V2-NB
Day 42
V4-NB
Year 1
Final Analysis 
Epoch 003
Child: V3-NB
Neonatal events of interest 6
LRTI Surveillance in Neonates / Infants
Pregnancy outcomes and maternal/fetal events of interest 
Study Procedure Related Serious Adverse Event Follow-up
US:
• Glucose
• Proteins
• RBC
• WBC
US :
• Glucose
• Proteins
• RBC
• WBC
V1 (D1)
GA: 24 0/7 -
27 6/7w
Epoch 001
Screening
Mother only
Informed 
consent
Inclusion, 
Exclusion 
Criteria
V3-NB
Month 6
Interim 
Analysis
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• 
Primary Completion Date (PCD): 42 days post-delivery/birth (i.e. Visit 6 for 
maternal subjects the mothers and Visit 2-NB for infant subjects the infants) or last 
visit of Epoch 002. 
• 
Duration of the study: Approximately 4.5 to 6 months for maternal subjects 
participating pregnant women; approximately 1 year for infant subjects participating 
infants. 
• 
Epoch 002: Primary starting at Visit 1 and ending 42 days post-delivery/birth (Visit 6 
for maternal subjects and Visit 2-NB for infant subjects ).* 
Section 5.4, Case Definitions, Table 3: 
Footnote 1: Based on history reported by parents/LARs and includes difficulty in 
breathing (e.g. showing signs of wheezing or stridor, tachypnoea, flaring [of nostrils], 
chest in-drawing, apnoea) associated with nasal obstruction. 
Footnote 5: RSV sampling and testing is described in Sections 8.6.7, 8.6.8 and 8.6.9. 
based on judgment of medical practitioner or driven by algorithm.  
Section 6.2.1, Inclusion criteria for maternal subjects 
* The level of diagnostic certainty of the gestational age should be established by using 
the GAIA gestational age assessment form tool (provided in APPENDIX C). 
• 
Women with pre-pregnancy body mass index (BMI) ≥18.5 and ≤ 39.9 kg/m2. 
V2 (D28)1
GA: 28 0/7
- 31 6/7w
Screening
GA: 24 0/7
- 27 6/7w
V5 
Delivery
V6
Day 42
BS:
• H/B
US :
• Glucose
• Proteins
• RBC
• WBC
Up to (approximately) 400 pregnant women (≥ Week 24 of gestation) per country
Up to (approximately) 4,000 pregnant women in total   
Pregnant women (mothers)
BS:
• H 3
US :
• Glucose
• Proteins
• RBC
• WBC
V3 (D56) 1
GA: 32 0/7 -
35 6/7w
BS 4
• Imm 2
Cord blood 5
• Imm
Epoch 002
Mother: V1 through V6
Child: V1-NB through V2-NB
V4 (D84) 1
GA: 36 0/7 -
39 6/7w
Analysis 1
Neonates/Infants
V1-NB
Birth
V2-NB
Day 42
V4-NB
Year 1
Final Analysis 
Epoch 003
Child: V3-NB
Neonatal events of interest 6
LRTI Surveillance in Neonates / Infants
Pregnancy outcomes and maternal/fetal events of interest 
Study Procedure Related Serious Adverse Event Follow-up
US :
• Glucose
• Proteins
• RBC
• WBC
US :
• Glucose
• Proteins
• RBC
• WBC
V1 (D1)
GA: 24 0/7 -
27 6/7w
Epoch 001
Screening
Mother only
Informed 
consent
Inclusion, 
Exclusion 
Criteria
V3-NB
Month 6
Interim 
Analysis
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6.3, Exclusion criteria for enrollment in maternal subjects: 
The following criteria should be checked at the screening visit and at Visit 1.time of 
study entry. 
• 
primary genital herpes simplex infection 
Section 8, Detailed Study Procedures 
Table 4 
Review and collect obstetric history 
from current pregnancy, including: 
gestational age, expected date of 
delivery and method of EDD 
estimation including pre-pregnancy 
weight 
O  
● 
 
 
 
 
 
 
Travel history to, or living in, 
countries/regions with Zika virus 
transmission (during the current 
pregnancy) 
O  
● 
O 
O 
O 
O 
 
● 
Footnote 7: If results of an oral glucose challenge / tolerance test are not available to confirm that the subject does not 
have Gestational Diabetes at screening, then fasting blood glucose or hemoglobin A1C test results (if performed 
by local healthcare provider and available) may be used as described in Table 27. 
Footnote 10:  In the Philippines, where If HIV test results are testing is not available at time part of the standard of 
care for pregnant women, the screening the HIV test can be performed locally as a study procedure under 
certain conditions. Refer to SPM for further details. If results are positive, subject will be referred per local 
standard of care. 
Footnote 11:  Height, weight during the month before the subject became pregnant, and pre-pregnancy BMI at 
screening. Weight, temperature, systolic/diastolic blood pressure, heart rate and respiratory rate after at 
least 10 minutes of rest, blood oxygen saturation by pulse oximetry vital signs, fetal heart tones, fetal 
movement, and fundal height at Screening and Visits 1 – 4.  Temperature, systolic/diastolic blood pressure, 
heart rate and respiratory rate after at least 10 minutes of rest, and blood oxygen saturation by pulse 
oximetry Vital signs at Visit 6.   
Table 5 footnotes 
a  If local regulations require that written consent / confirmation of consent for the infant’s participation be obtained at 
birth. 
c  If more than one assessment visit is conducted to evaluate a potential LRTIepisode, additional nasal swabs may be 
collected at the discretion of the Investigator. 
e Collect diary cards that are fully filled out and / or document (L)RTI episodes symptoms that have ended (as defined 
in Section 8.6.5.1).  Provide new diary cards as needed.  
f Collect all diary cards for potential RTIs that are considered resolved. Collect the diary card for the current potential 
LRTI once the episode LRTI symptoms have has ended (as defined in Section 8.6.5.1). 
g When approximately 50% of infants have completed up to Visit 3-NB, an interim analysis will be conducted to 
assess the accumulated RSV LRTI cases and the distribution of maternal and cord blood serum RSV A 
Ab. 
Section 8.5.2, History for Maternal subjects and Examinations for pregnant 
women/mothers 
Record demographic data, which may include (but are is not limited to) information such 
as geographic ancestry (race), month and year of birth, and ethnicity. 
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Record information about whether (during the current pregnancy) the subject has 
travelled to / is living in countries / regions with Zika virus 
Record the subject’s pre-pregnancy weight (i.e., weight during the months before the 
subject became pregnant) at screening.  This information can be obtained either via 
medical record review or subject interview and should be recorded in the subject’s 
eCRF. 
Confirm that the subject’s pre-pregnancy BMI is within the range specified in Section 
6.2.1.  This information can be obtained from the medical record, or, if unavailable, 
may be calculated based on the subject’s height and reported pre-pregnancy weight. 
Obtain the subject’s medical and obstetric history by interview and/or …… 
• 
Obtain the subject’s obstetric history by interview and/or review of her medical 
records.  
Section 8.5.3: Examinations of maternal subjects 
Record height at screening and weight at screening and Visits 1-4. 
• 
Screening and Visits 1 - 4 should include assessment of weight, fetal heart tones, 
fetal movement, and fundal height; 
• 
 Screening, Visits 1 to 4, and Visit 6 should include assessment of temperature, vital 
signs systolic/diastolic blood pressure, heart rate and respiratory rate after at least 10 
minutes of rest) and blood oxygen saturation by pulse oximetry. 
Section 8.5.8, Outcomes and Events of Interest 
− 
Record delivery and pregnancy outcomes. Of note, fetal death/stillbirth has 
multiple subcategories. For example, fetal death/stillbirth with no Record 
Delivery and Pregnancy Outcomes congenital anomalies is an outcome with 
two subcategories that include: 1) antepartum stillbirth; 2) intrapartum 
stillbirth. For each outcome, the investigator should select the applicable sub-
category. 
− 
Maternal events of interest (including, but not limited to, those described in 
Section 11.1.1) occurring up to Visit 6 (Post-delivery Day 42) should be 
recorded in the eCRF along with additional details pertinent to the diagnosis, 
GAIA assessment and level of diagnostic certainty (APPENDIX D), when 
applicable. Of note, some events of interest fall under a single category but 
have multiple subcategories. For example, hypertensive disorders of 
pregnancy is an event with three subcategories that include: 1) gestational 
hypertension; 2) pre-eclampsia; and 3) pre-eclampsia with severe features 
(including eclampsia). For each event, the investigator should identify the 
event and select the applicable sub-category. 
− 
Information about maternal hospitalizations, hospitalization and clinically 
significant events, and diagnoses that could impact the pregnancy will be 
recorded. 
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Section 8.6, Description of Study Procedures for Neonates/Infants 
Note that the investigator or study staff will perform (if not performed by local 
healthcare provider) a minimum of 2 clinical examinations: one at birth (or up to 10 
days after birth), and another at approximately 42 days of age.   
Section 8.6.2, History and Examinations for Neonates/Infants 
• 
Record demographic data including month and year of birth, gender, geographic 
ancestry (race) and ethnicity.  
Section 8.6.3, Infant Diary Cards 
8.6.3.1 Documentation of RTI episodes: 
One diary card should be completed for each RTI episode whether or not an Assessment 
Visit (Section 8.6.6) takes place. An RTI episode has “ended” if it satisfies the criteria in 
Section 8.6.5.1.   
At each study visit (including any assessment visits), RTI symptoms episode(s) may have 
ended or may be ongoing.  
If blocked nose, cough and symptoms of difficulty in breathing (including wheezing) 
For any RTI episode(s) that has/have ended by the time of a study visit: 
− 
Study staff should collect the Diary card(s), and replenish the 
parent(s)/LAR(s)/designate(s) supply of blank cards as needed.  
For any RTI episode that is If blocked nose, cough or symptoms of difficulty in 
breathing (including wheezing) are ongoing at the time of a study visit (including any 
assessment visit): 
− 
Study staff should review the diary card, make a photocopy of it, and return it to 
the parent(s)/LAR(s)/designate(s) so information can continue to be collected 
until the episode has the symptoms have ended.  
− 
As soon as possible after Once the episode these symptoms havehas ended, 
study staff must collect the completed diary card by a site visit, home visit, or 
postal mail, whichever is most effective based on local practice.  The site should 
make every effort to collect completed diary cards as soon after the end of an 
episode symptoms have ended as possible. If diary card collection occurs during 
a visit to the study site or to the subject’s home, a brief clinical evaluation may 
be performed to confirm that the episode symptoms have has ended.  
8.6.4, Surveillance for episodes of potential Lower Respiratory Tract Illness Infection 
(LRTI) 
• 
A An episode of potential lower respiratory tract illness infection (LRTI) is one in 
which the infant has one or more of the RTI symptoms listed above AND at least one 
of the following: 
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− 
Wheezing (a whistling sound when the infant breathes out) (another sign of 
difficulty in breathing); 
− 
Parental concern (the parent(s)/LAR(s) or their designate(s) are concerned about 
the infant’s respiratory tract illness, or general health in the context of the 
respiratory tract illness, and intend to seek medical care). 
Worsening means any clinically observed/diagnosed symptoms and signs that are 
reported during the same respiratory tract illness and reflect a deterioration in the 
child’s respiratory tract functions. 
• 
An RTI episode starts on the day when (per parental report, as written in the Diary 
Card and stop dates will be collected inor provided verbally during an assessment 
visit) the diary card for first RTI symptom started 
• 
An RTI episode ends on the day when (per parental report, as written in the Diary 
Card and/or provided verbally during an assessment visit) either cough, runny nose, 
blocked nose, wheezing and difficulty in breathing has resolved, whichever resolves 
later. 
• 
Start and stop dates will be collected in the diary card for cough, runny nose, 
blocked nose, wheezing and difficulty in breathing. 
• 
Start dates for all symptoms will also be recorded in the eCRF. 
• 
Only stop dates for cough and difficulty in breathing will be recorded in the eCRF 
so that GSK may later define the end of each LRTI episode (Section 5.4) 
• 
There must be at least 7 symptom-free days between 2 consecutive RTI episodes; the 
only exception is runny nose, which is a symptom that can persist during that 
minimum 7-day period that would distinguish one episode 
Figure 5 footnote 
Worsening is defined in Section 8.6.5.1  
8.6.5.3 Active Surveillance 
• 
there is parental concern as defined in Section 8.6.5.1 
8.6.5.4 Passive Surveillance 
• 
the infant’s symptoms worsen as defined in Section 8.6.5.1 
8.6.6 Decision to conduct a Visit to assess…… 
If there is NO suspicion of difficulty in breathing, nor wheezing, nor parental concern in 
the context of the RTI: 
If there IS difficulty in breathing, or wheezing (both based on parental assessment), or 
there is parental concern in the context of the RTI:  
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8.6.7.3 Nasal swabs 
…..If more than one assessment visit is conducted to evaluate a potential LRTIepisode 
8.6.8 Follow up after an assessment…… 
After an assessment visit (Section 8.6.7) the child will be followed with at least weekly 
active surveillance contacts, until the RTI/LRTI episode has resolved. During these active 
contacts, worsening of symptoms (clinically observed/diagnosed symptoms and signs 
that are reported during the same respiratory tract illness and reflect a deterioration in 
the child’s respiratory tract functions; for example, onset of additional symptoms or an 
increase in the intensity of a previously reported symptom) will be assessed. Parent(s) / 
LAR(s) / designate(s) will be reminded to call/contact/visit the site if symptoms worsen.  
After  symptoms an RTI episode that resulted in one or more assessment visits have has 
ended (Section 8.6.5.1), site staff will ensure that the diary card for those symptoms that 
episode is returned to the site via site visit, home visit, or postal mail (depending on the 
most effective local best practice for prompt retrieval of the completed infant diary card 
following the end of the symptoms an RTI episode).  
Table 7, Biological samples  
Sample Type† 
Quantity 
Unit 
Timepoint 
Group 
Samples preferentially collected by local health care provider per local practice1 
Maternal Blood for Hematocrit 
Hemoglobin  
Up to 2  
ml  
Visit 3 (Day 56) 
 
Table 8, Humoral Immunity, footnote 
** GSK Biologicals laboratory refers to the Clinical Laboratory Sciences (CLS) in Rixensart, Belgium; Wavre, Belgium. 
Marburg, Germany 
Table 9, Molecular Biology, footnote 
** GSK Biologicals laboratory refers to the Clinical Laboratory Sciences (CLS) in Rixensart, Belgium; Wavre, Belgium. 
Marburg, Germany 
Section 11.2 Determination of Sample size 
Assuming a drop-out rate of about 10% during the course of follow-up, there will be up 
to approximately 180 to 270 360 evaluable subjects by country. 
Considering a sample size of up to approximately 180 to 270 360 evaluable subjects by 
country, Table 16 illustrates the precision (exact 95% confidence interval [CI]) one can 
get on the percentage of subjects with maternal, fetal and neonatal events of interest. 
Precision (exact 95% CI) has also been computed for a sample size of 270, 180 and 100 
evaluable subjects for estimate by study site. 
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Table 16: Precision (exact 95% confidence interval) on the percentage of subjects 
with maternal, fetal and neonatal events of interest for sample size of 360 270, 180 
and 100 subjects 
 
360 subjects 
270 subjects 
180 subjects 
100 subjects 
% 
N 
Lower 
limit 
Upper 
limit 
N 
Lower 
limit 
Upper 
limit 
N 
Lower 
limit 
Upper 
limit 
N 
Lower 
limit 
Upper 
limit 
35 
126 
30.1 
40.2 
94.5 
29.3 
41.0 
63 
28.1 
42.4 
35 
25.7 
45.2 
30 
108 
25.3 
35.0 
81 
24.6 
35.8 
54 
23.4 
37.3 
30 
21.2 
40.0 
25 
90 
20.6 
29.8 
67.5 
19.9 
30.6 
45 
18.9 
32 
25 
16.9 
34.7 
20 
72 
16.0 
24.5 
54 
15.4 
25.3 
36 
14.4 
26.6 
20 
12.7 
29.2 
15 
54 
11.5 
19.1 
40.5 
11.0 
19.8 
27 
10.1 
21.1 
15 
8.6 
23.5 
10 
36 
7.1 
13.6 
27 
6.7 
14.2 
18 
6 
15.3 
10 
4.9 
17.6 
5 
18 
3.0 
7.8 
13.5 
2.7 
8.3 
9 
2.3 
9.3 
5 
1.6 
11.3 
3 
10.8 
1.5 
5.3 
8.1 
1.3 
5.8 
5.4 
1 
6.8 
3 
0.6 
8.5 
1 
3.6 
0.2 
2.7 
2.7 
0.2 
3.0 
1.8 
0.1 
3.9 
1 
0 
5.4 
0 
0 
0 
1 
0 
0 
1.4 
0 
0 
2 
0 
0 
3.6 
Section 11.6, Analysis of primary objectives 
The primary objectives analyses will be performed on the PPS cohorts overall by country, 
and possibly by region or other relevant grouping. 
The number and percentage (with exact 95% CI) of women presenting the following 
outcomes: live birth, fetal death/stillbirth (antepartum or intrapartum), and 
elective/therapeutic termination will be reported for each event by presence or absence of 
congenital anomalies.  
• 
To determine the frequencies of pregnancy related events of interest as specified in 
Section 11.1.1.2. 
The number and percentage (with exact 95% CI) of pregnant women presenting with the 
following events of interest specified in Section 11.1.1.2. The number and percentage 
(with exact 95% CI) of pregnant women presenting with the following events of interest 
specified in Section 11.1.1.2 will be tabulated for each event within appropriate time 
windows to be specified in the statistical analysis plan (SAP). 
The events are: 
− 
Hypertensive disorders of pregnancy:  
o 
gestational hypertension, and 
o 
Pre-eclampsia, and 
o 
Pre-eclampsia with severe features (including eclampsia) 
− 
Antenatal bleeding 
− 
Fetal growth restriction 
− 
Non reassuring fetal status 
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− 
Pathways to preterm birth:  
o 
premature preterm rupture of membranes,  
o 
preterm labor, and 
o 
provider-initiated preterm birth 
− 
Postpartum hemorrhage 
− 
Chorioamnionitis 
− 
Oligohydramnios 
− 
Polyhydramnios 
− 
Maternal death 
− 
To determine the frequencies of neonatal events of interest as specified in 
Section 11.1.1.3. 
The number and percentage (with exact 95% CI) of neonates presenting the following 
events of interest specified in Section 11.1.1.3………… 
− 
All of the following events of interest. 
o Small for gestational age 
o Low birth weight including very low birth weight 
o Large for gestational age 
o Macrosomia 
o Preterm birth 
o Neonatal encephalopathy 
o Respiratory distress in the neonate 
o Neonatal infections 
o Congenital microcephaly 
o Congenital anomalies 
Section 11.7 Analysis of Secondary objectives 
The secondary objectives analyses will be performed on the PPS cohorts (maternal or 
infant as applicable) overall by country and possibly by region or other relevant 
grouping. 
Section 11.8 Analysis of Tertiary objectives 
The following tertiary objectives analyses will be performed on infants within the PPS 
cohort overall and possibly by country region or other relevant grouping.  
• 
To describe co-infections of RSV-LRTI with other respiratory viruses in infants.  
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Considering all infants followed from visit 1-NB to visit 4-NB, the percentage of subjects 
with the occurrence of RSV-LRTI and having other respiratory viral co- infection or 
colonized with another viral etiology identified 
Section 11.11, Conduct of analyses 
Analyses will be performed in a stepwise manner after all subjects in all each country / 
group of countries / countries in a region have completed all study visits in Epoch 002 
and again after completion of all study visits in Epoch 003.   
… For these analyses a statistical report but no CSR will be prepared.for each country/ 
group of countries / countries in a region. No CSRs will be prepared. 
Final analyses will be performed when all data up to study end are available (Epoch 002 
and Epoch 003). One or more An integrated CSR clinical study reports (bycounty / group 
of countries / countries in a region)……….. 
Section 11.11.1 
Statistical considerations for interim analysis 
This interim analysis will be performed to obtain preliminary information on the 
performance of the case definitions used for RSV LRTI, severe LRTI, and very severe 
LRTI (Table 3) and to assess levels of RSV-A neutralising antibody in maternal and 
cord blood at delivery. The interim analysis will occur after the database freeze at the 
time point when approximately 50% of infants will have completed up to 6 months of 
follow up during the surveillance period following birth (up to Visit 3-NB). No CSR will 
be prepared. 
Section 12.1, Electronic case report form instructions 
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. 
Section 12.3, Study and site closure has been added. 
GSK or its designee reserves the right to close the study site or terminate the study at 
any time for any reason at the sole discretion of GSK, provided there is sufficient notice 
given to account for patient’s safe exit from study participation. Study sites regular 
closure will be upon study completion. A study site is considered closed when all 
required data/documents and study supplies have been collected and a study-site 
closure visit has been performed.  
The investigator may initiate study-site closure at any time, provided there is 
reasonable cause and sufficient notice is given in advance of the intended termination. 
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Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to: 
• 
Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines 
• 
Inadequate recruitment of subjects by the investigator 
• 
Discontinuation of further study treatment development 
Appendix B, Clinical Laboratories, table 17 
GSK Vaccines GmbH 
Clinical Laboratory Sciences, 
Marburg, Germany 
Emil-von-Behring-Str. 76 
35041 Marburg 
Germany 
Appendix B, Clinical Laboratories, Table 18 
NÉOMED-LABS Inc. 
525, Cartier Ouest Laval, 
Québec 
Canada H7V 3S8 
Appendix D, Definitions of maternal, fetal and neonatal events of interest as per 
GAIA 
The order of the tables has been adjusted for consistency with the order in which 
endpoints are presented in the body of the protocol.  Stillbirth (now Table 19) is 
presented as a pregnancy outcome rather than as a neonatal event of interest. 
Table 29 has been updated to include the following events: 
Gestational 
liver disease 
(Intrahepatic 
Cholestasis of 
Pregnancy or 
ICP)1 
Intrahepatic cholestasis also called obstetric cholestasis should be suspected when 
pruritis develops during pregnancy in the absence of a rash.  Lab evidence of 
cholestasis includes elevated bile acids (Glyco and Taurochenodeoxycholic Acid )(> 10 
umol/L).  Up to 60% of patients will have elevated transaminases and 20% of patients will 
have increased direct bilirubin levels. 
Jaundice may or may not be present. ICP typically is transient and resolves after 
delivery. Women that had ICP in previous pregnancy have higher risk to developing ICP 
in the following pregnancies or other hepatobiliary disorders in later life. ICP is 
associated with adverse fetal outcome like meconium-stained liquor, fetal asphyxia, 
spontaneous preterm delivery and  intrauterine death.  
Gestational 
liver disease 
(Acute Fatty 
Liver of 
Pregnancy)2 
Acute fatty liver of pregnancy (AFLP) is a rare, potentially fatal complication that occurs 
in the third trimester or early postpartum period. AFLP is characterized by 
microvesicular fatty infiltration of hepatocytes without any inflammation or necrosis. 
Most frequent signs and symptoms are the following: 
Jaundice 
Abdominal Pain (usually right upper quadrat, midepigastric or radiating to back) 
Central nervous system (altered sensorium, confusion, disorientation, psychosis, 
restlessness, seizures or even coma) 
Disseminated intravascular coagulation 
Nausea and vomiting 
Gastrointestinal bleeding 
Acute renal failure 
Oliguria 
Tachycardia 
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Late onset pyrexia 
Hypoglycemia 
ALT<500 U/L 
Hyperbilirubinemia, elevated ammonia, leukocytosis, hypofibrinogenemia 
Ultrasound examination and computed tomography may demonstrate fatty infiltration of 
the liver but are not sufficient for diagnosis 
Maternal 
Sepsis3 
Maternal sepsis is a life-threatening condition defined as organ dysfunction resulting 
from infection during pregnancy, child-birth, post-abortion, or post-partum period.  
Organ dysfunction can be identified as an acute change in total SOFA score ≥2 points 
consequent to the infection. 
The baseline SOFA score can be assumed to be zero in patients not known to have 
preexisting organ dysfunction. 
A SOFA score ≥2 reflects an overall mortality risk of approximately 10% in a general 
hospital population with suspected infection. Even patients presenting with modest 
dysfunction can deteriorate further, emphasizing the seriousness of this condition and 
the need for prompt and appropriate intervention, if not already being instituted. 
 
 
 
MAP = mean arterial pressure; qSOFA = quick SOFA; SOFA = Sequential [Sepsis-
related] Organ Failure Assessment 
References: 
1 Geenes V et al . Intrahepatic cholestasis of pregnancy 
 
 
 
2 Can J Gastroenterol Vol 20 26 No 1 January 2006 
 
 
 
3  Bonet et al. Reproductive Health (2017) 14:67 
Table 39, Failure to Thrive, has been added. 
Failure to Thrive (FTT) can be broadly defined as a faltering of growth from a 
previously established pattern of growth. It is universally established that a diagnosis of 
failure to thrive should be based on anthropometric data. However no consensus exits 
as to which measurements achieve the highest specificity and sensitivity. Weight is 
generally regarded is the indicator of choice, particularly a change in growth velocity, 
and as such has been selected as the standard for this case definition with a weight for 
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age deceleration as the primary indicator of failure to thrive.  The case definition 
should be applied when there is no clear alternative diagnosis for the reported event to 
account for the combination of symptoms. 
Level 
Description 
1 
Infant age1 determined by a documented birth date 
AND 
Weights obtained using an electronic scale 
AND 
At least 2 weights, measured at least 4 weeks apart 
AND 
Weight for age deceleration2 through at least 2 centile spaces on 
growth chart3 
2a 
Infant age determined by a documented birth date 
AND 
Weights obtained using a beam balance scale 
AND 
At least 2 weights, measured at least 4 weeks apart 
AND 
Weight for age deceleration through at least 2 centile spaces on 
growth chart 
OR 
 Infants with an undocumented birth date, where age is determined 
based on Mothers recall to nearest month 
AND 
Weights obtained using electronic scale 
AND 
At least 2 weights, measured at least 4 weeks apart 
AND 
 Weight for age deceleration through at least 2 centile spaces on 
growth chart 
2b 
Infant age determined by a documented birth date 
AND 
Weights obtained using a spring balance scale 
AND 
At least 2 weights, measured at least 4 weeks apart 
AND 
Weight for age deceleration through at least 2 centile spaces on 
growth chart  
OR  
Weight measured using electronic scale or beam balance scale 
AND 
Length taken using Infantometer 
AND 
Weight for length less than or equal to the 3rd centile on the 
appropriate growth chart 
3a 
Infants with an undocumented birth date, where age is determined 
based on Mothers recall to nearest month 
AND 
Weight obtain using either beam balance or spring balance 
scale 
AND 
At least 2 weights, measured as least 4 weeks apart 
AND 
Weight for age deceleration through at least 2 centile spaces on 
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Level 
Description 
growth chart 
3b 
Infants with no weight available 
AND 
Physical examination consistent with FTT4 
AND 
MUAC5 indicative of severe wasting 
1This case definition is limited to infants up to 12 months of age. 
2 Weight should be documented on the appropriate growth chart at the time of assessment. A fall through 2 
centile spaces may be demonstrated at any point in the first 12 months of life, using any two weights as 
long as they are taken at least 4 weeks apart. Details of use of the weight balances allowable under this 
case definition and use of the Infantometer for length assessment are presented in the reference given 
below. 
3 For infants born at 37 weeks gestation or above, the WHO growth charts should be applied. When using 
weight for age use the growth chart most accurate for the infants age. The birth to 6 months age range 
should be used where data is available for this range only, the birth to 2 years chart should be used where 
data is available beyond 6 months of life. When using weight for length, use the chart for birth to 2 years. 
For infants born less than 37 completed weeks gestation, the Intergrowth charts for postnatal growth 
standards in preterm infant should be used. All infants should be plotted on their respective growth chart 
using their corrected age. Links to relevant growth charts are presented in the reference given below. 
4 Physical examination with signs of Failure to Thrive (must include at least 2 findings, with at least one major 
finding) Major findings: Reduced subcutaneous fat stores; poor muscle mass; loose skin folds; 
prominent ribs; thin limbsOther less specific signs include: sparse hair; rashes; pallor; miserable; 
lethargy/fatigue. 
5 Mid Upper Arm Circumference (MUAC): For infants 0–6 months, a MUAC of 6 110 mm is indicative of severe 
wasting.For infants 6–12 months, a MUAC of 6 115 mm is indicative of severe wasting. Instructions on 
performing MUAC are presented in the reference given below. 
Reference: Ross E, Munoz F, Edem B et al. Failure to thrive: case definition and guidelines for data collection, 
analysis, and presentation of maternal immunization safety data. Vaccine. 2017; 35:6483-6491. 
Table 40, macrosomia definition has been corrected 
Macrosomia 
BW >4000 g (8 lb, 13 oz lb). 
 
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GlaxoSmithKline Biologicals 
Vaccines R & D 
Protocol Amendment 4  
eTrack study number and Abbreviated Title 
207636 (EPI-RSV-008 BOD) 
Amendment number: 
Amendment 4 
Amendment date: 
29-MAY-2020 
Co-ordinating author: 
, Lead Science Writer 
Rationale/background for changes:  
This amendment outlines measures that may be applicable during special 
circumstances (e.g., COVID-19 pandemic). The primary purpose of the amendment is 
to protect the subject’s welfare, and as far as possible ensure the potential benefit to the 
subject and promote data integrity.  Several additional modifications and clarifications 
have also been made.  
Changes are outlined below. 
• 
Globally:  
− 
Intervals between study visits/contacts/observations: the window for the first 
infant subject visit has been extended from 0-10 to 0-21 days to provide site 
personnel with additional time to obtain and document post-delivery/birth 
informed consent (where this is required). 
− 
References to Gestational Age Range at maternal Visits 2, 3 and 4 have been 
removed as their inclusion was only intended as a guide and was not intended 
to further restrict allowed intervals between study visits. 
• 
Synopsis, Section 3.3, Tertiary Objectives, and Section 11.1.3, Tertiary Endpoints, 
have been updated to indicate that the incidence of LRTIs/ Severe LRTIs (using 
alternative case definitions) will also be evaluated.   
• 
Synopsis and Section 11.1.3, Tertiary Endpoints, has been updated to clarify that 
further exploratory characterization of immune responses to RSV and/or other 
respiratory tract infections or infections of relevance to pregnant women and their 
newborns (based on maternal serum and cord blood) includes, for example, levels 
of RSV-B neutralizing antibodies. 
• 
The List of Abbreviations has been updated to include a reference to COVID-19. 
• 
Section 2.3, Overall Benefit: Risk Conclusion has been updated. 
• 
Section 4, Figure 1: A note has been added to indicate that COVID-19 cases 
identified within the surveillance framework of the study will be captured to the 
eCRF. 
• 
Section 5.4, Table 4, Alternative LRTI/Severe LRTI Case Definitions, has been 
added.  All subsequent Table numbers therefore increase by one. 
• 
Section 8.2.1, Study procedures during special circumstances, has been added. 
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• 
Section 8.3, Tables 5 and 6, List of study procedures for maternal subjects, and 
List of study procedures for neonates/infants, have been clarified to indicate that 
COVID-19 cases are considered clinically significant events and will be recorded 
as such in the eCRF.  
• 
Sections 8.5.8, 8.6.2, 8.6.7 have been modified to reference the collection of 
COVID-19 case information. 
• 
Section 8.6.5.2 has been modified to clarify that RTI surveillance in infants cannot 
begin before additional consent for the infant’s participation (where required) has 
been supplied. 
• 
Section 8.7, Reporting COVID-19 cases, has been added. 
• 
Section 11.3 has been modified to introduce definitions for the Enrolled set, and to 
clarify definitions for the Exposed and Per Protocol sets for analysis. 
• 
Sections 11.6, 11.7 and 11.8 have been modified for consistency with the changes 
in Section 11.3.  
• 
Section 11.11.1, Statistical considerations for interim analysis, has been modified 
to indicate that an interim analysis for RSV LRTIs may be performed if deemed 
necessary. 
• 
Section 14 has been updated to include a reference to the WHO Guidance for 
surveillance of COVID-19. 
• 
Additional editorial clarifications have been made and typographic errors have 
been corrected. 
Text that has been moved or added is presented in bold italics and deleted text in 
strikethrough in the following sections. 
Contributing Authors: 
• 
, Expert Epidemiology Biostatistician, 
 
 Lead Epidemiology StatisticianBiostatistician  
• 
, Clinical Trial Supply manager 
• 
, Clinical Laboratory Sciences Study Manager, Business & 
Decision Life Sciences Contractor for GSK Biologicals 
• 
, Oversight Data Manager 
• 
 Study Data Manager (Tata Consultancy Services for GSK Biologicals) 
Synopsis and Section 3.3, Tertiary objectives: 
• 
To determine the incidence of LRTIs/ Severe LRTIs (using alternative case 
definitions) 
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Synopsis and Section 11.1.3, Tertiary endpoints: 
• 
Episodes of LRTIs/Severe LRTIs up to one year of age - using alternative case 
definitions  
Any further exploratory characterization of immune responses to RSV and/or other 
respiratory tract infections or infections of relevance to pregnant women and their 
newborns (based on maternal serum and cord blood). (For example, levels of RSV-B 
neutralizing antibodies). 
List of Abbreviations: 
COVID-19 
Corona Virus Disease 2019 
Section 2.3, Overall Benefit:Risk Conclusion: 
This is an epidemiologic study that describes the prevalence of pregnancy outcomes 
and maternal/neonatal events of interest. The study does not include the administration 
of any investigational vaccine. It is not expected that the participation of pregnant 
women and their babies in the study would create any further risk to study participants. 
The study includes the establishment of a surveillance system for lower respiratory 
tract infections (LRTI) which may facilitate detection of respiratory tract infections, 
including COVID-19 cases, that might be diagnosed in children enrolled in the study. 
Section 4, Figure 1, Study Design:  
References to GA in the original figure have been removed and a footnote specifically 
referencing COVID-19 has been added. The previous figure and the current figure are 
presented in full below. 
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Section 5.4, Table 4, Alternative LRTI / Severe LRTI Case Definitions: 
RSV 
confirmed 
Documented physical examination 
(PE) findings indicating lower 
respiratory tract involvement (at least 
one symptom) 
Objective measures of clinical severity (at 
least one symptom) 
LRTI 
Confirmed 
RSV infection 
Rhonchi1 
Increased respiratory rate (bpm) 
Rales1 
≥ 60 for < 2 mo 
Crackles 
≥ 50 for 2-6 mo 
Wheeze 
Hypoxemia: 
 
SpO2  <95% at ≤1800 meters 
 
SpO2  <92% at > 1800 meters 
 
New onset apnea 
 
Nasal flaring 
 
Retractions2 
 
Grunting 
 
 
Severe 
LRTI 
Confirmed 
RSV infection 
Rhonchi1 
Hypoxemia 
Rales1 
SpO2  <93% at ≤1800 meters 
Crackles 
SpO2 <90% at > 1800 meters 
Wheeze 
Acute hypoxic or ventilatory failure3 
 
Dehydration due to respiratory distress 
requiring IV hydration4 
 
Failure to respond or unconscious 
1Term not listed in the eCRF page in this study.  
2 Intercostal recession or chest wall indrawing are considered synonymous with and will be used as 
alternatives to the term “retractions,” which is not listed in the eCRF page for this study.  
3 Acute hypoxic or ventilatory failure is not listed in the eCRF page for this study.  Instead, the presence of 
either respiratory support excluding mechanical ventilation OR requirement for mechanical ventilation or 
both will be used.  
4 Dehydration due to respiratory distress requiring IV hydration is not listed in the eCRF page for this study. 
Skin turgor > 2 seconds or administration of IV fluid therapy will be used instead.  
Section 6.1, Number of subjects / centers: 
The study will be conducted at multiple centres centers….. 
Section 6.2.2, Inclusion criteria for enrollment; infants: 
• 
If local law requires it: Written or witnessed/thumb printed informed consent for 
study participation of the infant obtained from parent(s)/LAR(s) within 10 21 days of 
birth.  
Section 8.2.1, Study procedures during special circumstances: 
During special circumstances (e.g., the COVID-19 pandemic), the specific guidance 
from local public health and other competent authorities regarding the protection of 
individuals’ welfare must be applied.  
For the duration of such special circumstances, the following measures may be 
implemented for enrolled subjects if deemed feasible by the investigator. 
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• 
If it is not possible to conduct a protocol-specified, scheduled or event-driven (e.g., 
LRTI assessment) visit as described in Section 8.3, the visit may be replaced with a 
contact conducted by telephone, videotelephony or telemedicine. SMS and email 
are not allowed.  
• 
Biological samples may be collected at a different location* other than the study 
site, or at the subject’s home. Biological samples should not be collected if they 
cannot be obtained within the visit interval (Section 8.4), processed in a timely 
manner or appropriately stored until the intended use.  
• 
Nasal swabs should only be collected using centrally provided supplies. 
• 
Cord Blood for assessment of immune response may be collected locally but must 
be retrieved, processed and stored  in accordance with the Investigator Laboratory 
Manual.  
• 
Additional blood samples for assessment of immune response should only be 
collected using centrally provided supplies. 
• 
Diary cards may be transmitted from and to the site by electronic mail, and / or 
conventional mail. 
Impact on the per protocol sets for analysis will be determined on a case by case basis. 
Any impact of the above mentioned measures on the study results will be described in 
the clinical study report. 
* It is the investigator’s responsibility to identify an alternate location. The investigator 
should ensure that this alternate location meets ICH GCP requirements, such as 
adequate facilities to perform study procedures, appropriate training of the staff and 
documented delegation of responsibilities in this location. This alternate location 
should be covered by proper insurance for the conduct of study on participants by 
investigator and staff at a site other than the designated study site. Refer to EMA 
Guidance on the Management of Clinical Trials during the COVID-19 (Coronavirus) 
pandemic (version 2, 27 March, 2020) for more details. 
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Section 8.3, Outline of Study Procedures, Table 5, list of study procedures for 
maternal subjects: 
Gestational age 
24 
0/7  
–  
 
27 
6/7 
24 
0/7 –   
27 
6/7 
28 0/7 
–
31 6/7 
32 0/7 
–
35 6/7 
36 0/7 –
delivery 
 
 
 
Timepoints 
 
Day 
1 
Day 
28 
Day 
56 
Day 84 
At 
Delivery 
Post-
Delivery 
Day 42 
 
Record pregnancy-
related events of 
interest. Record other 
clinically significant 
events or diagnoses15 
 
●  
●   
● 
● 
● 
● 
● 
1 Refer to Section 6.2.1, fifth sixth bullet.  
10 In the Philippines Where HIV testing is not part of the standard of care for pregnant women, the screening HIV test 
can be performed locally as a study procedure. Refer to SPM for further details. If results are positive, subject will 
be referred per local standard of care.  
15Includes events or diagnoses that could impact the pregnancy including COVID-19 cases  
Section 8.3, Outline of study procedures, Table 6, list of study procedures for 
neonates/Infants:  
Age 
0-10 21 days  
42 
Days 
6 
Months 
12 
months 
0-12 
months 
Timepoints 
Birth  
Day 
42 
M6 
Y1  
 
 
Record all 
hospitalizations 
and clinically 
significant 
events h  
● 
● 
● 
● 
● 
● 
Investigator 
sign-off on 
eCRF before 
analysis  
 
● 
  
● 
 
 
LAR = legally acceptable representative; LRTI = lower respiratory tract illness; NB = newborn; RTI = respiratory tract 
illness; SAE = serious adverse event; M=month; Y = year. 
 gWhen approximately 50% of infants have completed up to Visit 3-NB, an interim analysis will may be conducted to 
assess the accumulated RSV LRTI cases and the distribution of maternal and cord blood serum RSV A Ab. . 
h Includes COVID-19 cases 
Section 8.4, Intervals between study visits, Table 7: 
Interval 
Optimal interval 
Allowed interval** 
Birth → Visit 1-NB  
0 days  
0 – 10 21 days  
 
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Section 8.5.8, Outcomes and Events of Interest in maternal subjects: 
• 
Any events of interest in mother or fetus detected by surveillance will be referred to 
and managed by the routine health services as locally appropriate. 
• 
Record all hospitalizations and/or clinically significant events, including COVID-19 
cases.  
Section 8.6, Description of study procedures for Neonates / Infants: 
Note that the investigator or study staff will perform (if not performed by local healthcare 
provider) a minimum of 2 clinical examinations: one at birth (or up to 10 21 days after 
birth), and another at approximately 42 days of age.   
Section 8.6.2, History and Examinations for Neonates / Infants: 
Record all hospitalizations and/or clinically significant events, including COVID-19 
cases. 
Section 8.6.5.2, Surveillance for potential Lower Respiratory Tract Illness (LRTI); 
Overview: 
Surveillance for potential LRTIs begins at birth (or after additional consent, has been 
provided for the infant’s participation in the study, if required,) and ends with the Year 
1 study visit.   
Section 8.6.7.1, Visit to assess a potential LRTI; Overview: 
The appropriately qualified person will also evaluate whether the LRTI might be 
related to COVID19. The appropriately qualified person must follow the local standard 
of care regarding the reporting, and management of COVID-19 cases (suspected, 
probable or confirmed COVID-10 case), and complete both the COVID-19 form and 
LRTI form in the CRF.  Refer to Section 8.7. 
Section 8.6.7.2, Visit to assess a potential LRTI; Clinical Evaluation: 
• 
Possible presence of COVID-19 infection (Section 8.7). As noted above, both the 
LRTI and COVID-19 eCRFs are to be completed (whether or not the 
investigator/study staff consider the LRTI to be due to COVID-19.. 
Section 8.7, Reporting Covid-19 Cases – Maternal and Infant subjects: 
In addition to satisfying local reporting requirements for COVID-19 cases, maternal 
and infant COVID-19 cases identified within the existing framework of the study will 
be captured and reported on the COVID-19 eCRF for the study. 
COVID-19 cases should be reported in the eCRF according to the WHO Case 
Definition [WHO, 2020] using one of the following terms:  
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• 
Suspected COVID-19 infection  
• 
Probable COVID-19 infection 
• 
Confirmed COVID-19 infection 
Section 8.11.3.1, Antibody determination, Table 9: 
System 
Component 
Method 
Kit / 
Manu-
facturer 
Unit 
Cut-off 
Laboratory* 
SERUM 
Respiratory 
Syncytial 
Virus A Ab  
NEUTRALISATION 
In house 
ED60 
and/or 
IU/ML 
ED60: 18; 
IU/ml: 56 
GSK Biologicals** 
or GSK designated 
lab*** 
Ab = antibody; ED60 = serum dilution inducing 60% inhibition in plaque forming units; IU/mL: International 
Unit/milliliter 
Section 9.7, Follow-up of SAEs related to study participation: 
The investigator will follow-up subjects with SAEs related to study participation until the 
event has resolved, subsided, stabilised stabilized….. 
Section 9.7.2, Follow-up after the subject is discharged from the study: 
The investigator is obliged to assist. If a subject dies during participation in the study or 
during a recognised recognized….. 
Section 11.1.3, Tertiary endpoints: 
• 
Any further exploratory characterization of immune responses to RSV and/or other 
respiratory tract infections or infections of relevance to pregnant women and their 
newborns (based on maternal serum and cord blood)  (For example, levels of RSV-B 
neutralizing antibodies.)   
• 
Episode(s) of RSV-LRTI/severe LRTI based on alternative case definitions, from 
birth up to 1 year of age. 
Section 11.3.1.1, Exposed Sets, Pregnant women (mothers): 
The ES will include all pregnant women (mothers) who signed a valid informed consent 
form. 
Section 11.3.1.2, Exposed Sets, Neonates/Infants: 
Not applicable. 
Section 11.3.2.1, Enrolled Sets, Pregnant women (mothers): 
The enrolled set will include all pregnant women (mothers) with a valid informed 
consent who completed Visit 1. 
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Section 11.3.2.2, Enrolled Sets, Neonates/infants: 
The ESEnrolled Set will include all study eligible neonates/infants with 
• 
 born to pregnant women in the enrolled set, and  
• 
Who have a valid ICF signed by the mother/ parent(s) /LAR(s) (as appropriate per 
local regulations). 
11.3.3, Per Protocol Sets (PPS), Pregnant women (mothers): 
• 
The maternal PPS will include all pregnant women (mothers) meeting in the 
enrolled set who meet….. 
11.3.3.2, Per Protocol Sets (PPS), Neonates/infants: 
The infant PPS will include all enrolled neonates / infants meeting 
• 
born to pregnant women in  the PPS and  
• 
who meet……….. 
Sections 11.6, Analysis of primary objectives and 11.7, Analysis of Secondary 
Objectives: 
 If there is a difference of 5% or more between the number of participants in the 
enrolled set and the PPS, primary objectives analyses on the enrolled set will also be 
performed. 
Section 11.8, Analysis of tertiary objectives: 
If there is a difference of 5% or more between the number of participants in the 
enrolled set and the PPS, primary objectives analyses on the enrolled set will also be 
performed. 
• 
To determine the incidence of LRTIs/Severe LRTIs (using alternative case 
definitions) 
• 
If deemed necessary, to further characterize the immune responses to RSV and other 
infections in maternal subjects and infants (based on maternal serum and cord 
blood).  
− 
For example, for levels of neutralizing antibodies such as but not limited to 
RSV-B: 
Section 11.11.1, Statistical considerations for interim analysis: 
If deemed necessary, an interim analysis will may be performed on RSV surveillance 
data as part of the secondary objective of determining incidence of RSV LRTI. This 
interim analysis will may be performed to obtain preliminary information on the 
performance of the case definitions used for RSV LRTI, severe LRTI, and very severe 
LRTI (Table 3) and to assess levels of RSVA neutralising antibody in maternal and cord 
blood at delivery. The interim analysis willmay occur after the database freeze at the time 
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point when approximately 50% of infants will have completed up to 6 months of follow 
up during the surveillance period following birth (up to Visit 3-NB). If an interim 
analysis is performed, data cleaning plans will be scheduled as needed to supply data for 
interim analyses in a timely manner. This interim analysis will may be performed on data 
that is as clean as possible. Preliminary results will be made available in a timely manner 
for use in the potential adjustment of the RSV LRTI case definitions to be used in pivotal 
clinical trials scheduled to begin shortly thereafter. The results pertaining to this analysis 
(if performed) will be purely descriptive, with no adjustment of type I error, and will be 
reported in an interim statistical report. No CSR will be prepared. 
Section 14, References: 
World Health Organization [WHO]. Global Surveillance for COVID-19 caused by 
human infection with COVID-19 virus: Interim Guidance. March 2020. Available at: 
https://apps.who.int/iris/rest/bitstreams/1272502/retrieve.  Accessed 8 May 2020. 
 
 
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