A Phase 3, Randomized, Observer-Blind, Placebo-Controlled, Group-Sequential Study to Determine the Immunogenicity and Safety of a Respiratory Syncytial Virus (RSV) F Nanoparticle Vaccine With Aluminum in Healthy Third-trimester Pregnant Women; and Safety and Efficacy of Maternally Transferred Antibodies in Preventing RSV Disease in Their Infants
Phase: PHASE3
Conditions: Respiratory Syncytial Virus Infections
Sponsor: Novavax

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PROTOCOL APPROVAL PAGE
The principal investigator is responsible for ensuring that all study site personnel, including 
sub-investigators and other staff members conduct this study according to this protocol, Good 
Clinical Practice (GCP) and International Conference on Harmonization (ICH) guidelines, the 
Declaration of Helsinki, and the pertinent individual country laws/regulations and to comply 
with its obligations, subject to ethical and safety considerations during and after study 
completion. The principal investigator also agrees not to disclose the information contained in 
this protocol or any results obtained from this study without written authorization.
Investigational 
Material:
RSV Recombinant F Nanoparticle Vaccine (Sf9 cells with recombinant 
Baculovirus expression) with aluminum
Reference Material:
Formulation buffer (placebo)
Protocol:
RSV-M-301
Date of Issue:
12 October 2018
Prepared By:
Louis F. Fries MD
I have read and approve the protocol specified above and agree on its content:
Novavax Representatives:
Louis F. Fries, MD
Senior Vice President,
Chief Medical Officer
Date
D. Nigel Thomas, PhD
Vice President, Clinical Operations
Date
Clinical Study Site:
Print Name – Principal Investigator
Date
Signature
Electronically signed
Electronically signed

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CONFIDENTIAL
The information in this document is considered privileged and confidential by Novavax, Inc. and may not be disclosed to others 
except to the extent necessary to obtain Institutional Review Board/Ethics Committee approval and informed consent, or as 
required by national and local laws. Persons to whom this information is disclosed must be informed that this information is 
privileged and confidential and that it should not be further disclosed.
Novavax, Inc. 
20 Firstfield Road, Gaithersburg, MD 20878 USA
(240) 268-2000
A PHASE 3, RANDOMIZED, OBSERVER-BLIND, PLACEBO-CONTROLLED, 
GROUP-SEQUENTIAL STUDY TO DETERMINE THE IMMUNOGENICITY AND 
SAFETY OF A RESPIRATORY SYNCYTIAL VIRUS (RSV) F NANOPARTICLE 
VACCINE WITH ALUMINUM IN HEALTHY THIRD-TRIMESTER PREGNANT 
WOMEN; AND SAFETY AND EFFICACY OF MATERNALLY TRANSFERRED 
ANTIBODIES IN PREVENTING RSV DISEASE IN THEIR INFANTS
Investigational Material:
Respiratory Syncytial Virus (RSV) Recombinant F 
Nanoparticle Vaccine (Spodoptera frugiperda [Sf9] cells 
with recombinant Baculovirus expression) with aluminum 
phosphate adjuvant (herein referred to as aluminum)
Reference Material:
Formulation buffer (placebo)
Protocol Number:
RSV-M-301
Short Title:
A Study to Evaluate the Efficacy of Maternal Immunization 
with RSV F Vaccine in Preventing RSV Lower Respiratory 
Tract Infection in Young Infants
Sponsor:
Novavax, Inc. (Novavax)
20 Firstfield Road
Gaithersburg, MD 20878 USA
Responsible Clinical Operations 
Manager:
Judy L. Wen
Director, Clinical Operations
Novavax, Inc.
Office: +1-240-268-2105
Mobile: +1-301-693-3931
Email: jwen@Novavax.com
Version – Date:
10.1 – 12 October 2018
Prior Version(s):
10.0 – 02 October 2018
9.0 – 21 July 2017
8.0 – 23 August 2016
7.0 – 15 July 2016
6.0 – 09 May 2016
5.0 – 09 February 2016
4.0 – 08 January 2016
3.0 – 09 July 2015
2.0 – 11 June 2015
1.0 – 20 April 2015

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PROTOCOL CHANGE HISTORY
Protocol Version 10.1, 12 October 2018 (revised from 10.0, 02 October 2018)
The following is a summary of the changes made to this version of the protocol.
Location of 
Change
Change/Modification in Version 10.1
Protocol Title 
on Title page 
and Synopsis 

The title of the study has been reverted to the original title from Version 9.0 by 
the addition of “group-sequential”. Version 10.1 is otherwise identical to 
Version 10.
Rationale: Protocol RSV-M-301 was originally designed as a group-sequential 
study and all subjects were enrolled under prior versions of the protocol (Version 
9 or earlier) in which the study design was specified as group-sequential. Version 
10 of the protocol removed the group sequential study design as the Sponsor 
decided that the first analysis with the ~4600 subjects enrolled to date would be the 
final analysis. The rationale to stop the study and conduct the final analysis is that 
the minimum required safety database of at least 3000 active subjects has been met 
and the Sponsor believes the trial has adequate power to make a statistically sound 
conclusion based on the aggregate number of blinded primary endpoint cases 
accrued and the projected placebo attack rate of 3-4%. To ensure continued 
traceability between the current protocol and the numerous study-related 
documents which include the protocol title, “group-sequential” will be retained in 
the protocol title. 
Protocol Version 10.0, 02 October 2018 (revised from 9.0, 21 July 2017)
The following is a summary of the changes made to this version of the protocol.
Note: A complete tabular summary of changes made to previous versions of the protocol has 
been provided in Appendix 5. 
Location of 
Change
Change/Modification in Version 10.0
Study Title 

The title of the study has been updated by the removal of “group-sequential”. 
Rationale: As a group-sequential design with multiple interim analyses is no 
longer planned, the reference to the phrase has been deleted from the study title. 
Section 1.7, 
Synopsis

The sentence, “Two recent reports of prospective studies have confirmed the 
existence of a symptomatic RSV disease burden in mothers [Hause 2018, 
Madhi 2018].”, has been added and referenced.
Rationale: This statement updates the current knowledge of the burden of RSV 
illness in pregnancy based on recent publications.

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Section 2.1, 
Synopsis 

The words “through the first” have been added before the enumeration of the 
120, 150, and 180 day intervals.

The sentence “Success will be demonstrated under the primary hypothesis 
that the event ratio (RSV F Vaccine/Placebo is ≤ 0.70 (i.e., vaccine efficacy is 
≥ 30%” has been modified to: “Success under the primary hypothesis will be 
achieved by demonstration of a lower bound of a two-sided 97.52% 
confidence interval for the Day 90 analysis (lower bound of a 95% confidence 
interval for later time points) for the estimate of vaccine efficacy which 
equals or exceeds target values agreed with regulatory authorities.”
Rationale: The words “through the first” were added to clarify that the successive 
120, 150, and 180 day analyses are intended to span the entire intervals from 
delivery through the specified days. This is a clarification and not a change to the 
intended analysis. The sentence concerning the success criteria for the primary 
objective has been modified to reflect the Type 1 error rate agreed with the US-
FDA. The target values to be exceeded vary from jurisdiction to jurisdiction and 
have now been specified in Section 10.4.3.
Section 2.2, 
Synopsis 

“in infants” has been added to the closed bullet sentence “to determine the 
efficacy of maternal immunization with the RSV F vaccine in reducing the 
incidence in infants of”.
Rationale: These words were added to clarify the precise subject population being 
referenced in the objective. 

The two open bullet objectives: 
“RSV LRTI with severe hypoxemia (SpO2 < 92% at sea level or < 87% at 
altitudes > 1800 meters) or the need for high flow nasal cannula, or 
mechanical ventilatory support” 
and 
“RSV LRTI leading to hospitalization” 
have been modified as (shown in bold): 
RSV LRTI with EITHER severe hypoxemia (SpO2 < 92% at sea level or 
< 87% at altitudes > 1800 meters) OR the documented use of oxygen by 
high flow nasal cannula OR a requirement for continuous positive 
airway pressure (CPAP) OR bilevel positive airway pressure (BiPAP) 
OR Bubble CPAP OR bag-mask ventilation OR intubation with 
subsequent mechanical (or manual) ventilation OR extracorporeal 
membrane oxygenation (ECMO), through the first 90 days of life in 
infants of maternal RSV F vaccinees as compared to placebo recipients. In 
the event that efficacy is shown through the first 90 days of life, a 
hierarchical sequence of hypothesis tests will be carried out to examine 
efficacy through 120, 150, and 180 days of life.

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and 
RSV LRTI leading to hospitalization through the first 90 days of life in 
infants of maternal RSV F vaccinees as compared to placebo recipients. In 
the event that efficacy is shown through the first 90 days of life, a 
hierarchical sequence of hypothesis tests will be carried out to examine 
efficacy through 120, 150, and 180 days of life.
Rationale: The wording of these two important secondary endpoints was altered 
to: a) provide more specific enumeration of methodologies used for respiratory 
support in infants that are more advanced than simple oxygen supplementation by 
standard flow-rate nasal cannula and imply greater compromise and b) to clarify 
that, as in the case of the primary endpoint, successive analyses consider the 
intervals from delivery through 90, 120, 150, and 180 days of life, inclusive.

The following sentence has been added: 
“The two secondary efficacy objectives will be evaluated in term infants (≥ 37 
weeks gestational age at delivery) born to maternal subjects who received a 
study injection ≥ 2 weeks (14 days) prior to delivery. Infants with multiple RSV 
episodes meeting a given criterion will be counted only once, using data from 
the first episode. Success under the secondary efficacy hypotheses will be 
achieved by demonstration of a lower bound of a two-sided 95% confidence 
interval for the estimate of vaccine efficacy which exceeds 0%.”
Rationale: The above sentence has been added to clarify the population to be used 
to support the analysis of the secondary endpoints.  This is a clarification, not a 
change of the protocol.

The following open bullet secondary objective has been recategorized as 
exploratory: 
“RSV LRTI resulting in death”
Rationale: This endpoint has been downgraded to exploratory status, based on the 
very low incidence rate of RSV-related death in populations with access to 
adequate supportive care – which precludes statistically robust conclusions. 

The following two secondary objectives have been recategorized as 
exploratory: 
“To determine the efficacy of maternal immunization with the RSV F 
vaccine in reducing the incidence of all RSV LRTI through the first 90
days of life in infants of maternal RSV F vaccinees as compared to placebo 
recipients. In the event that efficacy is shown through the first 90 days of 
life, a hierarchical sequence of hypothesis tests will be carried out to 
examine efficacy at 120, 150, and 180 days of life.” 
and
“To determine the efficacy of maternal immunization with the RSV F 
vaccine in reducing the incidence of healthcare interventions associated 

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with wheezing through the first year of life in infants of maternal RSV F 
vaccinees as compared to placebo recipients.” 
Rationale: The first of these objectives was downgraded to exploratory status 
because the endpoint, while potentially medically meaningful is very 
heterogeneous and unsupported by any objective measure other than 
documentation of RSV recovery from the nasopharynx.  The second was 
downgraded to exploratory status because of the uncertain reliability of parental 
reports of wheezing as a driver for medical intervention.
Section 2.3, 
Synopsis 

The following exploratory objectives have been added: 
o
To describe the efficacy of maternal immunization with the RSV F vaccine 
in reducing the incidence in infants of medically-significant RSV LRTI 
defined as per the primary objective but with the inclusion of data 
concerning documentation of RSV infection, LRTI symptoms and signs, 
hypoxemia and/or tachypnea obtained from the observations of the clinical 
site staff OR review and abstraction of medical records for infants 
undergoing hospitalization for a respiratory serious adverse event. 
o
To describe the efficacy of maternal immunization with the RSV F vaccine 
in reducing the incidence of RSV LRTI with EITHER severe hypoxemia 
(SpO2 < 92% at sea level or < 87% at altitudes > 1800 meters) OR the 
documented use of oxygen by high flow nasal cannula OR continuous 
positive airway pressure (CPAP) OR bilevel positive airway pressure 
(BiPAP) OR Bubble CPAP OR bag-mask ventilation OR intubation with 
subsequent mechanical (or manual) ventilation OR extracorporeal 
membrane oxygenation (ECMO) defined as per the first secondary 
objective but with the inclusion of data concerning documentation of RSV 
infection, LRTI symptoms and signs, and hypoxemia obtained from the 
observations of the clinical site staff OR review and abstraction of medical 
records for infants undergoing hospitalization for a respiratory serious 
adverse event. 
o
To describe the efficacy of maternal immunization with the RSV F vaccine 
in reducing the incidence of RSV LRTI requiring hospitalization defined 
as per the second secondary objective but with the inclusion of data 
concerning documentation of RSV infection, LRTI symptoms and signs 
obtained from the observations of the clinical site staff OR review and 
abstraction of medical records for infants undergoing hospitalization for a 
respiratory serious adverse event. 
o
To describe the efficacy of maternal immunization with the RSV F vaccine 
in reducing the incidence in infants of RSV LRTI associated with EITHER 
hypoxemia (peripheral oxygen saturation [SpO2] < 95% at sea level or < 
92% at altitudes > 1800 meters) OR tachypnea (≥ 60 bpm for infants 0 to 
59 days of age or ≥ 50 bpm for infants ≥ 60 days of age [WHO Handbook, 
Integrated Management of Childhood Illness criteria for tachypnea]) with 
the inclusion of data concerning documentation of RSV infection, LRTI 
symptoms and signs, hypoxemia and/or tachypnea obtained from the 
observations of the clinical site staff OR review and abstraction of medical 

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records for infants undergoing hospitalization for a respiratory serious 
adverse event. 
o
To describe the efficacy of maternal immunization with the RSV F vaccine 
in reducing the incidence in infants with RSV LRTI resulting in death.  
Evidence of RSV infection and LRTI may be based on either or both of the 
observations of the clinical site staff using sponsor-supplied devices and 
diagnostic tests OR review and abstraction of medical records for infants 
undergoing hospitalization for a respiratory serious adverse event. 
o
To describe the efficacy of maternal immunization with the RSV F vaccine 
in reducing the incidence in infants of all RSV LRTI.
o
To describe the efficacy of maternal immunization with the RSV F vaccine 
in reducing the incidence of healthcare interventions associated with 
wheezing through the first year of life in infants of maternal RSV F 
vaccinees as compared to placebo recipients.

The following note has also been added 
“For all of the above exploratory analyses infants, if efficacy is 
shown through the first 90 days of life, a hierarchical sequence of 
hypothesis tests will be carried out to examine efficacy through 
120, 150, and 180 days of life.”
Rationale: The first three of these objectives mirror the primary and two secondary 
objectives, but allow for the inclusion of data derived from the adequately 
documented medical observations of non-study medical personnel, using pulse 
oximeters and/or diagnostic tests not supplied by the sponsor but in use within local 
clinics and/or hospitals.  While these do not have the standardization or validation 
of the protocol-mandated primary or secondary efficacy endpoint parameters, they 
allow for the inclusion of many observations concerning infants transported 
directly to hospital for the evaluation and treatment of medically-important 
respiratory illnesses, as well as infants first evaluated at the clinical sites, who then 
subsequently deteriorated and fulfilled the endpoint criteria while inaccessible to 
the investigators in hospitals or emergency departments.  This broader definition 
allows for capture of RSV LRTI cases which may have evaded direct observation 
by site personnel.
The fourth new exploratory objective has been added to capture medically-
significant RSV LRTI characterized by hypoxemia or a level of tachypnea 
approximately 10 breaths per minute lower than that used to define the primary 
endpoint.  This lower level of tachypnea is specified by the WHO Handbook for 
Integrated Management of Childhood Illness, and may represent illness of 
sufficient severity to trigger (potentially inappropriate) therapy and/or 
consideration of hospitalization; thus imposing a healthcare resources burden.
Three of these exploratory objectives have been shifted from the secondary 
objective list for the reasons listed above under Section 2.2.
Section 3.1, 
Synopsis 

The first paragraph of the study design description has been modified as 
follows:

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The total number of enrolled maternal subjects has been updated from 
approximately 8,618 to approximately 4,600. 
The following sentence has been added:
“Randomization will be configured to provide approximately 3,000 exposures 
to the active test article.” 
The following sentence has been deleted: 
“Although the trial is projected to enroll an estimated 8,618 third-trimester 
pregnant subjects, numbers may be smaller based on the operation of the 
group-sequential design (see details in Section 3.2), the incidence rate of the 
primary clinical endpoint events, and the efficacy of the intervention.”
Rationale: It has been determined to terminate the trial at a total enrollment of 
approximately 4,600 pregnant women because the accrual rate of primary 
endpoints renders a statistically robust conclusion concerning the primary endpoint 
likely, which is congruent with the provisions of Section 6.6. In addition, the 
enrolled number of approximately 4,600 pregnant women, in conjunction with the 
1:1 randomization in season one and 2:1 subsequently, is sufficient to yield ≥3,000 
pregnant women in the active treatment group, thereby providing a safety database 
sufficient to observe, with 95% confidence, at least one instance of a unique 
vaccine-related event. Because the protocol will no longer follow a group-
sequential design, mention of the operation of such a design is deleted.

Table 1 has been updated to provide approximate number of subjects in 
treatment groups, i.e., Group A ~ 1,562 (originally 2,930) and Group B ~ 3,038 
(originally 5,688). 
Rationale: Table 1 has been modified the approximate number of subjects to be 
included in the two treatment groups based on the new final enrollment target and 
the randomization scheme.

The last sentence “A Data and Safety Monitoring Board (DSMB) will 
supervise enrollment and monitoring of subject safety throughout the trial” has 
been extended to include the following: 
“A Data and Safety Monitoring Board (DSMB) will supervise enrollment 
and monitor subject safety throughout the trial (see Section 8.10).  In order 
to ensure that mothers and infants are not placed at risk with scant 
possibility of success, repeated futility analyses will be performed 
twice per year during the period of the study.  Due to the seasonal nature 
of RSV disease and the occurrence of RSV seasons in a roughly sequential 
manner across the Northern and Southern hemispheres, futility analyses, 
for detecting situations in which the existing efficacy data is not consistent 
with a predefined minimal clinical benefit, will occur at the approximate 
end of each Northern hemisphere season (data as of approximately 
30 May) and each global RSV season (data as of approximately 

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30 September, comprising a Northern hemisphere season and the 
following Southern hemisphere season); and subject to constraint (applied 
by the DSMB statistician) that at least 10 cases will have accrued in the 
active treatment arm. A determination of futility at any futility analysis, 
will lead to a DSMB recommendation to terminate the trial, and stop 
further enrollment. 
The primary analysis of the trial is an evaluation of the superior 
efficacy of the RSV F vaccine relative to the placebo in reducing the 
rate of medically-significant RSV LRTI in infants from delivery 
through the first 90 days of life. If successful outcomes are obtained 
through 90 days of life, then additional analyses for efficacy will be 
performed in a closed hierarchical sequence considering data from 
delivery through 120, 150, and 180 days of life (with each sequential 
analysis being enabled by a significant result at the preceding shorter 
interval).  Multiple secondary and exploratory efficacy analyses will 
also address other infant and maternal RSV disease outcomes.
All primary and secondary efficacy endpoints, as well as exploratory 
efficacy endpoints in infants concerning RSV-associated illness, will be 
reviewed and validated by an independent Clinical Endpoint 
Adjudication Committee (CEAC) prior to unblinding (see Section 
10.4.2).  Only endpoints validated by CEAC review will be used for the 
efficacy analyses. Section 10.4.3 provides details of the futility and 
efficacy analyses.”
Rationale: The above additions to the final paragraph of Section 3.1 replace 
closely similar or identical text in the prior Section 3.2 of protocol version 9.0, 
which described the operation of the group-sequential design and has now been 
deleted.  The added text describes the rationale for repeated futility analyses (which 
have occurred throughout the life of the trial), the timing of those analyses as driven 
by the seasonality of RSV disease, and the planned DSMB response to a 
determination of futility.  The section concludes with a general description of the 
primary efficacy analysis concerning medically-significant RSV LRTI from 
delivery through 90 days of life, followed by a closed hierarchical sequence of tests 
through 120, 150, and 180 days of life.  This description is unchanged from the 
prior Section 3.2.  In addition, reference is made to the introduction of a Clinical 
Endpoint Adjudication Committee (CEAC), a group of pediatricians who will 
examine the data content, and temporal sequencing of that content, of each primary, 
secondary, and infant RSV illness exploratory endpoint to ensure that these fulfill 
the relevant definitions in a clinically reasonable temporal sequence.
Section 3.2, 
Synopsis 

The section “Group Sequential Design Strategy” has been deleted in its 
entirety. 
Rationale: As a group-sequential design with multiple interim analyses is no 
longer planned, the prior Section 3.2 has been deleted in toto.  Information that 
remains relevant concerning the DSMB, futility analysis strategy, and overarching 
efficacy analysis plan are incorporated into Section 3.1 (see above).  Note that this 
change alters the subsection numbering within Section 3, with the description of 
endpoints (prior Section 3.3) now forming Section 3.2.

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Section 3.2.1, 
Synopsis 

The language to describe the primary efficacy endpoint has been clarified from 
“incidence of medically-significant RSV LRTI” to “Percentages of infants 
with medically-significant RSV LRTI through 90, 120, 150, and 180 days of 
life.”
Rationale:  The description of all efficacy endpoints has been amended to more 
specifically state that the endpoints are in fact Percentages of subjects with a given 
clinical disease state.  These counts will be used to calculate incidence rates and 
perform statistical contrasts.  This is a change for clarity and consistency only, it 
does not affect the execution of the trial or the efficacy analyses.

The following sentences have been deleted:
“The primary analysis will consider term infants (≥ 37 weeks of gestation 
at delivery) of mothers who received test article ≥ 2 weeks prior to delivery.  
Analyses at 120, 150, and 180 days of life will be performed dependent on 
successful outcomes at the prior, shorter intervals.”  
“Note that, where it appears as a component of secondary or exploratory 
endpoints, the term “RSV LRTI” will be defined by the first two major 
bullet points above, with the additional characteristic specified in that 
particular endpoint, e.g., hospitalization.”  
Rationale: The first sentence, specifying the primary analysis population, 
has been relocated to the primary objective description (Section 2.1).  The 
second sentence has been removed as unnecessary; all conditions required 
for any given endpoint are now described within the endpoint.  Neither of 
these changes affect the execution of the trial or the efficacy analyses.

The following sentences have been added: 
“Data elements supporting the three (3) criteria for a primary endpoint case 
will be present within the start and stop dates of a continuous illness 
episode and derived from clinical observations (LRTI signs and symptoms 
and respiratory rates) made by qualified clinical trial site staff, pulse 
oximetry performed by site personnel using a Masimo RAD-5 pulse 
oximeter supplied by the sponsor, and RSV detection based on study-
specified RT-PCR performed by the validated GenMark eSensor assay in 
place at the central laboratory (Marshfield Clinic Research Institute, 
Marshfield, Wisconsin).”
  
“A Clinical Endpoint Adjudication Committee (CEAC) composed of 
expert pediatricians (see Section 10.4.2) will carry out a blinded review of 
all potential primary endpoint cases to determine if they fulfill the primary 
endpoint criteria in a temporally plausible relationship consistent with RSV 
disease as observed in clinical practice.  Only CEAC-confirmed cases will 
be used for the primary endpoint.” 

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Rationale: The first sentence above specifies the exact source of the data 
supporting the primary endpoint events. This sentence is a clarification and 
represents no change in the execution or analysis of the trial. The second sentence 
indicates that the primary endpoint events will be subject to review and validation 
by an independent, blinded committee of pediatricians prior to inclusion in the 
primary efficacy analysis. This Clinical Endpoint Adjudication Committee has 
been added to ensure that temporally or clinically implausible events are not 
included in the analyses.
Section 3.2.2, 
Synopsis 

The two secondary efficacy endpoints have been modified as follows: 
Percentages of infants with RSV LRTI with EITHER severe hypoxemia 
(SpO2 < 92% at sea level or < 87% at altitudes > 1800 meters) OR the 
documented use of oxygen by high flow nasal cannula OR a requirement 
for continuous positive airway pressure (CPAP) OR bilevel positive airway 
pressure (BiPAP) OR Bubble CPAP OR bag-mask ventilation OR 
intubation with subsequent mechanical (or manual) ventilation OR 
extracorporeal membrane oxygenation (ECMO) from delivery through 90, 
120, 150 and 180 days of life. An event is considered RSV LRTI with 
severe hypoxemia if all parameters outlined below are present during a 
continuous symptomatic illness episode: 
o
RSV infection as confirmed by detection of the RSV genome by 
RT-PCR, AND
o
At least one manifestation of lower respiratory tract infection 
(LRTI) from among the following: cough, nasal flaring, lower 
chest wall indrawing, subcostal retractions, stridor, rales, rhonchi, 
wheezing, crackles/crepitations, or observed apnea, AND
o
Evidence of severe hypoxemia or the requirement for respiratory 
support as defined by the presence of:
-
EITHER severe hypoxemia (peripheral oxygen saturation 
[SpO2] < 92% at sea level or < 87% at altitudes > 1800 
meters) OR
-
The documented use of oxygen by high flow nasal cannula
OR continuous positive airway pressure (CPAP) OR bilevel 
positive airway pressure (BiPAP) OR Bubble CPAP OR bag-
mask ventilation OR intubation with subsequent mechanical 
(or manual) ventilation OR extracorporeal membrane 
oxygenation (ECMO).
-
and
Percentages of infants with RSV LRTI with hospitalization from delivery 
through 90, 120, 150, and 180 days of life. An event is considered RSV 
LRTI hospitalization if all parameters outlined below are present during a 
continuous symptomatic illness episode:

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o
RSV infection as confirmed by detection of the RSV genome by 
RT-PCR, AND
o
At least one manifestation of lower respiratory tract infection 
(LRTI) from among the following: cough, nasal flaring, lower 
chest wall indrawing, subcostal retractions, stridor, rales, rhonchi, 
wheezing, crackles/crepitations, or observed apnea, AND
o
Documented hospitalization.  

Rationale: The endpoints described correspond to the secondary 
objectives.  The description of the endpoints has been modified for clarity
to utilize the terminology of “Percentages” and include all of the elements 
necessary for each endpoint. The endpoint relating to severe hypoxemia 
has been modified to provide specific enumeration of methodologies used 
for respiratory support in infants that are more advanced than simple 
oxygen supplementation by standard flow-rate nasal cannula and imply 
greater compromise. The endpoint relating to hospitalization is unchanged 
in content.

The following sentences have been added:
“Data elements supporting the criteria for secondary endpoint cases will be 
present within the start and stop dates of a continuous illness episode and 
derived from clinical observations (LRTI signs and symptoms and 
respiratory rates) made by qualified clinical trial site staff, pulse oximetry 
performed by site personnel using a Masimo RAD-5 pulse oximeter 
supplied by the sponsor, and RSV detection based on study-specified RT-
PCR performed by the validated GenMark eSensor assay in place at the 
central laboratory (Marshfield Clinic Research Institute, Marshfield, 
Wisconsin). Evidence of hospitalization and/or in-hospital use of high-flow 
nasal cannula, CPAP, BiPAP, bubble PAP, intubation, or mechanical 
ventilation or ECMO will be supported by hospital records obtained by the 
clinical site staff.”
“A Clinical Endpoint Adjudication Committee (CEAC) composed of 
expert pediatricians (see Section 10.4.2) will carry out a blinded review of 
all potential secondary endpoint cases to determine if they fulfill the 
relevant endpoint criteria in a temporally plausible relationship consistent 
with RSV disease as observed in clinical practice.  Only CEAC-confirmed 
cases will be used for secondary endpoints.”
Rationale: As above for the primary endpoints, the first sentence above specifies 
the exact source of the data supporting the secondary endpoint events. This sentence 
is a clarification and represents no change in the execution or analysis of the trial.  
The second sentence indicates that the secondary endpoint events will be subject to 
review and validation by an independent, blinded committee of pediatricians prior 
to inclusion in the secondary efficacy analysis. This Clinical Endpoint Adjudication 
Committee has been added to ensure that temporally or clinically implausible 
events are not included in the analyses.

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
The following original secondary endpoints have been removed as secondary 
endpoints and placed under exploratory endpoints: 
“Incidence of RSV LRTI resulting in death in infants through 90 days of 
life,”
“Incidence of RSV LRTI (all severities) in infants through 90 days of life.
“Incidence of healthcare interventions associated with wheezing through 
the first year of life.”
Rationale: In parallel with changes in the secondary objectives, these three 
endpoints have been downgraded to exploratory endpoints.
Section 3.2.3

“seroconversion rate, SCR [maternal subjects only]” has been added to the first 
bullet of the immunogenicity endpoints.

It has been specified that micronuetralization titers “may be generated for a 
subset of the population”. The following sentence has been added: “An external 
laboratory, whose personnel are blinded to study treatment, will perform 
RSV/A and B MN testing during study conduct and after Day 180 unblinding.  
Final MN results, because of their time-consuming nature, may be provided as 
one or more sequential addenda to the main study report.”
 Rationale:  These changes correct the omission of the term “seroconversion rate” 
from prior versions (the analyses were planned and were represented as “2- and 4-
fold rises) and provide an expectation for the schedule of completion of 
microneutralization.
Section 3.2.4 

The language used to describe the safety endpoints has been changed from 
“counts and percentages” to “percentages” for all safety endpoints. 
Rationale:  To be more specific in describing how the safety endpoints will be 
described.
Section 3.2.5, 
Synopsis 

The following seven exploratory endpoints have been added: 
o
Percentages of infants with medically-significant RSV LRTI from delivery 
through 90, 120, 150 and 180 days of life defined as per the primary 
efficacy endpoint with the exception that evidence of RSV infection, LRTI, 
hypoxemia, and/or tachypnea may be based on either or both of the 
observations of the clinical site staff using sponsor-supplied devices and 
diagnostic tests OR review and abstraction of medical records for infants 
undergoing hospitalization for a respiratory serious adverse event. 
o
Percentages of infants with RSV LRTI with EITHER severe hypoxemia 
(SpO2 < 92% at sea level or < 87% at altitudes > 1800 meters) OR the 
documented use of oxygen by high flow nasal cannula OR continuous 
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(BiPAP) OR Bubble CPAP OR bag-mask ventilation OR intubation with 
subsequent mechanical (or manual) ventilation OR extracorporeal 
membrane oxygenation (ECMO) from delivery through 90, 120, 150, and 
180 days of life defined as per the corresponding secondary efficacy 
endpoint with the exception that evidence of RSV infection, LRTI, severe 
hypoxemia, and/or respiratory support may be based on either or both of 
the observations of the clinical site staff using sponsor-supplied devices 
and diagnostic tests OR review and abstraction of medical records for 
infants undergoing hospitalization for a respiratory serious adverse event. 
o
Percentages of infants with RSV LRTI requiring hospitalization from 
delivery through 90, 120, 150, and 180 days of life defined as per the 
corresponding secondary efficacy endpoint with the exception that 
evidence of RSV infection and LRTI may be based on either or both of the 
observations of the clinical site staff using sponsor-supplied devices and 
diagnostic tests OR review and abstraction of medical records for infants 
undergoing hospitalization for a respiratory serious adverse event. 
o
Percentages of infants with RSV LRTI associated with EITHER 
hypoxemia (peripheral oxygen saturation [SpO2] < 95% at sea level or 
< 92% at altitudes > 1800 meters) OR tachypnea (≥ 60 bpm for infants 0 
to 59 days of age or ≥ 50 bpm for infants ≥ 60 days of age [WHO 
Handbook, Integrated Management of Childhood Illness criteria for 
tachypnea]) from delivery through 90, 120, 150, and 180 days of life. Data 
concerning documentation of RSV infection, LRTI symptoms and signs, 
hypoxemia and/or tachypnea may be obtained from the observations of the 
clinical site staff OR review and abstraction of medical records for infants 
undergoing hospitalization for a respiratory serious adverse event. 
o
Percentages of infants with RSV LRTI resulting in death from delivery 
through 90, 120, 150, and 180 days of life. Evidence of RSV infection and 
LRTI may be based on either or both of the observations of the clinical site 
staff using sponsor-supplied devices and diagnostic tests OR review and 
abstraction of medical records for infants undergoing hospitalization for a 
respiratory serious adverse event. 
o
Percentages of infants with RSV LRTI (all severities) from delivery 
through 90, 120, 150, and 180 days of life.  Evidence of RSV infection and 
LRTI may be based on either or both of the observations of the clinical site 
staff using sponsor-supplied devices and diagnostic tests OR review and 
abstraction of medical records for infants undergoing hospitalization for a 
respiratory serious adverse event.
o
Counts and incidence rates of infant healthcare interventions associated 
with wheezing through the first year of life.
Rationale: In parallel with the first three new exploratory objectives, these changes 
to the exploratory endpoints mirror the primary and secondary endpoints, but allow 
for the inclusion of data derived from the adequately documented medical 
observations of non-study medical personnel, using pulse oximeters and/or 
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hospitals.  While these do not have the standardization or validation of the protocol-
mandated primary or secondary efficacy endpoint parameters, they allow for the 
inclusion of many observations concerning infants transported directly to hospital 
for the evaluation and treatment of medically-important respiratory illnesses, as 
well as infants first evaluated at the clinical sites, who then subsequently 
deteriorated and fulfilled the endpoint criteria while inaccessible to the 
investigators. This broader definition allows for capture of RSV LRTI cases which 
may have evaded direct observation by site personnel.
The fourth new exploratory endpoint parallels the fourth new exploratory efficacy 
objective and is intended to evaluate efficacy against RSV LRTI characterized by 
hypoxemia or tachypnea consistent with the WHO Handbook for Integrated 
Management of Childhood Illness.
The fifth, sixth, and seventh new exploratory endpoints represent three prior 
secondary endpoints moved to exploratory status in parallel with the related 
objectives. In addition, the fifth and sixth new exploratory endpoints permit the use 
of well-documented medical record data in the ascertainment of RSV LRTI.  
o
The following text has been added: 
“A Clinical Endpoint Adjudication Committee (CEAC) composed of 
expert pediatricians (see Section 10.4.2) will carry out a blinded review of 
all potential exploratory endpoint cases involving RSV LRTI in infants to 
determine if they fulfill the relevant endpoint criteria in a temporally 
plausible relationship consistent with RSV disease as observed in clinical 
practice. Only CEAC-confirmed cases will be used for exploratory 
endpoints.”
Rationale: This summary paragraph indicates the introduction of a committee of 
expert pediatricians to adjudicate all endpoint cases involving RSV disease in 
infant subjects to ensure that these endpoints fulfill the requisite criteria and are 
temporally and clinically plausible before their use in efficacy analyses.

The endpoint: “Percentages of maternal subjects with RSV-related respiratory 
illness as observed by the clinical study staff, and detected by active and 
passive surveillance from vaccination through six months after delivery, 
overall and by pathogen(s)”, has been modified by the additional of the text in 
bold. 
Rationale: To clarify the source of data for the referenced endpoint. 
Section 3.3 

The second sentence of Section 3.3 has been modified to delete mention of the 
group-sequential design as a determinant of study duration.
Rationale: As the trial will no longer be governed by a group-sequential design, 
this reference is now irrelevant. The estimated total duration remains 

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approximately four years, considering completed safety follow-up on the last infant 
born.
Section 3.5 

The first sentence of Section 3.5 has been modified to specify a total enrollment 
of approximately 4,600 women and their infants.
Rationale:  With the decision to terminate enrollment and delete the group-
sequential design, the final enrollment target of approximately 4,600 pregnant 
women can be specified; the additional specification of their infants is a 
clarification.
Section 7.2

The first sentence of this section has been modified to indicate that 
immunologic testing will be performed on subjects’ sera “at protocol-specified 
time-points.”  In addition, the following sentence has been added:
“Completion of microneutralization testing may be staged, due to its 
cumbersome nature, and results may be reported in addenda to the primary 
clinical study report.”  
Rationale:  Sera that are collected outside protocol-defined windows may not be 
contributory to the overall analysis of immunogenicity and may not undergo 
testing. Micronuetralization testing requires substantially greater time and 
technician/supervisor hours per assay than anti-F IgG or PCA ELISA, and may 
therefore impede progress to the initial report of study results.  Therefore, the option 
to complete microneutralization testing in a staged manner with reporting in 
addenda to the final study report is provided.
Section 8.6

The following sentence has been added to the end of the first paragraph. 
“Since there are multiple potential sources to determine the gestational age 
(GA) at birth, the study defined EDD and the birth date will be used to 
determine the GA at birth for the summary of the preterm birth categories 
(Very preterm and Moderate to late preterm).”
Rationale:  The sentence provides clarity on how the GA at birth will be 
determined. 
Section 8.10

The phrase “or for demonstration of efficacy” has been deleted. 

The sentence “the DSMB may elect, based on a vote of the members, to meet 
less frequently (e.g. quarterly), after the first year of the study” has been added.
Rationale:  The changes have been applied to provide clarity on the functioning of 
the data and safety monitoring board (DSMB). 
Section 10.1

A separate definition of the infant safety population has been added to 
distinguish it from the maternal safety population. The infant safety population 
(Safety-I) has been defined as all infants born live to maternal subjects who 
received any test article. 

“and post-partum, respectively” has been added to the intent-to-treat efficacy 
population definition. 

Phrases “post-treatment” and “and have no major protocol deviations affecting 
the primary efficacy outcomes as determined and documented by Novavax 

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prior to database lock and unblinding” have been added to the definition of the 
per-protocol efficacy population for maternal subjects.

Phrases “between birth and Day 180 after delivery” and “and e) have no major 
protocol deviations affecting the primary efficacy outcomes as determined and 
documented by Novavax prior to database lock and unblinding” have been 
added to the definition of the per-protocol population for infant subjects.
Rationale: These additions are intended to add clarity to the population definitions; 
they do not alter the underlying analysis plan.
Section 
10.4.1.2, 
Synopsis 

The definition of symptomatic RSV infection in maternal subjects has been 
modified with the addition of the text in bold. 
An acute, clinical study site-observed RSV infection, manifesting as one 
or more of cough, stuffy nose, runny nose, dyspnea, sore throat, fever, new 
or increasing wheezing, or new or increasing sputum production; with 
detection of RSV in respiratory secretions by RT-PCR.
Rationale: To clarify the source of data for the referenced endpoint.
Section 
10.4.1.1 

The definition of RSV LRTI with severe hypoxemia has been changed from 
“An RSV LRTI episode with a resting SpO2 < 92% at sea level or SpO2 < 87% 
at altitudes > 1800 meters by pulse oximetry on room air” to “An RSV LRTI 
episode with a resting SpO2 < 92% at sea level or SpO2 < 87% at altitudes 
> 1800 meters by pulse oximetry on room air OR the documented use of 
oxygen by high flow nasal cannula OR a requirement for continuous positive 
airway pressure (CPAP) OR bilevel positive airway pressure (BiPAP) OR 
Bubble CPAP OR bag-mask ventilation OR intubation with subsequent 
mechanical (or manual) ventilation OR extracorporeal membrane oxygenation 
(ECMO).”
Rationale: This altered definition reflects the specific enumeration of respiratory 
support modalities in the secondary and exploratory endpoints.
Section 10.4.2 

This section has been added to present information about the CEAC. The 
following text has been added: 
“A clinical endpoint adjudication committee (CEAC) comprising an odd 
number of three or more clinically-experienced voting pediatricians, a non-
voting chair who will oversee meetings of the CEAC, and a non-voting 
coordinator for administrative support will be empaneled to review all 
primary, secondary, and exploratory efficacy endpoints relative to infant 
subjects.  The operations of the CEAC will be carried out according to a 
charter which will be collaboratively drafted by the CEAC and the sponsor, 
and will be adopted prior to any review CEAC activities.  The CEAC will 
review each potential infant efficacy endpoint event to determine whether 
the protocol-specified criteria have been fulfilled in a plausible temporal 
relationship. All deliberations of the CEAC will be carried out in blinded 
manner with regard to treatment assignment and the determination of the 

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CEAC with regard to each endpoint event will be final and binding on the 
sponsor.”
Rationale: This paragraph describes the projected membership and operations of 
the Clinical Endpoint Adjudication Committee (CEAC) of expert pediatricians 
which has been empaneled to adjudicate all endpoint cases involving RSV disease 
in infant subjects. The goal of this is to ensure that these endpoints fulfill the 
requisite criteria and are temporally and clinically plausible before their use in 
efficacy analyses.
Section 10.4.3

The section has been updated to reflect aforementioned changes to the study 
objectives and endpoints and the decision to eliminate the group-sequential 
design strategy. The section has been updated to include the following new 
text: 
“The primary efficacy endpoint will be analyzed on the ITT-EFF-I and PP-
EFF-I (infant) Populations. Conclusions concerning stopping for futility, 
the informational analysis, or declaration of attainment of the primary 
efficacy endpoint at the completion of the study, will only be based on the 
PP-EFF-I Population. In addition, supportive analyses based on the ITT-
EFF-I Population will also be performed. 
The Vaccine Efficacy (VE) is defined as VE (%) = (1 – RR) x 100, where 
RR = Relative Risk of incidence rates between the two treatment groups 
(RSV F Vaccine / Placebo). The final analysis will be carried out at one-
sided Type I error rate of 0.0124 (i.e., the lower bound of 2-sided 97.52% 
confidence interval). An estimate of vaccine efficacy will be reported using 
a two-sided 95% confidence interval. This conservative Type I error rate 
was determined as a part of the original group sequential design (GSD) 
approach and will be retained to guard against a potential Type I error 
inflation resulting from the decision to stop the study at ~4,600 maternal 
subjects given this decision occurred after the informational analysis. Since 
this change was not part of the original study design at the initiation of the 
study, the agreement on how to implement the change with respect to Type 
I error rate was finalized in consultation with the US-FDA. 
For the original design using the GSD, a simulation of 5,000 trials was 
performed under a range of scenarios (including both varying placebo rates 
of medically-significant RSV LRTI and endpoint event ratios in infants of 
active vaccinees relative to placebo recipients). A summary of the 
simulation results is provided in the adaptive design report as Appedix 1 in 
the SAP. 
The RR and its CI will be estimated using Poisson regression with Robust 
error variance [Zou 2004]. The generalized linear model with unstructured 
correlation matrix (Robust error variances) will be used. The explanatory 
variables in the model will include the treatment group. The dependent 
variable will be the incidence rate of the endpoint of interest. The Robust 

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error variances will be estimated using repeated statement and the subject 
identifier. Poisson distribution will be used with a link function logarithm.  
Hypothesis testing of the primary efficacy endpoint will be carried out 
sequentially for H0: VE ≤0% and H0: VE < 30%. Rejection of the first null 
hypothesis, H0: VE ≤0% demonstrates a statistically significant vaccine 
effect. Rejection of the second null hypothesis, H0: VE < 30% at Type I 
error rate of 1-sided 0.0124 is required to meet the statistical success 
criterion pre-specified for the US-FDA. Should success be declared for the 
primary endpoint through 0 - 90 days of age, the hierarchical sequential 
analyses of 0 - 120, 0 - 150, and 0 - 180 days of age will be carried out 
using the Type I error rate of 1-sided 0.025 and the same null hypothesis. 
Two types of analyses concerning the primary efficacy endpoint will be 
performed prior to the final analysis: recurring futility analyses 
approximately twice per year after the Northern and Southern hemisphere 
winter virus season, and an informational analysis with approximately 1/3 
of projected subjects enrolled and followed through at least 90 days.   
For the futility analyses and the informational analysis, a Bayesian 
approach will be used and the analyses will be performed by the 
Independent Biostatistical Group (IBG) as originally designed.
The null hypothesis, H0: VE ≤0%, using the 1-sided Type I error rate (i.e., 
lower bound of 2-sided 95% CI) will be used for analyses of all secondary 
efficacy endpoints in infants. For each endpoint, in the event that efficacy 
is shown through the first 90 days of life, a hierarchical sequence of 
hypothesis tests will be carried out to examine efficacy through 120, 150, 
and 180 days of life.
Additional efficacy analyses may describe the incidence of symptoms used 
to define RSV LRTI. Percentages of infant subjects with any RSV-
confirmed 
respiratory 
illness 
accompanied 
with 
the 
following 
events/complaints will be presented by treatment group through six months 
postpartum: cough, nasal flaring, difficulty breathing, manifesting in any 
of the following clinical signs or symptoms as lower chest wall indrawing, 
subcostal retractions, abnormal breath sounds (inclusive of stridor, rales, 
rhonchi, wheezing, and crackles/crepitations), and/or observed apnea. 
Time to the first RSV-associated event referenced above will also be 
analyzed using Kaplan-Meier methods for each event category and by 
treatment group.”
Rationale: This text introduces the plan to eliminate the group-sequential design, 
convert the primary analysis to a frequentist approach, avoid Type 1 error inflation 
due to the decision to stop the study early at ~4600 maternal subjects, and 
summarizes the three different analytical uses of the primary efficacy data. The 
section then continues as originally worded to describe the Bayesian methods 
already used in the futility and informational analyses to date.

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Section 10.5

The phases “(2- and 4-fold seroconversion rates [SCR])” have been added to 
numbered items 1 and 2.
Rationale: To be consistence within the document. 
Section 10.6 

The phrase “Counts and percentages” for the assessment of safety endpoints 
has been replaced with “percentages” 
Rationale: To provide precision on how the safety endpoints will be described. 
Section 10.7 

The following text has been added:
“The relative risk (RR) and its 95% CI will be estimated using Poisson 
regression with robust error variance [Zou 2004]. A generalized linear 
model with unstructured correlation matrix (robust error variances) will be 
used. The explanatory variables in the model will include the treatment 
group. The dependent variable will be the incidence rate. The Robust error 
variances will be estimated using repeated statement and the subject 
identifier. Poisson distribution will be used with a link function logarithm.
The vaccine efficacy, and the corresponding two-sided 95% CI will be 
calculated. 
For each endpoint, in the event that efficacy is shown through the first 90 
days of life, a hierarchical sequence of hypothesis tests will be carried out 
to examine efficacy through 120, 150, and 180 days of life.”
Rationale: The original text has been modified and new text has been added to 
better describe the analyses regarding the updated proposed exploratory objectives 
of the study. 
Section 10.8 

The original text has been deleted entirely and replaced with the following:
“This study is designed to enroll approximately 4,600 total subjects that 
include a minimum of 3,000 RSV F vaccine recipients over 4 global RSV 
seasons.  
Assuming a medically-significant RSV LRTI incident rate of 4% in the 
placebo group and a vaccine efficacy of 65%, then the power of the design 
to claim success is 87%.  Table 3 summarizes the power for different 
placebo attack rates and vaccine efficacies. Power calculations were 
performed using the normal approximation (NCSS PASS 14). An 
estimated PP population size of 4,218 total evaluable infant subjects (2,786 
in the RSV F vaccine group and 1,432 in the placebo group to account for 
1:1 and 2:1 randomization ratios in Year 1 and the subsequent years, 
respectively) was used for all calculations.  
The target sample size of the safety and efficacy database in third trimester 
pregnancy that will be required for licensure is at least 3,000 actively-
immunized maternal subjects and their infants. Therefore, the final analysis 

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for efficacy will commence only after a total of 3,000 subjects have been 
enrolled in the active treatment arm. If no events of a given class are 
observed among the 3,000 subjects receiving the RSV F vaccine, an 
approximation to the one-sided upper 95% confidence bound on the rate of 
SAE occurrence would be 0.1%.”
Rationale: Because of the conversion from a Bayesian analysis of a group-
sequential design to a single final analysis based on frequentist methodology, the 
prior Bayesian simulation-based summary of operating characteristics for 
implementation of the group-sequential design have been replaced by a frequentist 
power calculation for a range of placebo attack rates consistent with the literature 
and a panel of potential vaccine efficacies and considering the single target 
enrollment and known randomization ratio.
Section 10.9 

It has been clarified that “interim” analyses refer to futility and informational 
analyses. 
Section 10.10.1 

The original text has been deleted entirely and replaced with the following: 
“The sequencing of RSV seasons in the Northern and Southern 
hemispheres lends a natural periodicity which will be reflected in the 
futility analyses.  Futility analyses will be conducted based on data 
available 30 May (for convenience called “Northern hemisphere,” 
although a small number of Southern hemisphere subjects may also meet 
the criteria for inclusion) and on approximately 30 September (for 
convenience called “Southern hemisphere” or “global season”); and 
subject to the constraint (applied by the DSMB statistician) that at least 10 
cases will have accrued in the active treatment arm. The DSMB will 
communicate to the Sponsor after each futility analysis its recommendation 
that the trial is either: a) futile and should be discontinued, or b) should 
continue enrollment.
When futility (with no requirement for further subject enrollment) has been 
declared, or when all live-born infants of all enrolled pregnant mothers 
have completed 180 days of follow-up after delivery, a final Day 180 
Unblinded Analysis of Efficacy, Immunogenicity, and Safety will be 
performed upon completion of the last infant D+180 visit and the last 
maternal postpartum Day 180 visit for all enrolled subjects. This unblinded 
analysis of efficacy, immunogenicity, and safety will include all available 
efficacy, immunogenicity and safety (inclusive of clinical assessments and 
concomitant medications) data through the infant D+180 visit and the 
maternal postpartum Day 180 visit. Treatment codes for this analysis will 
only be unblinded to the Sponsor statistician after all of these data are 
monitored, all applicable queries are resolved, and the database is locked. 
The data provided in this analysis will be considered final for the material 
contained therein, and will not change. In order to execute this unblinded 
analysis, a select group of study staff will be unblinded at Novavax. No 
individual unblinded at a subject treatment level will be involved in follow-
up safety monitoring. Specifically, personnel at the clinical study site 

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including, investigators and study staff, research site, and study subjects, 
will remain blinded to subject treatment assignments until the end of study 
for the last infant on post-delivery study D+364. 
In addition, an informational analysis of efficacy as specified in 
Section 10.10.2 may be performed when approximately 25 primary events, 
i.e. medically-significant RSV LRTI, though the first 90 days among the 
PP-EFF-I population, have accrued.  The success criterion is defined as the 
posterior probability that the event ratio is less than or equal to 1.00 (i.e. 
Vaccine Efficacy ≥0%) is greater than or equal to 0.90. This analysis will 
be performed by the DSMB biostatistician and the IBG in a manner entirely 
analogous to the analyses for efficacy and futility. The DSMB will 
communicate the results of the analysis to the Sponsor only in terms of 
fulfillment or non-fulfillment of the target criterion.  Novavax will remain 
blinded and the outcome will not result in any change in the conduct of the 
study or the primary efficacy objectives and endpoints. 
Results of the unblinded analysis of efficacy, immunogenicity, and safety
through Day 180 may be presented by the Sponsor, and may be submitted 
to the appropriate regulatory authorities as needed.  
Modifications or additions to the analyses described above will be included 
in the SAP. Any decisions to deviate from the planned analyses described 
in the protocol and in the statistical analysis plan will be described in detail 
in the final study report.”
Rationale:   In parallel with Sections 10.4.3 and 10.8, this text outlines the temporal 
sequence of futility analyses, the implementation of an informational analysis, and 
the plan to trigger a single final efficacy analysis when all live-born infants of 
enrolled mothers have completed Day+180 follow-up.
Section 10.10.3 

The following text has been deleted: 
“Modifications or additions to the analyses described above will be 
included in the SAP. Any decisions to deviate from the planned analyses 
described in the protocol and in the statistical analysis plan will be 
described in detail in the final study report.”
Rationale: To avoid redundancy. 
Section 12 

The following 3 references have been added: 
o
Hause AM, Avadhanula V, Maccato ML, et al.  A cross-sectional 
surveillance study of the frequency and etiology of acute respiratory illness 
among pregnant women.  J Infect Dis 2018; 218:528-35.
o
Madhi SA, Cutland CL, Downs S, et al.  Burden of respiratory syncytial 
virus infection in South African human immunodeficiency virus (HIV)-
infected and HIV-uninfected pregnant and postpartum women: a
longitudinal cohort study.  Clin Infect Dis 2018; 66(11):1658-65. 

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o
Zou G. A modified poisson regression approach to prospective studies with 
binary data. Am J Epidemiol. 2004; 159(7):702-6.
General
Minor changes have been made to improve the readability of the document.

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TABLE OF CONTENTS
PROTOCOL APPROVAL PAGE.......................................................................................... 2
PROTOCOL CHANGE HISTORY....................................................................................... 3
TABLE OF CONTENTS....................................................................................................... 24
LIST OF TABLES ................................................................................................................. 28
GLOSSARY OF ABBREVIATIONS................................................................................... 29
CLINICAL PROTOCOL SYNOPSIS ................................................................................. 33
1
INTRODUCTION ........................................................................................................ 68
1.1
Respiratory Syncytial Virus (RSV) Background ........................................................68
1.2
Summary of RSV Disease in Various Geographies....................................................68
1.2.1
High-resource Countries in the Northern and Southern Hemispheres................ 68
1.2.2
Argentina............................................................................................................. 69
1.2.3
South Africa ........................................................................................................ 69
1.2.4
India, Southern Asia, and the Philippines ........................................................... 70
1.3
Therapeutic and Prophylactic Agents Against RSV ...................................................70
1.4
Maternal Immunization...............................................................................................71
1.5
RSV F Vaccine............................................................................................................71
1.6
Safety and Immunogenicity of RSV F Vaccine in Animals and Humans ..................72
1.6.1
Nonclinical Experience ....................................................................................... 72
1.6.2
Clinical Experience ............................................................................................. 73
1.7
Study Rationale ...........................................................................................................76
1.8
Risk..............................................................................................................................77
2
STUDY OBJECTIVES ................................................................................................ 79
2.1
Primary Objective........................................................................................................79
2.2
Secondary Objectives..................................................................................................79
2.3
Exploratory Objectives................................................................................................80
3
STUDY DESIGN .......................................................................................................... 83
3.1
Design..........................................................................................................................83
3.2
Study Endpoints ..........................................................................................................85
3.2.1
Primary Efficacy Endpoint (In Infant Subjects).................................................. 85
3.2.2
Secondary Efficacy Endpoints (In Infant Subjects) ............................................ 85
3.2.3
Immunogenicity Endpoints (In Maternal and Infant Subjects as Stated)............ 86
3.2.4
Safety Endpoints.................................................................................................. 87
3.2.4.1
In All Infant Subjects................................................................................... 87
3.2.4.2
In Maternal Subjects .................................................................................... 88
3.2.5
Exploratory Endpoints (In Maternal and Infant Subjects as Stated)................... 88
3.3
Study Duration ............................................................................................................90

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3.4
Study Population .........................................................................................................90
3.5
Randomization Scheme...............................................................................................90
3.6
Randomization and Blinding Procedure......................................................................90
3.7
Procedure for Unblinding Individual Subject Treatment Assignments ......................91
4
TEST ARTICLES ........................................................................................................ 92
4.1
Overview of Product and Manufacturing Process for Clinical Trial Material............92
4.1.1
Production and Purification of RSV F Protein.................................................... 92
4.1.2
Aluminum Adjuvant............................................................................................ 92
4.1.3
Final Drug Product.............................................................................................. 93
4.1.4
Formulation Buffer Placebo................................................................................ 93
4.2
Investigational Product Packaging, Storage, and Handling ........................................93
4.3
Compliance and Drug Accountability.........................................................................93
5
SELECTION OF STUDY SUBJECTS ...................................................................... 94
5.1
Inclusion Criteria.........................................................................................................94
5.2
Exclusion Criteria........................................................................................................95
6
STUDY ASSESSMENTS AND PROCEDURES....................................................... 98
6.1
Study Visit Procedures................................................................................................98
6.1.1
Maternal Subject Study Visit Procedures............................................................ 98
6.1.1.1
Up to Two (2) Months Prior to Study Start – Pre-Screening....................... 98
6.1.1.2
Day -28 to 0 – Screening (up to four weeks before the planned day of 
vaccination).................................................................................................. 98
6.1.1.3
Day 0 – Vaccination (gestational week 28 to 360/7)................................... 100
6.1.1.4
Day 7 (+ 2 days) – In-clinic or Home Follow-up Visit ............................. 100
6.1.1.5
Day 14 (± 2 days) – In-clinic or Home Follow-up Visit ........................... 101
6.1.1.6
Day 28 (± 2 days) – Telephone/SMS Contact, In-clinic or Home Visit 
Safety Follow-up........................................................................................ 101
6.1.1.7
Delivery (D) – Hospital Follow-up Visit................................................... 102
6.1.1.8
D+35 (± 7 days) – In-clinic or Home Post-delivery Follow-up Visits ...... 102
6.1.1.9
D+180 (± 14 days) – In-clinic or Home Post-delivery Follow-up Visit.... 103
6.1.1.10
Unscheduled Visits .................................................................................... 103
6.1.2
Infant Subject Study Visit Procedures............................................................... 104
6.1.2.1
Visit 1: Delivery – Hospital Follow-up Visit............................................. 104
6.1.2.2
Visit 2: D+14 (± 3 days) – In-clinic or Home Follow-up Visit................. 104
6.1.2.3
Visit 3: D+35 (± 7 days) – In-clinic or Home Follow-up Visit................. 105
6.1.2.4
Visit 4: D+60 (± 7 days) – In-clinic or Home Follow-up Visit................. 106
6.1.2.5
Visit 5: D+90 (± 7 days) – In-clinic or Home Follow-up Visit................. 106
6.1.2.6
Visit 6: D+120 (± 7 days) – In-clinic or Home Follow-up Visit............... 106
6.1.2.7
Visit 7: D+180 (± 14 days) – In-clinic or Home Follow-up Visit............. 106

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6.1.2.8
Visit 8: D+252 (± 14 days) – In-clinic or Home Follow-up Visit............. 107
6.1.2.9
Visit 9: D+364 (±14 days) – In-clinic or Home Follow-up Visit.............. 107
6.1.2.10
Unscheduled Visits .................................................................................... 108
6.2
RSV Surveillance: Active and Passive......................................................................108
6.2.1
Active and Passive Components of Surveillance.............................................. 108
6.2.2
Trigger Symptoms for RSV-suspected Illness.................................................. 109
6.2.3
Clinical Study Site Response to Reports of Initial Trigger Symptoms............. 110
6.2.4
Follow-up of RSV-Suspect Illnesses................................................................. 111
6.2.5
Definitions and Rules for RSV Surveillance..................................................... 112
6.3
Concomitant Therapy................................................................................................113
6.4
Declining Study Treatments or Procedures...............................................................113
6.5
Premature Discontinuation from Study.....................................................................114
6.6
Study Termination.....................................................................................................114
7
LABORATORY REQUIREMENTS........................................................................ 115
7.1
Clinical Laboratory Testing.......................................................................................115
7.2
Assessments of Immunogenicity...............................................................................115
7.2.1
Anti-F IgG ELISA............................................................................................. 116
7.2.2
Palivizumab-Competitive Antibody (PCA) ELISA.......................................... 116
7.2.3
RSV/A and B Microneutralization (MN).......................................................... 116
7.3
Detection of RSV and Other Pathogens by RT-PCR................................................117
7.4
Retention and Use of Archived Specimens...............................................................117
8
ASSESSMENT OF SAFETY .................................................................................... 118
8.1
Adverse Events..........................................................................................................118
8.2
Maternal Adverse Events ..........................................................................................119
8.2.1
Solicited Adverse Events Collected by Subject Diary...................................... 119
8.2.2
Unsolicited Adverse Events .............................................................................. 120
8.2.3
Clinical Laboratory Findings as Adverse Events.............................................. 120
8.2.4
Vital Sign Abnormalities as Adverse Events .................................................... 121
8.3
Infant Subject Safety Assessments............................................................................121
8.3.1
Ages and Stages Questionnaire......................................................................... 121
8.4
Medically-Attended Events and Significant New Medical Conditions ....................122
8.5
Serious Adverse Events.............................................................................................123
8.6
Maternal/Fetal/Neonatal Adverse Events of Special Interest....................................123
8.7
Safety Reporting Requirements and Timelines for SAEs and Certain Other Events125
8.8
Severity......................................................................................................................126
8.8.1
Maternal Subjects.............................................................................................. 126
8.8.2
Infant Subjects................................................................................................... 128
8.9
Relationship (Causality)............................................................................................129

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8.10
Data and Safety Monitoring Board (DSMB) ............................................................130
9
DATA MANAGEMENT............................................................................................ 131
9.1
Recording and Collection of Data.............................................................................131
9.2
Data Quality Assurance.............................................................................................131
9.2.1
Monitoring......................................................................................................... 131
9.2.2
Audit and Inspection ......................................................................................... 132
9.3
Adherence to and Changes to the Protocol ...............................................................132
9.4
Retention of Records.................................................................................................132
10
STATISTICAL CONSIDERATIONS...................................................................... 133
10.1
Subject Populations...................................................................................................133
10.2
General ......................................................................................................................134
10.3
Demographics and Protocol Compliance..................................................................134
10.4
Efficacy Analyses......................................................................................................135
10.4.1
Study Definitions for Efficacy Determination .................................................. 135
10.4.1.1
Infant Subjects ........................................................................................... 135
10.4.1.2
Maternal Subjects ...................................................................................... 135
10.4.2
Clinical Endpoint Adjudication Committee (CEAC)........................................ 135
10.4.3
Analysis of Primary and Secondary Efficacy Endpoints .................................. 136
10.5
Immunogenicity Analyses.........................................................................................138
10.6
Safety Analyses.........................................................................................................139
10.7
Exploratory Analyses ................................................................................................140
10.8
Sample Size and Power .............................................................................................140
10.9
Interim (Futility and Informational) Analyses and Data and Safety Monitoring 
Board Responsibilities...............................................................................................142
10.9.1
Blinding and Interim Analyses.......................................................................... 142
10.9.2
Maintaining Sponsor Study Blind..................................................................... 142
10.9.3
Unblinded Personnel ......................................................................................... 142
10.10
Plan for Analyses and Reporting of Data..................................................................143
10.10.1 Unblinded Analysis of Efficacy, Immunogenicity, and Safety......................... 143
10.10.2 Informational Analysis...................................................................................... 144
10.10.3 Final Clinical Study Report (CSR).................................................................... 144
10.11
Computer Methods....................................................................................................144
11
LEGAL AND ETHICAL REQUIREMENTS ......................................................... 145
11.1
Compliance with Regulatory Requirements..............................................................145
11.2
Institutional Review Board/Independent Ethics Committee.....................................145
11.3
Informed Consent......................................................................................................145
11.4
Required Site Documentation ...................................................................................145
11.5
Subject Confidentiality..............................................................................................146

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11.6
Disclosure of Information .........................................................................................146
12
REFERENCES ........................................................................................................... 148
Appendix 1 – RSV-M-301 Study Procedures Schedule .................................................... 154
Appendix 2 – RSV-M-301 Draft Subject Diary (for Maternal Subjects Only) .............. 158
Appendix 3 – RSV-M-301 Blood Draw Schedule (for Maternal and Infant Subjects).. 159
Appendix 4 – RSV-M-301 Subject Measurement Tool..................................................... 160
Appendix 5 – RSV-M-301 Protocol Change History ........................................................ 161
LIST OF TABLES
Table 1:
Treatment Assignments......................................................................................... 83
Table 2:
Signs and (Trigger) Symptoms of RSV-suspected Illness in Infant and 
Maternal Subjects................................................................................................ 109
Table 3:
Clinical Signs/Symptoms to be Clinically Evaluated during an RSV-suspected 
Illness .................................................................................................................. 111
Table 4:
Listing of Diary Solicited Events........................................................................ 119
Table 5:
Maternal/Fetal/Neonatal Adverse Events of Special Interest ............................. 124
Table 6:
Severity Grade Definitions for Adverse Events, Maternal Subjects................... 127
Table 7:
Severity Grade Definitions for Solicited Gastrointestinal Adverse Events, 
Fever, and Fetal Heart Tones, Maternal Subjects ............................................... 128
Table 8:
Severity Grade Definitions for Adverse Events Occurring in Infant Subjects ... 128
Table 9:
Definition of Relationship for Adverse Events................................................... 129
Table 10:
Power Calculations for the Primary Efficacy Endpoint (Medically-Significant 
RSV LRTI Through 90 Days)............................................................................. 141

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GLOSSARY OF ABBREVIATIONS
Abbreviation or Term
Definition
AD
After Delivery
AE
Adverse Event
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase 
ANMAT
Administración Nacional de Medicamentos, Alimentos y 
Tecnología Médica
APGAR
Appearance, Pulse, Grimace, Activity, Respiration
ASQ 
Ages and Stages Questionnaire  
AST
Aspartate Aminotransferase 
BiPAP
Bilevel Positive Airway Pressure 
BMI
Body Mass Index
bpm
Breaths per Minute 
BUN
Blood Urea Nitrogen
C
Celsius or Caesarean
CBC
Complete Blood Count
CBER
Center for Biologics Evaluation and Research
CD
Compact Disc
CEAC
Clinical Endpoint Adjudication Committee 
CI
Confidence Interval
CPAP
Continuous Positive Airway Pressure 
CPE
Cytopathic Effect
CQA
Clinical Quality Assurance
CRO
Contract Research Organization
CSR
Clinical Study Report
CVS
Chorionic Villus Sampling
DSMB
Data and Safety Monitoring Board
EC
Exclusion Criterion
ECMO
Extracorporeal Membrane Oxygenation 
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
EDD
Estimated Date of Delivery
EDD-E
Estimated Date of the Earliest Delivery
EDD-L
Estimated Date of the Latest Delivery

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Abbreviation or Term
Definition
ELISA
Enzyme-linked Immunosorbent Assay
EU
ELISA Unit
FDA
Food and Drug Administration
FI-RSV
Formalin Inactivated-Respiratory Syncytial Virus
FOC
Frontal Occipital Head Circumference
GA
Gestational Age 
GBS
Group B Streptococcus
GCP
Good Clinical Practice
GLP
Good Laboratory Practice
GMC
Geometric Mean Concentration
GMEU
Geometric Mean ELISA Unit
GMFR
Geometric Mean Fold-rise
GMR
Geometric Mean Ratio
GMT
Geometric Mean Titer
GP
General Practitioner 
GSD
Group Sequential Design 
HBV
Hepatitis B Virus
HCV
Hepatitis C Virus
HIV
Human Immunodeficiency Virus
HSV
Herpes Simplex Virus
IB
Investigator’s Brochure
IBG
Independent Biostatistical Group
IC
Inclusion Criterion
ICF
Informed Consent Form
ICH 
International Conference on Harmonization
IEC
Independent Ethics Committee
IgG
Immunoglobulin G
IM
Intramuscular
IRB
Institutional Review Board
ISP
Instituto de Salud Pública de Chile
ITT
Intent-to-treat
IVF
In vitro Fertilization
IWRS
Interactive Web Randomization System
kg
Kilogram

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Abbreviation or Term
Definition
L
Liter
LMP
Last Menstrual Period
LRTI
Lower Respiratory Tract Infection
M
Molar Concentration
MAE
Medically-attended Event
MCC
Medicines Control Council 
MedDRA
Medical Dictionary for Regulatory Activities 
MEDSAFE
Medicines and Medical Devices Safety Authority 
MFNAESI
Maternal/Fetal/Neonatal Adverse Event of Special Interest 
μg
Microgram
μM
Micromolar
mg
Milligram
mL
Milliliter
mM
Millimolar
MN
Microneutralization; an assay
MS
Maternal Serum
NaCl
Sodium Chloride
ng
Nanogram
NOAEL
No-Observed-Adverse-Effect-Level
OD
Optical Density
PCA
Palivizumab-Competitive Antibody
PCP
Primary Care Physician 
PP
Per Protocol
PPS
Predictive Probability of Success
PT
Preferred Term
RBC
Red Blood Cell
RR
Relative Risk
RSV
Respiratory Syncytial Virus
RT-PCR
Reverse Transcriptase Polymerase Chain Reaction
SAE
Serious Adverse Event
SCR
Seroconversion Rate
SD
Standard Deviation
Sf9
Spodoptera frugiperda — Insect Cells
SMS
Short Message Service (i.e., text messaging)

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Abbreviation or Term
Definition
SNMC
Significant New Medical Condition
SOC
System Organ Class
SpO2
Peripheral Oxygen Saturation
SRR
Seroresponse Rate
Tdap
Tetanus, Diphtheria, Acellular Pertussis; a vaccine
TGA
Therapeutic Goods Administration 
TGS
Toxicity Grading Scale
Th2
T Helper Cell Type 2
TIV
Trivalent Influenza Vaccine
TMB
3, 3’5, 5-tetramethyl-benzidine
TMF
Trial Master File
US
United States
WBC
White Blood Cell 
WHO
World Health Organization
yo
Years of Age

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CLINICAL PROTOCOL SYNOPSIS 
NAME OF COMPANY
Novavax, Inc.
INDIVIDUAL 
STUDY TABLE 
SYNOPSIS
(FOR NATIONAL AUTHORITY 
USE ONLY)
NAME OF ACTIVE 
INGREDIENT
RSV Recombinant F Nanoparticle 
Vaccine
Protocol Number:  RSV-M-301
Protocol Title: A Phase 3, Randomized, Observer-Blind, Placebo-Controlled, Group-Sequential
Study to Determine the Immunogenicity and Safety of a Respiratory Syncytial Virus (RSV) F 
Nanoparticle Vaccine with Aluminum in Healthy Third-trimester Pregnant Women; and Safety and 
Efficacy of Maternally Transferred Antibodies in Preventing RSV Disease in their Infants
Clinical Development Program: Maternal Immunization for Prevention of RSV Lower Respiratory 
Tract Infection (LRTI) in Infants
Sponsor: Novavax, Inc., 20 Firstfield Road, Gaithersburg MD 20878 USA
Investigational Material: RSV Recombinant F Nanoparticle Vaccine (Spodoptera frugiperda [Sf9] 
cells with recombinant Baculovirus expression) with aluminum 
Reference Material: Formulation buffer (placebo) 
Regimen and Dosing:  Maternal subjects will receive a single 0.5 mL intramuscular (IM) injection 
with the assigned test article, either a 120 µg dose of RSV F protein adsorbed to a 0.4 mg dose of 
aluminum as the phosphate salt (herein referred to as RSV F vaccine) or placebo, on Study Day 0.
Phase of Development:  Phase 3
Rationale:  
The goal of this clinical development program is to establish efficacy of the RSV F vaccine in 
providing protection against RSV disease in infants during the first three to six months of life via 
active immunization of pregnant women in the third trimester of pregnancy. Passive immunization of 
infants will be achieved through transplacental transfer of maternal IgG antibodies from the pregnant 
mother who has received the RSV F vaccine in the third trimester of her pregnancy. Maternally-
derived, transplacentally-mediated immunity is a physiologic, effective, and established means for 
protecting infants against infectious diseases during the first months of life. Active Fc-gamma 
receptor-mediated transport of maternal IgG begins early in gestation, but reaches significant levels 
at 28 weeks gestational age [Palmeira 2012].  By ≥ 36 weeks gestational age, antibody levels in the 
fetus are generally in excess of levels found in the mother [Lindsey 2013]. Maternal immunization 
programs addressing tetanus, pertussis, and influenza have all shown benefits to infants. Albeit less 
well-recognized than influenza, anecdotal observations suggest that significant RSV disease may also 
occur in pregnant women themselves, and thus an additional benefit to the mother may also be 
obtained by immunization with an RSV vaccine [Wheeler 2015]. Two recent reports of prospective 
studies have confirmed the existence of a symptomatic RSV disease burden in mothers [Hause 2018, 
Madhi 2018].
For this global clinical trial of the RSV F vaccine in pregnant women, a 120 μg dose of RSV F protein 
with 0.4 mg aluminum as the phosphate salt, administered as a single injection, was selected based on 
a previous study of women of child-bearing age, where this formulation and regimen were well-
tolerated and produced the highest peak anti-F antibody responses at 14 days post-vaccination when 

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evaluated against other vaccine formulations and regimens. This rapid response reflects the fact that 
all adults are immunologically primed to RSV. The RSV F vaccine in general has been shown to elicit 
high levels of antibodies to the neutralizing RSV F protein antigenic site II epitope, based on 
competition with the globally-licensed, proven-efficacious monoclonal antibody palivizumab, as well 
as assays of direct binding of immunoglobulin G (IgG) to the antigenic site II linear peptide 
encompassing amino acid residues 254-278. Levels of these antibodies may exceed the trough levels 
of palivizumab associated with clinical protection of infants by 10-fold.  This in turn, suggests that 
with active placental transfer and possible concentration of these antibodies, infant protection 
extending through at least 3 to 6 months of life might be feasible.
Data from the first-in-pregnant women study (RSV-M-203, N=50) with the RSV F vaccine conducted 
in the United States (US) showed the vaccine was well-tolerated, posing no significant safety risk to 
pregnant women or their infants that was apparent in this limited dataset; and was immunogenic, 
eliciting antibody responses that were analogous in kinetics and magnitude to levels observed in non-
pregnant women of childbearing age. Results indicated the antibody profile achieved with a single 
dose of the RSV F vaccine in pregnant subjects immunized at 33 to 35 weeks gestation was robust, 
with substantial responses measurable by 14 days post-vaccination; and diverse, eliciting antibodies 
with binding activity to the antigenic sites I and IV neutralizing epitopes on the F protein in addition 
to antigenic site II. Transplacental transfer of maternal antibodies with specificity to the RSV F protein 
in delivered infants averaged 90 to 100% of the actively-treated matched mother, but averaged 110 to 
120% when immunization preceded delivery by ≥ 30 days. This supports immunization of pregnant 
women between 28 to 36 weeks gestation in this study, as widening the window for vaccination to 
include women at the beginning of the third trimester is not expected to result in increased safety risk 
to the woman or fetus [Madhi 2014, Munoz 2014], and may increase the potential for higher vaccine-
specific antibody titers in the delivered infant due to extended transplacental transfer [Abu Raya 2014, 
Eberhardt 2016, Naidu 2016].
The objectives of the Phase 2 trial were to establish an initial maternal safety database in pregnancy, 
assess the amplitude of transplacental transfer of vaccine-induced antibodies in humans, estimate the 
decay half-life of such antibodies in infants, and detect any signal suggestive of “vaccine-enhanced 
disease” in infants over their first RSV transmission season. Please refer to the Investigator’s Brochure 
(IB) for current updates and new findings pertaining to the RSV F vaccine. 
Study Definitions:
Infant Subjects
RSV LRTI:
Confirmed RSV LRTI will feature detection of RSV in respiratory 
secretions by RT-PCR and at least one of the following clinical 
manifestations observed and documented by appropriately-trained study 
staff: cough, nasal flaring, lower chest wall indrawing, subcostal 
retractions, abnormal breath sounds (inclusive of stridor, rales, rhonchi, 
wheezing, and crackles/crepitations); and/or observed apnea.
Medically-
significant RSV 
LRTI:
An RSV LRTI episode with EITHER a resting SpO2 < 95% at sea level or 
< 92% at altitudes > 1800 meters by pulse oximetry on room air OR 
tachypnea defined as ≥70 bpm in an infant 0 to 59 days of age, or ≥60 
bpm in an infant ≥60 days of age.
RSV LRTI with 
Severe Hypoxemia:
An RSV LRTI episode with a resting SpO2 < 92% at sea level or SpO2
< 87% at altitudes > 1800 meters by pulse oximetry on room air OR 
documented use of oxygen by high flow nasal cannula OR a requirement 
for continuous positive airway pressure (CPAP) OR bilevel positive 
airway pressure (BiPAP) OR Bubble CPAP OR bag-mask ventilation OR 

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intubation with subsequent mechanical (or manual) ventilation OR 
extracorporeal membrane oxygenation (ECMO).
Correlate of Risk:
An immune marker statistically correlated with risk, either absolute or 
relative to a control population, of meeting an RSV infection clinical 
endpoint.
Maternal Subjects
Symptomatic RSV 
Infection:
An acute, clinical study site-observed, RSV infection manifesting as one 
or more of cough, stuffy nose, runny nose, dyspnea, sore throat, fever, new 
or increasing wheezing, or  new or increasing sputum production; with 
detection of RSV in respiratory secretions by RT-PCR.
Study Objectives:
Primary:
The primary objective of this study is: 

To determine the efficacy of maternal immunization with the RSV F vaccine against 
medically-significant RSV lower respiratory tract infection (LRTI) with EITHER hypoxemia 
(peripheral oxygen saturation [SpO2] < 95% at sea level or < 92% at altitudes > 1800 meters) 
OR tachypnea (≥ 70 bpm for infants 0 to 59 days of age or ≥ 60 bpm for infants ≥ 60 days of 
age) through the first 90 days of life in infants of maternal RSV F vaccinees as compared to 
placebo recipients. In the event that efficacy is shown through the first 90 days of life, a 
hierarchical sequence of hypothesis tests will be carried out to examine efficacy through the 
first 120, 150, and 180 days of life.
The primary efficacy objective will be evaluated in term infants (≥ 37 weeks gestational age at 
delivery) born to maternal subjects who received a study injection ≥ 2 weeks (14 days) prior to 
delivery. Infants with multiple RSV episodes will be counted only once, using data from the first 
episode of medically-significant RSV LRTI.  Success under the primary hypothesis will be achieved 
by demonstration of a lower bound of a two-sided 97.52% confidence interval for the Day 90 analysis 
(lower bound of a 95% confidence interval for later time points) for the estimate of vaccine efficacy 
which equals or exceeds target values agreed with regulatory authorities.
Secondary: 
The secondary objectives of this study are: 

To determine the efficacy of maternal immunization with the RSV F vaccine in reducing the 
incidence in infants of:
o
RSV LRTI with EITHER severe hypoxemia (SpO2 < 92% at sea level or < 87% at 
altitudes > 1800 meters) OR documented use of oxygen by high flow nasal cannula OR a 
requirement for continuous positive airway pressure (CPAP) OR bilevel positive airway 
pressure (BiPAP) OR Bubble CPAP OR bag-mask ventilation OR intubation with 
subsequent mechanical
(or manual) ventilation OR extracorporeal membrane 
oxygenation (ECMO), through the first 90 days of life in infants of maternal RSV F 
vaccinees as compared to placebo recipients. In the event that efficacy is shown through 
the first 90 days of life, a hierarchical sequence of hypothesis tests will be carried out to 
examine efficacy through 120, 150, and 180 days of life.
o
RSV LRTI leading to hospitalization through the first 90 days of life in infants of maternal 
RSV F vaccinees as compared to placebo recipients. In the event that efficacy is shown 

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through the first 90 days of life, a hierarchical sequence of hypothesis tests will be carried 
out to examine efficacy through 120, 150, and 180 days of life.
The two secondary efficacy objectives will be evaluated in term infants (≥ 37 weeks gestational age 
at delivery) born to maternal subjects who received a study injection ≥ 2 weeks (14 days) prior to 
delivery. Infants with multiple RSV episodes meeting a given criterion will be counted only once, 
using data from the first episode. Success under the secondary efficacy hypotheses will be achieved 
by demonstration of a lower bound of a two-sided 95% confidence interval for the estimate of vaccine 
efficacy which exceeds 0%.

To describe the immunologic responses to the RSV F vaccine in healthy maternal subjects, in 
the third trimester of pregnancies deemed to be at low risk of obstetrical complications, 
through delivery and six months thereafter.

To describe the transplacental transfer of maternal antibodies specific for RSV and its 
F protein based on the ratio of levels in maternal and cord blood at delivery.  

To estimate the rate of decay of RSV and F protein-specific antibodies in infants through the 
first six months of life. 

To develop an immune correlate of risk of the RSV LRTI syndromes in infants based on anti-
F protein antibody and/or palivizumab-competitive antibody levels measured in the infant 
and/or cord blood. 

To develop an immune correlate of risk of the RSV LRTI syndromes in infants based on anti-
F protein antibody and/or palivizumab-competitive antibody levels measured in maternal 
subjects at delivery. 

To describe the safety of third-trimester maternal immunization with the RSV F vaccine in 
infants of vaccinated maternal subjects through their first year of life, which will include at 
least one RSV season.

To describe the safety of the RSV F vaccine in healthy maternal subjects, in the third trimester 
of pregnancies deemed to be at low risk of obstetrical complications, through delivery and six 
months thereafter. 
Exploratory:
The exploratory objectives of this study are: 

To describe the efficacy of maternal immunization with the RSV F vaccine in reducing the 
incidence in infants of medically-significant RSV LRTI defined as per the primary 
objective but with the inclusion of data concerning documentation of RSV infection, LRTI 
symptoms and signs, hypoxemia and/or tachypnea obtained from the observations of the 
clinical site staff OR review and abstraction of medical records for infants undergoing 
hospitalization for a respiratory serious adverse event. 

To describe the efficacy of maternal immunization with the RSV F vaccine in reducing the 
incidence of RSV LRTI with EITHER severe hypoxemia (SpO2 < 92% at sea level or < 87% 
at altitudes > 1800 meters) OR the documented use of oxygen by high flow nasal cannula OR
continuous positive airway pressure (CPAP) OR bilevel positive airway pressure (BiPAP) OR 
Bubble CPAP OR bag-mask ventilation OR intubation with subsequent mechanical (or 
manual) ventilation OR extracorporeal membrane oxygenation (ECMO) defined as per the 
first secondary objective but with the inclusion of data concerning documentation of RSV 
infection, LRTI symptoms and signs, and hypoxemia obtained from the observations of the 
clinical site staff OR review and abstraction of medical records for infants undergoing 
hospitalization for a respiratory serious adverse event. 

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
To describe the efficacy of maternal immunization with the RSV F vaccine in reducing the 
incidence of RSV LRTI requiring hospitalization defined as per the second secondary 
objective but with the inclusion of data concerning documentation of RSV infection, LRTI 
symptoms and signs obtained from the observations of the clinical site staff OR review and 
abstraction of medical records for infants undergoing hospitalization for a respiratory serious 
adverse event. 

To describe the efficacy of maternal immunization with the RSV F vaccine in reducing the 
incidence in infants of RSV LRTI associated with EITHER hypoxemia (peripheral oxygen 
saturation [SpO2] < 95% at sea level or < 92% at altitudes > 1800 meters) OR tachypnea (≥ 
60 bpm for infants 0 to 59 days of age or ≥ 50 bpm for infants ≥ 60 days of age [WHO 
Handbook, Integrated Management of Childhood Illness criteria for tachypnea]) with the 
inclusion of data concerning documentation of RSV infection, LRTI symptoms and signs, 
hypoxemia and/or tachypnea obtained from the observations of the clinical site staff OR 
review and abstraction of medical records for infants undergoing hospitalization for a 
respiratory serious adverse event. 

To describe the efficacy of maternal immunization with the RSV F vaccine in reducing the 
incidence in infants with RSV LRTI resulting in death.  Evidence of RSV infection and LRTI 
may be based on either or both of the observations of the clinical site staff using sponsor-
supplied devices and diagnostic tests OR review and abstraction of medical records for infants 
undergoing hospitalization for a respiratory serious adverse event. 

To describe the efficacy of maternal immunization with the RSV F vaccine in reducing the 
incidence in infants of all RSV LRTI.
For all of the above exploratory analyses infants, if efficacy is shown through the first 90 days of life,
a hierarchical sequence of hypothesis tests will be carried out to examine efficacy through 120, 150, 
and 180 days of life.

To describe the efficacy of maternal immunization with the RSV F vaccine in reducing the 
incidence of healthcare interventions associated with wheezing through the first year of life 
in infants of maternal RSV F vaccinees as compared to placebo recipients.

To describe the efficacy of maternal immunization with the RSV F vaccine in reducing the 
incidence of all symptomatic RSV respiratory tract infections detected by active/passive 
surveillance in maternal subjects from immunization through six months after delivery.

To describe the incidence of all-cause LRTI, with and without tachypnea, hypoxemia, or 
severe hypoxemia, in infant subjects as detected by active and passive surveillance from 
vaccination through six months after delivery, and the efficacy of maternal immunization with 
the RSV F vaccine in reducing the incidence of these endpoints. 

To describe the epidemiology of non-RSV respiratory viruses detected by RT-PCR in infant 
and maternal subjects presenting with respiratory symptoms, through six months after 
delivery.

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Study Endpoints:
Primary Efficacy Endpoint (In Infant Subjects):

Percentages of infants with medically-significant RSV LRTI from delivery through 90, 120, 
150, and 180 days of life, as defined by: 
o
The presence of RSV infection confirmed by detection of RSV genome by RT-PCR 
on respiratory secretions (obtained within the continuous illness episode which 
fulfills the other criteria listed below); AND
o
At least one manifestation of lower respiratory tract infection (LRTI) from among the 
following: cough, nasal flaring, lower chest wall indrawing, subcostal retractions, 
stridor, rales, rhonchi, wheezing, crackles/crepitations, or observed apnea; AND
o
Evidence of medical significance as defined by the presence of:
-
EITHER hypoxemia (peripheral oxygen saturation [SpO2] < 95% at sea level 
or < 92% at altitudes > 1800 meters) OR 
-
Tachypnea (≥ 70 breaths per minute [bpm] in infants 0 to 59 days of age and 
≥60 bpm in infants ≥60 days of age). 
Data elements supporting the three (3) criteria for a primary endpoint case will be present within the 
start and stop dates of a continuous illness episode and derived from clinical observations (LRTI signs 
and symptoms and respiratory rates) made by qualified clinical trial site staff, pulse oximetry 
performed by site personnel using a Masimo RAD-5 pulse oximeter supplied by the sponsor, and RSV 
detection based on study-specified RT-PCR performed by the validated GenMark eSensor assay in 
place at the central laboratory (Marshfield Clinic Research Institute, Marshfield, Wisconsin).  
A Clinical Endpoint Adjudication Committee (CEAC) composed of expert pediatricians (see 
Section 10.4.2) will carry out a blinded review of all potential primary endpoint cases to determine if 
they fulfill the primary endpoint criteria in a temporally plausible relationship consistent with RSV 
disease as observed in clinical practice.  Only CEAC-confirmed cases will be used for the primary 
endpoint. 
Secondary Efficacy Endpoints (In Infant Subjects):

Percentages of infants with RSV LRTI with EITHER severe hypoxemia (SpO2 < 92% at sea 
level or < 87% at altitudes > 1800 meters) OR the documented use of oxygen by high flow 
nasal cannula OR a requirement for continuous positive airway pressure (CPAP) OR bilevel 
positive airway pressure (BiPAP) OR Bubble CPAP OR bag-mask ventilation OR intubation 
with subsequent mechanical (or manual) ventilation OR extracorporeal membrane 
oxygenation (ECMO) from delivery through 90, 120, 150, and 180 days of life. An event is 
considered RSV LRTI with severe hypoxemia if all parameters outlined below are present 
during a continuous symptomatic illness episode:
o
RSV infection as confirmed by detection of the RSV genome by RT-PCR, AND
o
At least one manifestation of lower respiratory tract infection (LRTI) from among the 
following: cough, nasal flaring, lower chest wall indrawing, subcostal retractions, 
stridor, rales, rhonchi, wheezing, crackles/crepitations, or observed apnea, AND
o
Evidence of severe hypoxemia or the requirement for respiratory support as defined 
by the presence of:
-
EITHER severe hypoxemia (peripheral oxygen saturation [SpO2] < 92% at sea 
level or < 87% at altitudes > 1800 meters) OR

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-
The documented use of oxygen by high flow nasal cannula OR continuous 
positive airway pressure (CPAP) OR bilevel positive airway pressure (BiPAP) 
OR Bubble CPAP OR bag-mask ventilation OR intubation with subsequent 
mechanical (or manual) ventilation OR extracorporeal membrane oxygenation 
(ECMO).

Percentages of infants with RSV LRTI with hospitalization from delivery through 90, 120, 
150, and 180 days of life. An event is considered RSV LRTI hospitalization if all parameters 
outlined below are present during a continuous symptomatic illness episode:
o
RSV infection as confirmed by detection of the RSV genome by RT-PCR, AND
o
At least one manifestation of lower respiratory tract infection (LRTI) from among the 
following: cough, nasal flaring, lower chest wall indrawing, subcostal retractions, 
stridor, rales, rhonchi, wheezing, crackles/crepitations, or observed apnea, AND
o
Documented hospitalization.  
Data elements supporting the criteria for secondary endpoint cases will be present within the start and 
stop dates of a continuous illness episode and derived from clinical observations (LRTI signs and 
symptoms and respiratory rates) made by qualified clinical trial site staff, pulse oximetry performed 
by site personnel using a Masimo RAD-5 pulse oximeter supplied by the sponsor, and RSV detection 
based on study-specified RT-PCR performed by the validated GenMark eSensor assay in place at the 
central laboratory (Marshfield Clinic Research Institute, Marshfield, Wisconsin). Evidence of 
hospitalization and/or in-hospital use of high-flow nasal cannula, CPAP, BiPAP, bubble CPAP, 
intubation, or mechanical/manual ventilation or ECMO will be supported by hospital records obtained 
by the clinical site staff.
A Clinical Endpoint Adjudication Committee (CEAC) composed of expert pediatricians (see 
Section 10.4.2) will carry out a blinded review of all potential secondary endpoint cases to determine 
if they fulfill the relevant endpoint criteria in a temporally plausible relationship consistent with RSV 
disease as observed in clinical practice.  Only CEAC-confirmed cases will be used for secondary 
endpoints.
Immunogenicity Endpoints (In Maternal and Infant Subjects as Stated):

Serum immunoglobulin G (IgG) antibody concentrations specific for the F protein antigen 
measured by enzyme-linked immunosorbent assay (ELISA) and serum concentrations of 
antibodies competitive with palivizumab for binding to the RSV F protein.  
Derived/calculated endpoints based on these data will include geometric mean concentrations 
as ELISA Units (GMEU) or µg/mL as appropriate, geometric mean fold-rise (GMFR),
proportion of subjects with ≥ 2-fold and ≥ 4-fold increases in concentration from baseline 
(seroconversion rate, SCR [maternal subjects only]), and seroresponse rate (SRR). Analyses 
will be used to evaluate:
o
Immunogenicity through six months post-delivery in maternal subjects.
o
Transplacental transfer of maternal antibodies specific for RSV described as a ratio of 
levels in maternal and cord blood at delivery.
o
Infant RSV-specific antibody decay during the first six months of life relative to cord 
blood levels. 
o
Immune correlates of risk of RSV LRTI in infants based on anti-RSV F protein IgG or 
palivizumab-competitive antibody responses in the infant and/or cord blood, and maternal 
subjects at delivery.

Serum microneutralization (MN) titers against RSV/A and B in maternal and infant subjects 
at select time-points may be generated for a subset of the population using the 

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derived/calculated endpoints previously referenced, based on geometric mean titer (GMT). 
An external laboratory, whose personnel are blinded to study treatment, will perform RSV/A 
and B MN testing during study conduct and after Day 180 unblinding.  Final MN results, 
because of their time-consuming nature, may be provided as one or more sequential addenda 
to the main study report
Safety Endpoints:
In Infant Subjects:

Percentages of term (≥ 37 weeks gestational age), healthy infants appropriate for gestational 
age (as determined by ultrasound gestational age assessment), APGAR scores, length, birth 
weight, frontal-occipital head circumference (FOC), and physical examination at birth. 

Percentages of infants with AEs and SAEs (with special attention to congenital anomalies; 
respiratory failure other than RSV-associated hospitalization; neonatal death; infant death; 
sudden infant death syndrome; asphyxia; neonatal or hypoxic-ischemic encephalopathy; or 
other adverse events or complications of adverse events that necessitate hospitalization) 
during the neonatal period and through the first year of life.

Percentages of infants with unsolicited adverse events (including abnormalities detected in 
routine metabolic screening blood and neonatal hearing tests), unscheduled medical visits for 
adverse events, and serious adverse events through the first year of life.

Percentages of infants with developmental delay, as measured by the outcome of testing using 
a validated developmental scale at six months and at one year, in infants of RSV F vaccinees 
as compared to placebo. 
In Maternal Subjects:

Percentages of subjects with solicited injection site and systemic reactogenicity within seven 
days of vaccination.

Percentages of subjects with unsolicited (local and systemic) adverse events (AEs), 
unscheduled medically-attended adverse events (MAEs), significant new medical conditions 
(SNMCs), and serious adverse events (SAEs) through delivery and six (6) months thereafter. 

Clinical safety laboratory assessments of select serum chemistry and hematology parameters 
through delivery.

Percentages of subjects with Caesarean, vaginal, or instrument-assisted vaginal modes of 
delivery.

Percentages of subjects with post-immunization onset of specific complications of third-
trimester pregnancy and delivery including:
o
Pregnancy complications: 
-
Stillbirth, 
-
Preterm birth (moderate to late preterm: 32 to < 37 weeks of gestation; very preterm: 
28 to < 32 weeks of gestation),
-
Preterm premature rupture of membranes, 
-
Placental abruption,
-
Hypertensive disorders of pregnancy including: gestational hypertension, pre-
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-
Third-trimester hemorrhage, and
-
Gestational diabetes.
o
Labor and delivery complications: 
-
Emergency Caesarean (C)-section for maternal or fetal indications,
-
Postpartum hemorrhage, 
-
Chorioamnionitis, and
-
Maternal fever or infection.
Exploratory/Informational Endpoints (In Maternal and Infant Subjects as Stated):

Percentages of infants with medically-significant RSV LRTI from delivery through 90, 120, 
150 and 180 days of life defined as per the primary efficacy endpoint with the exception that 
evidence of RSV infection, LRTI, hypoxemia, and/or tachypnea may be based on either or 
both of the observations of the clinical site staff using sponsor-supplied devices and diagnostic 
tests OR review and abstraction of medical records for infants undergoing hospitalization for 
a respiratory serious adverse event. 

Percentages of infants with RSV LRTI with EITHER severe hypoxemia (SpO2 < 92% at sea 
level or < 87% at altitudes > 1800 meters) OR the documented use of oxygen by high flow 
nasal cannula OR continuous positive airway pressure (CPAP) OR bilevel positive airway 
pressure (BiPAP) OR Bubble CPAP OR bag-mask ventilation OR intubation with subsequent 
mechanical (or manual) ventilation OR extracorporeal membrane oxygenation (ECMO) from 
delivery through 90, 120, 150, and 180 days of life defined as per the corresponding secondary 
efficacy endpoint with the exception that evidence of RSV infection, LRTI, severe 
hypoxemia, and/or respiratory support may be based on either or both of the observations of 
the clinical site staff using sponsor-supplied devices and diagnostic tests OR review and 
abstraction of medical records for infants undergoing hospitalization for a respiratory serious 
adverse event. 

Percentages of infants with RSV LRTI requiring hospitalization from delivery through 90, 
120, 150, and 180 days of life defined as per the corresponding secondary efficacy endpoint 
with the exception that evidence of RSV infection and LRTI may be based on either or both 
of the observations of the clinical site staff using sponsor-supplied devices and diagnostic tests 
OR review and abstraction of medical records for infants undergoing hospitalization for a 
respiratory serious adverse event. 

Percentages of infants with RSV LRTI associated with EITHER hypoxemia (peripheral 
oxygen saturation [SpO2] < 95% at sea level or < 92% at altitudes > 1800 meters) OR 
tachypnea (≥ 60 bpm for infants 0 to 59 days of age or ≥ 50 bpm for infants ≥ 60 days of age 
[WHO Handbook, Integrated Management of Childhood Illness criteria for tachypnea]) from 
delivery through 90, 120, 150, and 180 days of life. Data concerning documentation of RSV 
infection, LRTI symptoms and signs, hypoxemia and/or tachypnea may be obtained from the 
observations of the clinical site staff OR review and abstraction of medical records for infants 
undergoing hospitalization for a respiratory serious adverse event. 

Percentages of infants with RSV LRTI resulting in death from delivery through 90, 120, 150, 
and 180 days of life. Evidence of RSV infection and LRTI may be based on either or both of 
the observations of the clinical site staff using sponsor-supplied devices and diagnostic tests 
OR review and abstraction of medical records for infants undergoing hospitalization for a 
respiratory serious adverse event. 

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
Percentages of infants with RSV LRTI (all severities) from delivery through 90, 120, 150, and 
180 days of life.  Evidence of RSV infection and LRTI may be based on either or both of the 
observations of the clinical site staff using sponsor-supplied devices and diagnostic tests OR 
review and abstraction of medical records for infants undergoing hospitalization for a 
respiratory serious adverse event.

Counts and incidence rates of infant healthcare interventions associated with wheezing 
through the first year of life.

Percentages of maternal subjects with RSV-related respiratory illness as observed by the 
clinical study staff, and detected by active and passive surveillance from vaccination through 
six months after delivery, overall and by pathogen(s).

Percentages of infant subjects with all-cause LRTI, with or without tachypnea, hypoxemia, or 
severe hypoxemia, as detected by active and passive surveillance from vaccination through 
six months after delivery, overall and by pathogen(s). 

Percentages of infant and maternal subjects with non-RSV respiratory viruses, overall and by 
pathogen(s), through six months after delivery.
A Clinical Endpoint Adjudication Committee (CEAC) composed of expert pediatricians (see 
Section 10.4.2) will carry out a blinded review of all potential exploratory endpoint cases involving 
RSV LRTI in infants to determine if they fulfill the relevant endpoint criteria in a temporally plausible 
relationship consistent with RSV disease as observed in clinical practice. Only CEAC-confirmed cases 
will be used for exploratory endpoints.
Study Design:  
This is a randomized, observer-blind, placebo-controlled trial enrolling up to approximately 4,600
third-trimester pregnant women in the Northern and Southern hemispheres. Randomization will be 
configured to provide approximately 3,000 exposures to the active test article. 
Healthy women in the third trimester of a singleton uncomplicated pregnancy, at low risk of obstetrical 
complications, and ≥18 to ≤40 years of age (lower limit of 18 years and 0 days and an upper limit of 
40 years and 0 days) will be enrolled and randomized, initially in a 1:1 ratio, into one of two treatment 
groups, active or placebo, over approximately the three months prior to peak RSV season as shown in 
Treatment Assignments. After the first global season of enrollment, the randomization scheme will be 
changed to a 2:1 (active / placebo) ratio to enable more efficient accrual of the safety database. Due 
to the importance of infant RSV exposure in order to demonstrate efficacy of the maternal 
immunization strategy, investigators will be instructed to base maternal enrollment on a projected date 
of delivery for each maternal subject. The estimated date of the earliest delivery (EDD-E) will be
approximately 6 weeks prior to the historic average onset date of increased RSV transmission at each 
study site. The estimated date of the latest delivery (EDD-L) will be calculated based on the historic 
average end date of RSV transmission at each study site, such that participating infants are likely to 
have a minimum 3 month exposure to RSV transmission. The Sponsor will assist and provide guidance 
to each site in determining the EDD-E and EDD-L using best available site-specific, local, 
state/provincial, or national surveillance data to the extent available.  Please refer to the Study 
Operations Manual for further details.

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Treatment Assignments
Treatment 
Group
Target Maternal 
Subjects/Group[1]
Test
Article
Dosing 
Volume
Vaccination 
Day
A
~ 1562
Placebo
0.5 mL
Day 0
B
~ 3038
RSV F vaccine
[1] The target number of subjects that may be enrolled over multiple global RSV seasons, based on a 1:1 randomization 
for the first season and 2:1 (active / placebo) randomization for all subsequent seasons. 
Randomization of maternal subjects will be done at the site level and will be stratified by age (i.e., 18 
to < 29 years and 29 to ≤ 40 years). No specific proportion in either age group will be sought, rather 
the intent of stratification will be to distribute the proportion of maternal subjects presenting for 
enrollment in each age group equally across the two treatment arms. In addition, infant subjects born 
to randomized maternal subjects will be prospectively and randomly assigned to one of three 
postpartum phlebotomy cohorts, which will differ only in the timing of blood sampling (see Infant 
Subject Study Visit). It is anticipated that a percentage of the randomized maternal subjects and their 
delivered infant may not complete the study; subjects (maternal and infant) who withdraw or are 
discontinued will not be replaced.
All maternal subjects will receive a single IM injection on Day 0 with the assigned test article, either 
the RSV F vaccine or placebo (see Treatment Assignments table). The procedures to be performed in
the study are described in detail in this protocol and are summarized in the Maternal Subject Study 
Visit and Infant Subject Study Visit Procedures sections. Maternal subjects will be monitored for 
typical vaccine reactogenicity, clinical laboratory impacts, and specified adverse pregnancy outcomes, 
as well as general AEs and SAEs. In addition, because the maternal illness and obstetrical risk burden 
due to RSV is largely unknown, the occurrence of RSV disease in maternal subjects will be monitored 
before and after delivery. 
Vaccine impacts on markers of infant development and well-being at birth will be monitored, as will 
growth and development through the first year of life.  Infant blood samples will be taken to assess 
the decay half-life of maternally-derived RSV antibodies. Symptomatic infant and maternal RSV 
infections will be monitored through the first RSV season using both active and passive surveillance 
mechanisms; and will be etiologically-confirmed using RSV RT-PCR. Infant RSV infections will be 
characterized based on their symptomatology, associated degree of hypoxemia as measured by pulse 
oximetry, respiratory rate as measured by observation for 1 minute, and required medical 
interventions. 
For each maternal subject, study participation will span approximately nine (9) months from the first 
dose, ending six (6) months post-delivery. Study follow-up for infant subjects who are consented will 
span approximately one (1) year post-delivery.
A Data and Safety Monitoring Board (DSMB) will supervise enrollment and monitor subject safety 
throughout the trial (see Section 8.10).  In order to ensure that mothers and infants are not placed at 
risk with scant possibility of success, repeated futility analyses will be performed twice per year during 
the period of the study.  Due to the seasonal nature of RSV disease and the occurrence of RSV seasons 
in a roughly sequential manner across the Northern and Southern hemispheres, futility analyses, for 
detecting situations in which the existing efficacy data is not consistent with a predefined minimal 
clinical benefit, will occur at the approximate end of each Northern hemisphere season (data as of 
approximately 30 May) and each global RSV season (data as of approximately 30 September, 
comprising a Northern hemisphere season and the following Southern hemisphere season); and 
subject to constraint (applied by the DSMB statistician) that at least 10 cases will have accrued in the 
active treatment arm. A determination of futility at any futility analysis, will lead to a DSMB 
recommendation to terminate the trial, and stop further enrollment. 

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The primary analysis of the trial is an evaluation of the superior efficacy of the RSV F vaccine relative 
to the placebo in reducing the rate of medically-significant RSV LRTI in infants from delivery through 
the first 90 days of life. If successful outcomes are obtained through 90 days of life, then additional 
analyses for efficacy will be performed in a closed hierarchical sequence considering data from 
delivery through 120, 150, and 180 days of life (with each sequential analysis being enabled by a 
significant result at the preceding shorter interval).  Multiple secondary and exploratory efficacy 
analyses will also address other infant and maternal RSV disease outcomes.
All primary and secondary efficacy endpoints, as well as exploratory efficacy endpoints in infants 
concerning RSV-associated illness, will be reviewed and validated by an independent Clinical 
Endpoint Adjudication Committee (CEAC) prior to unblinding (see Section 10.4.2).  Only endpoints 
validated by the CEAC review will be used for the efficacy analyses. Section 10.4.3 provides details 
of the futility and efficacy analyses. (see Section 8.10). 
Eligibility Criteria: 
Inclusion:
Pregnant women must meet all of the following criteria to be eligible for participation in the study:
1)
≥ 18 and ≤ 40 years-of-age (which connotes a lower limit of 18 years and 0 days and an upper 
limit of 40 years and 0 days).  
2)
Singleton pregnancy of 28 to 360/7 weeks gestation on the day of planned vaccination. 
Documentation of gestational age will be based on one of the following composite criteria (Note: 
The investigator should use the earliest ultrasound data available to establish the study-specific 
gestational age dating):
(a) Gestational Age Dating Based on First Trimester Data (data obtained ≤ 136/7 weeks):
The date of the first day of the reported last menstrual period (LMP) may be used to establish 
the gestational age if corroborated by a first trimester ultrasound. If the gestational age 
estimation derived using the LMP and the first trimester ultrasound are discrepant by > 7 days, 
the ultrasound will be used to establish the gestational age. 
If LMP is uncertain or unknown, the ultrasound-established gestational age estimation will be 
used to establish the gestational age of the pregnancy. 
(b) Gestational Age Dating Based on Early Second Trimester Data (data obtained 140/7 to 216/7): 
The date of the first day of the reported LMP may be used to establish the gestational age if 
corroborated by an early second trimester ultrasound (that estimates the gestational age 
between 140/7 and 216/7 weeks). If the gestational age estimation derived using the LMP and 
the early second trimester ultrasound are discrepant by > 10 days, the ultrasound will be used 
to establish the gestational age. 
If LMP is uncertain of unknown, the ultrasound-established gestational age estimation will be 
used to establish the gestational age of the pregnancy. 
(c) Gestational Age Dating Based on Later Second Trimester Data (data obtained 220/7 to 276/7
weeks by LMP): 
The date of the first day of the reported LMP may be used to establish the gestational age if 
corroborated by a later second trimester ultrasound (that estimates the gestational age between 
220/7 to 276/7 weeks). If the gestational age estimation derived using the LMP and the later 

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second trimester ultrasound are discrepant by > 14 days, the ultrasound will be used to 
establish the gestational age. 
If LMP is uncertain or unknown, the ultrasound-established gestational age estimation will be 
used to establish the gestational age of the pregnancy.
(d) Gestational Age Dating When the LMP is Uncertain or Unknown AND No Prior First or 
Second Trimester Ultrasound Has Been Performed:
An ultrasound performed at screening within the second trimester (≤276/7 weeks) will be used 
to establish the gestational age dating. 
3)
Documentation of a second or third trimester (between 180/7 weeks and prior to randomization) 
ultrasound with no major fetal anomalies identified. 
4)
Good general maternal health as demonstrated by:
o Medical history (including history of clinically significant adverse reactions to prior vaccines 
and allergies). 
o Physical examination including at least vital signs (blood pressure, pulse, respirations, and
axillary body temperature); weight; height; examination of the HEENT, cardiovascular, 
pulmonary, gastrointestinal (abdominal), musculoskeletal, lymphatic, and dermatologic organ 
systems; and documentation of fetal heart tones. Note that abnormal vital signs may be 
repeated at the investigator’s discretion since these measures may be labile. Vital signs should 
be assessed in the context of normal values for the third trimester of pregnancy (see the Study 
Operations Manual).
o Clinical laboratory parameters that include:
-
For the first year of study conduct in any country, normal/clinically insignificant blood 
urea nitrogen (BUN), creatinine, alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), total bilirubin, alkaline phosphatase (ALP), hemoglobin, white 
blood count, and platelet count. Note that normal ranges for clinical laboratory 
parameters will be based on reference ranges appropriate for the third trimester of 
pregnancy, specified in the toxicity grading scale (TGS) provided in the Study 
Operations Manual) and should be referenced to assess for any abnormalities. This 
testing should be performed by the central laboratory.
-
For all subjects, serologic exclusion of infection with hepatitis B (HBV) and C (HCV) 
viruses, syphilis, and HIV as documented by testing (performed at the central or local 
laboratory) at screening or by medical records during the current pregnancy. 
5)
Able to understand, and both willing and physically able to comply with study procedures.  This 
includes anticipation of reasonable geographic proximity to the study clinic and adequate 
transportation to comply with scheduled and unscheduled study follow-up visits. 
6)
Able and willing to provide written informed consent for themselves and infant. 
Exclusion:
Pregnant women will be excluded if there is historical, physical examination, or laboratory evidence 
of any of the following:
1)
Symptomatic cardiac or pulmonary disease requiring chronic drug therapy, including 
hypertension and asthma. Asthma will be exclusionary if the subject is receiving chronic systemic 

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glucocorticoids at any dose or inhaled glucocorticoids at any dose > 500 µg per day of 
beclamethasone or fluticasone, or > 800 μg per day of budesonide.
2)
Pregnancy complications (in the current pregnancy) such as preterm labor, hypertension (blood 
pressure [BP] > 140/90 in the presence of proteinuria or BP > 150/100 with or without proteinuria) 
or currently on an antihypertensive therapy, or pre-eclampsia, or evidence of intrauterine growth 
restriction.
3)
Grade 2 or higher clinical laboratory or vital sign abnormality. Exclusion of subjects with grade 1 
abnormalities will be based on the subject’s prior medical history and the investigator’s clinical 
judgment that the abnormality is indicative of a meaningful physiologic event. 
4)
Receipt of any licensed vaccine (e.g., Tdap, inactivated influenza vaccine) within 14 days of study 
vaccination. 
5)
Received any RSV vaccine at any time.
6)
Body mass index (BMI) of ≥ 40, at the time of the screening visit. 
7)
Hemoglobinopathy (even if asymptomatic) or blood dyscrasias.
8)
Hepatic or renal dysfunction. 
9)
Established diagnosis of seizure disorder, regardless of therapy.
10) Known, active auto-immune disease or immunodeficiency syndrome.
11) Endocrine disorders, including (but not limited to) untreated hyperthyroidism, untreated 
hypothyroidism (unless due to auto-immune disease), and glucose intolerance (e.g., diabetes 
mellitus type 1 or 2) antedating pregnancy, or occurring during pregnancy and requiring 
interventions other than diet for control. 
12) History of major gynecologic or major abdominal surgery, including bariatric surgery (previous 
Caesarean section is not an exclusion).
13) Known HIV, syphilis, HBV, or HCV infection, as assessed by serologic tests conducted during 
the current pregnancy or as a procedure during the screening period of the study.
14) Primary genital Herpes simplex (HSV) infection during the current pregnancy.
15) Current alcohol or drug abuse based on the investigator’s knowledge of present or recent (within 
the last 2 years) use/abuse of alcohol or illegal or non-prescription drugs.
16) Documentation that current pregnancy results from in vitro fertilization (IVF). 
17) Documentation that current pregnancy results from rape or incest.
18) Documentation that the infant will be a ward of the state or be released for adoption.
19) History/presence of deep venous thrombosis or thromboembolism, or the use of anticoagulants 
during pregnancy (the use of low-dose aspirin as prophylaxis [e.g., for the prevention of morbidity 
and mortality from preeclampsia] is acceptable in dosages consistent with local standards of care). 
20) Red blood cell allo-immunization.
21) Prior stillbirth or neonatal death, or multiple (≥ 3) spontaneous abortions. 
22) Prior preterm delivery ≤34 weeks gestation or having ongoing intervention (medical/surgical) in 
current pregnancy to prevent preterm birth.
23) Greater than five (5) prior deliveries.

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24) Previous infant with a known genetic disorder or major congenital anomaly.
25) Receipt of investigational drugs or immune globulins (with the exception of prophylactic anti-
Rho D immune globulin) within six (6) months prior to the administration of the study vaccine.
26) Chronic administration (defined as more than 14 continuous days) of immunosuppressants or 
other immune-modifying drugs within 6 months prior to the administration of the study vaccine. 
An immunosuppressant dose of glucocorticoid will be defined as a systemic dose ≥10 mg of 
prednisone per day or equivalent. The use of topical, inhaled, and nasal glucocorticoids will be 
permitted except for the limit established in exclusion criterion #1.
27) Neuro-psychiatric illness, including a history of severe post-partum depression, deemed likely to 
interfere with protocol compliance, safety reporting, or receipt of pre-natal care; or requiring 
treatment with psychotropic drugs (excluding treatment for depression and anxiety).
28) Any other physical, psychiatric or social condition which may, in the investigator’s opinion, 
increase the risks of study participation to the maternal subject or the fetus/infant; or may lead to 
the collection of incomplete or inaccurate safety data.
29) Acute disease within 72 hours of the day of the planned vaccination (defined as the presence of a 
moderate or severe illness with or without fever, or an axillary body temperature > 38.0°C).
30) History of a serious adverse reaction (e.g., anaphylaxis) to any prior vaccine.
Maternal Subject Study Visit Procedures:
Up to Two (2) Months Prior to Study Start – Pre-Screening 
Obstetrical investigators may, at their discretion, introduce the concept of participation in a third-
trimester RSV vaccine trial to women who they regard as potentially fulfilling the inclusion/exclusion 
criteria. If required by the Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
having authority, interested women may be asked to provide informed consent in order for the 
investigator to collect information regarding their general health history, obstetrical history, and 
results of screening testing performed for the current pregnancy. The screening consent will be for 
collection of existing data only, and will not provide for any invasive procedure (including 
phlebotomy). Screening consent may be withdrawn at any time, and will not bind the prospective 
subject to enroll in the clinical trial or the investigator to offer enrollment.
Day -28 to 0 – Screening (up to four weeks before the planned day of vaccination)
Healthy pregnant subjects, who are considered to be at low-risk of obstetrical complications, ≥ 18 to 
≤ 40 years of age (18 years and 0 days to 40 years and 0 days), have provided written Informed 
Consent for themselves and their infants to participate in the main study, and are able to comply with 
study requirements, will have the following procedures performed:

Review of medical history, including history of clinically significant adverse reactions to prior 
vaccines and allergies. 

Review of the parameters by which the gestational age dating of the current pregnancy was 
established, to include the LMP (if known), physical examination, and the results of a first-or  
second-trimester ultrasound.

Performance of a second trimester (≤ 276/7 weeks) ultrasound (if not previously done) that 
establishes gestational age dating.

Performance of a second or third trimester ultrasound (if not previously done) that confirms 
there are no major fetal anomalies. 

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
Review of obstetrical history to include the following outcomes of previous pregnancies: 
length of gestation, birth weight, length of labor, type of delivery, fetal/neonatal outcomes, 
complications of pregnancy, including history of fetal losses and elective abortions.

Review of surgical history including prior gynecologic, abdominal, or uterine surgery. 

Document results of any Group B streptococcus (GBS) screening (urine or recto-vaginal swab 
as applicable), or other infectious disease screening (i.e., for syphilis, gonorrhea, Herpes 
simplex, chlamydia, HBV, HCV, and HIV).

Administration of a licensed vaccine recommended during pregnancy, if indicated. Note: This 
dose should be administered at least 14 days before or at least 14 days after the Day 0 
vaccination.

Document current smoking, alcohol, and recreational drug use.

Document results of gestational diabetes screen.

Vital signs (blood pressure, pulse, respirations, and axillary body temperature. (Note that 
repeat testing may be performed for subjects with any abnormality), height, and weight. 

Physical examination including the following body systems: HEENT, cardiovascular, 
pulmonary, gastrointestinal (abdominal), musculoskeletal, lymphatic, and dermatologic; and 
confirmation of fetal heart tones.  

Blood draw:
o
For RSV baseline serology (20 mL)
o
For subjects participating in the first year of any country: Clinical laboratory assessments 
(10 mL) for select serum chemistry (i.e., blood urea nitrogen, creatinine, alanine 
aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase [ALP], 
total bilirubin) and hematology (i.e., hemoglobin, white blood cell [WBC], and platelet 
counts) parameters as applicable by central laboratory testing; AND HIV, syphilis, HBV, 
and HCV antigen tests/serologies as required by central or local laboratory testing (i.e., 
if screening results are not available in prior data collected during the course of the 
current pregnancy). Since results of the clinical laboratory testing are needed to confirm 
subject eligibility, it is recommended this phlebotomy be performed at least two days
before the planned Day 0 vaccination.
o
For subjects participating in all other years in any country: HIV, syphilis, HBV, and 
HCV antigen tests/serologies (10 mL, as required) by central or local laboratory if 
screening results are not available in prior data collected during the course of the current 
pregnancy.

Medication history, including concomitant medications. 

Query for any AE experienced since informed consent was obtained. 
Note that further procedures may be performed at the Investigator’s discretion in order to adequately 
screen subjects against eligibility criteria and/or to confirm medical history. Potential subjects who 
meet all inclusion criteria and none of the exclusion criteria (see Eligibility Criteria) may be enrolled. 
Day 0 – Vaccination (gestational week 28 to 360/7)
All subjects who have vital signs taken, fetal heart tones checked, and eligibility reconfirmed will be 
randomized to a treatment group and infant serology cohort. Information concerning the occurrence 
of any AE (and SAE specifically) experienced by the subject since informed consent was obtained 

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will be collected.  Subjects will then receive a single IM injection in the deltoid with the assigned 
study treatment, followed by monitoring in the clinic for approximately 30-60 minutes post 
vaccination for the occurrence of any local injection site and systemic reactions. Prior to completion 
of this visit, subject locator information and the delivery center to be utilized will be verified. Vital 
signs and a fetal heart tone check will be performed approximately 30 minutes (permissive range: 30 
- 60 minutes) post-vaccination.
A diary will be distributed to subjects before release from the clinic. Starting on vaccination day and 
for 6 days thereafter (Day 0 to Day 6 inclusive), subjects will record their oral temperature using a 
supplied oral thermometer, and any adverse event experienced in their diary, daily. The following 
local and systemic reactions will be solicited by diary: injection site (local) events – pain, bruising 
(ecchymosis), redness (erythema), and swelling (edema); systemic events – oral temperature 
(collected as a continuous variable), chills, muscle pain or aching remote from the injection site 
(myalgia), joint pain or aching (arthralgia), diarrhea, nausea, vomiting, headache, and fatigue. Subjects 
will also be asked to record any concomitant medications taken, and to document any unscheduled 
physician visit or hospitalization associated with an adverse even through to Day 6 (inclusive). 
Subjects will be instructed to notify the study staff promptly using the 24-hour telephone contact 
number(s) provided in the diary in the event of any severe (grade 3) solicited or unsolicited AE, new 
obstetrical complications, or symptoms suggestive of an RSV infection. A separate Study 
Identification Card will also be issued that indicates the maternal subject is part of an investigational 
vaccine trial and provides the contact number(s) of obstetrical investigator’s study staff. The 
identification card will also include a list of the clinical signs and symptoms of an RSV infection in 
adults and infants. In the event the maternal subject experiences symptoms suggestive of an RSV 
infection, she will be instructed to contact study staff promptly and, if warranted, may be asked to 
provide a sampling of upper respiratory secretions for detection of respiratory viruses. (Please refer to 
the RSV Surveillance section for further details.) The next visit will be scheduled before subjects are 
released from the clinic. 
Day 7 (+ 2 days) – In-clinic or Home Follow-up Visit
Subjects will return to the clinic or participate in a home visit for vital sign collection, to review and 
return their symptom diaries, and to report any unsolicited AEs, MAEs, SNMCs, and SAEs they have 
experienced and concomitant medications taken for these events. Subjects will also be queried 
regarding symptoms suggestive of an RSV infection (see Signs and (Trigger) Symptoms of RSV-
suspected Illness in Infant and Maternal Subjects table) and, in the event onset is within seven (7) 
days, will undergo a sampling of upper respiratory secretions for detection of respiratory viruses. In 
addition to normal obstetrical follow-up, including confirmation of fetal heart tones, a physical exam 
may also be performed to evaluate any adverse event reported. Before release from the clinic, a 
replacement Study Identification Card will be offered to subjects, if needed, along with a memory aid 
for them to record any medical events experienced in between extended clinic visits. (Note that the 
memory aid is considered a tool that subjects may or may not choose to use, and as such is NOT 
considered a source document and WILL NOT be collected.) The next visit will also be scheduled 
before subjects are released from the clinic. 
Day 14 (± 2 days) – In-clinic or Home Follow-up Visit
Subjects will return to the clinic or participate in a home visit for vital sign collection and to report 
any unsolicited AEs, MAEs, SNMCs, and SAEs they have experienced and concomitant medications 
taken for these events. Subjects will also be queried regarding symptoms suggestive of an RSV 
infection (see Signs and (Trigger) Symptoms of RSV-suspected Illness in Infant and Maternal 
Subjects table) and, in the event onset is within seven (7) days, will undergo a sampling of upper 
respiratory secretions for detection of respiratory viruses. In addition to normal obstetrical follow-up, 
including confirmation of fetal heart tones, a physical exam may also be performed to evaluate any 

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adverse event reported. A blood sample will be obtained for RSV serology (20 mL) and (if applicable) 
clinical laboratory safety (10 mL). If a subject has delivered prior to the Day 14 visit, then the visit 
will be considered closed and no missed visit protocol deviation will be captured. The single exception 
is the blood draw for the clinical safety laboratory assessment [which only applies to subjects enrolled 
in the first year of study conduct in any country] that should be obtained at the Delivery visit.
Before subjects are released from the clinic, a replacement Study Identification Card will be offered 
to subjects, if needed, and the next visit will be scheduled. Subjects will also be reminded to contact 
the site to report the onset of labor, any severe or serious AE, any obstetrical complication, or 
symptom(s) suggestive of an RSV infection. The next visit will also be scheduled before subjects are 
released from the clinic. 
Day 28 (± 2 days) – Telephone/Short Message Service (SMS) Contact, In-clinic, or Home Visit 
Safety Follow-up 
Subjects who have not yet delivered will have a safety follow-up performed as either a telephone/SMS 
contact visit using an IRB/IEC-approved script (if applicable), an in-clinic visit, or a home visit. At 
this visit, whether conducted in in-clinic or at a home visit, study staff will assess the general health 
of the subject and query for any severe unsolicited AE, SAE, SNMC, MAE, clinical symptoms or 
signs of a suspected RSV illness, or any new obstetrical complication occurring since the last visit, 
and any concomitant medications taken for these events. Subjects participating in this visit via 
telephone or SMS and who report any severe or serious adverse event or symptoms suggestive of an 
RSV infection, may be asked to return to the clinic or schedule a home visit for evaluation of the 
event(s) to assess any effect(s) it may have on the pregnancy, and to potentially undergo a sampling 
of upper respiratory secretions for detection of respiratory viruses if symptom onset is within seven 
(7) days. The same procedures will be performed for subjects participating in this follow-up as an in-
clinic or home visit, with the addition that a replacement Study Identification Card will be offered to 
all subjects (if needed) at the completion of this visit. 
Delivery (D) – Hospital Follow-up Visit
Subjects will be counselled to notify the obstetrician of the start of labor and will go to the registered 
hospital or delivery center for delivery. A venous blood sample (20 mL) for RSV serology should be 
obtained from the mother any time after hospital admission and optimally up to 12 hours post-delivery, 
which in extenuating circumstances (such as a delivery on a holiday or weekend), may be obtained up 
to 72 hours post-delivery. For applicable subjects (i.e., those enrolled in the first year of study conduct 
in any country) who deliver prior to the Day 14 visit, a venous blood sample (10 mL) for the clinical 
safety laboratory assessment should also be obtained. A cord blood sample (at least 5 mL) for RSV 
serology should be obtained by the obstetrician or designee immediately at the time of delivery. If 
cord blood is not obtained, then this information should be conveyed to the study staff responsible for 
the infant, so that infant sera may be collected in lieu of the cord blood (see Infant Subject Study Visit
at the Delivery Day visit for details).  The obstetrician or designee will also collect vital sign data at 
admission from the subject’s medical chart and record all unsolicited adverse events experienced, and 
concomitant medications taken by, or administered to, the subject since the last visit. (Note that routine 
medications for the management of labor and delivery do not need to be recorded.) In addition, study 
staff will document the presence of perinatal management (including antibiotic therapy and any 
medical or surgical interventions for cause) and of any GBS screening result and treatment. Study 
staff will inform the infant’s primary healthcare provider/pediatrician of the child’s anticipated 
participation in the study before or immediately after delivery. A replacement Study Identification 
Card will be offered to all maternal subjects (as needed), and subjects will be reminded to contact 
study staff if symptoms suggestive of an RSV infection are experienced.

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D+35 (± 7 days) – In-clinic or Home Post-delivery Follow-up Visit
Maternal subjects will return to the clinic or will be evaluated by study staff at a home visit at 
approximately 35 days post-delivery for vital sign collection and to report any unsolicited AEs, MAEs, 
SNMCs, and SAEs that may have occurred since the last visit, and concomitant medications taken for 
these events. A physical exam may also be performed at the investigator’s discretion to evaluate any 
adverse event reported. Maternal subjects will also be queried regarding symptoms suggestive of RSV 
infection and, in the event symptom onset is within seven (7) days, will undergo a sampling of upper 
respiratory secretions for detection of respiratory viruses. A replacement Study Identification Card 
will be offered to all subjects, as needed. A blood sample (20 mL) will be obtained for RSV serology. 
D+180 (± 14 days) – In-clinic or Home Post-delivery Follow-up Visit
Maternal subjects will return to the clinic or will be evaluated by study staff at a home visit at 
approximately 180 days post-delivery for vital sign collection, pregnancy testing, and to report any 
unsolicited AEs, MAEs, SNMCs, and SAEs that may have occurred since the last visit, and 
concomitant medications taken for these events. A physical exam may also be performed at the 
investigator’s discretion to evaluate any adverse event reported. Maternal subjects will also be queried 
regarding symptoms suggestive of RSV infection and, in the event symptom onset is within seven (7) 
days, will undergo a sampling of upper respiratory secretions for detection of respiratory viruses. A 
blood sample (20 mL) will be obtained for RSV serology. This visit will mark the end of study 
participation for the maternal subject. However, maternal subjects with ongoing respiratory episodes
at the D+180 visit will be contacted weekly by telephone and followed until symptoms for that episode 
have resolved or have returned to baseline. In addition, maternal subjects with a positive pregnancy 
result will be followed for safety through the time of delivery to determine the outcome of this 
pregnancy.
Unscheduled Visits
Maternal subjects will be encouraged to notify the investigator if any severe (grade 3) local or systemic 
solicited AE occurs during the 7-day post-immunization period, or if any severe, serious, or otherwise 
concerning AE occurs at any time following vaccination. If symptoms are presented that would require 
a physical exam to adequately assess potential AEs, the exam should be performed and vital signs 
collected. Note the RSV Surveillance visits are not considered unscheduled visits.

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Time and Events Schedule - Maternal Subject:
Maternal Subject Study Procedures
Study Day:
-28 to 
0
0
0-6
7[1]
14[1]
28[1]
Delivery D+35[1] D+180[1]
Window (days):
--
--
--
+2
±2
±2
--
±7
±14
Approximate 
Week of Gestation:
24-
360/7
28-360/7
28-36
29-37
30-38
32-40
--
--
--
Informed consent
x
Medical history
x
Physical exam
x
Vital signs
x
x[5]
x
x
x[10]
x
x
Physical exam, if indicated
x
x
x
x
x
x
Ultrasound
x[2]
Clinical safety phlebotomy
x[3]
x[3]
x[11]
Confirm eligibility
x
Injection with recommended 
licensed vaccine 
x[6]
Injection with RSV F 
vaccine or placebo 
x
Diary card completed
x
Diary card reviewed and 
collected
x
Distribution of Study 
Identification Card[9]
x
x
x
x
x
x
Memory aid distribution
x
RSV serology phlebotomy
x
x
x[7]
x
x
Cord blood
x[8]
RSV surveillance
Continuous
AEs, MAEs, SNMCs, and 
SAEs query
x
x
x
x
x
x
x
x
Concomitant medications
x
x
x
x
x
x
x
Document perinatal 
management & GBS 
screening/treatment results
x
x
[1] Performed as a telephone/SMS contact visit (Day 28 only) using an IRB/IEC-approved script, if 
applicable, or as an in-clinic or home visit (Day 7, Day 14, D+35, and D+180) to monitor for safety. 
Depending on responses, maternal subjects participating via telephone or SMS contact or home visit, may 
be asked to return to the clinic or to schedule a home visit for further evaluation.
[2] May be performed if subject does not have a prior second or third-trimester ultrasound that indicates there 
are no fetal anomalies.
[3] To be performed at least two days prior to the planned Day 0 vaccination and on Day 14 in all subjects 
enrolled in the first year of study conduct in any country for select serum chemistry (ALT, AST, total 
bilirubin, ALP, creatinine, and BUN) and hematology (hemoglobin, platelet count, and WBC count) 
assessments.
[4] To be performed as required by the central or local laboratory if screening results are not available in prior 
data collected during the course of the current pregnancy.

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[5] To be performed before and 30 minutes after vaccine administration.
[6] Must be administered at least 14 days before or at least 14 days after the Day 0 vaccination, if applicable. 
[7] The blood draw will be performed at any time from admission to the hospital up to 12 hours post-delivery 
for most deliveries, but may be obtained up to 72 hours post-delivery in extenuating circumstances such 
as a the occurrence of a delivery on a holiday or weekend.
[8] Obstetrical investigator or designee should inform the investigator to the infant (or designee) of the 
collection status of the cord blood sample.
[9] The Study Identification Card will be distributed at the Day 0 visit; a replacement card will be offered at 
all follow-up visits. 
[10] Limit collection to clinically significant vital sign data at hospital admission.
[11] Performed only for applicable subjects (i.e., those enrolled in the first year of study conduct in any country) 
who deliver prior to the Day 14 visit.
Infant Subject Study Visit Procedures:
Delivery (D) – Hospital Follow-up Visit
All procedures, including routine vaccinations that are considered standard of care for the newborn 
infant may be performed at any study visit which coincides with the usual timing for such procedures. 
Before any study-specific procedures are performed, informed consent for the infant subject and 
release of medical records will be reviewed with the maternal subject (i.e., the mother will not be re-
consented) or will be obtained from the other parent or guardian if not already captured under the 
institution’s policy. If cord blood is not obtained at the time of delivery (see delivery procedures for 
maternal subjects), an infant blood draw will be obtained within 72 hours of birth. (Note that cord 
blood is markedly preferred and all efforts should be directed to obtaining this specimen.  A 
phlebotomy/heel stick within 72 hours is a fall back procedure only.  The volume of a postpartum 
phlebotomy/heel stick must be accounted for within the phlebotomy limits as per the investigator’s 
institution [whereas a cord blood sample need not]). The investigator (or trained designee) will collect 
results of the physical exam, weight, length, frontal-occipital circumference (FOC), and APGAR 
measurements performed following birth and used to assess the overall health of the infant. The results 
of questions pertaining to the exposure of the infant to certain environments or behaviors, such as the 
mode of infant feeding (e.g., exclusively breastfed, exclusively formula fed, breast milk and
supplemented with formula, expressed breast milk, wet nurse, receiving solids), if a smoker or one or 
more children < 5 years of age will reside in the same household, and whether the infant or another 
child in the household (< 5 years of age) will be/is cared for in a group setting with other children 
(e.g., daycare) for ≥ 3 days per week, will also be documented.
Parents and/or guardians will be issued a Study Identification Card for their infant that indicates he/she 
is part of an investigational vaccine trial and provides the contact number of the investigator and study 
staff responsible for study-related follow-up of the infant. The Study Identification Card will also 
include details of the signs and symptoms of RSV infection in adults and infants. If the infant subject 
develops an “RSV-suspect illness” characterized by the symptoms listed in the Signs and (Trigger) 
Symptoms of RSV-suspected Illness in Infant and Maternal Subjects table, parents/guardians are to 
contact the study site, but will be instructed to seek appropriate medical care for the infant first. This 
is especially important in instances when the initial evaluating physician providing care to the infant 
is not affiliated with the study. 
D+14 (± 3 days) – In-clinic or Home Post-delivery Follow-up Visit
At approximately 14 days post-delivery, all infants will participate in a study visit at home or in-clinic 
for evaluation of any AEs, MAEs, SNMCs, or SAEs experienced since delivery and concomitant 
medications taken for these events. The parent or guardian of the infant will also be asked to report 
any healthcare provider-confirmed episodes of wheezing; and the mode of infant feeding, if a smoker 
or one or more children < 5 years of age reside in the same household, and whether the infant or 

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another child in the household (< 5 years of age) is cared for in a group setting with other children 
(e.g., daycare) for ≥3 days per week. A physical exam may be performed to evaluate any adverse 
events as needed. Symptoms suggestive of an RSV infection will be sought and, if onset has been 
within seven (7) days, a sampling of upper respiratory secretions for detection of respiratory viruses 
will be performed. A blood sample will be obtained from infants in phlebotomy Cohort 1 for RSV 
serology.
All procedures, including routine vaccinations that are considered standard of care for a corresponding 
baby-wellness visit may be performed at this visit. Prior to release from the clinic, study staff will 
schedule the next visit and remind the parent or guardian to contact the study staff directly if the infant 
develops symptoms suggestive of an RSV infection (see RSV Surveillance section). A replacement 
Study Identification Card will be offered to the parent/guardian of the infant before discharge, if 
needed. 
D+35 (± 7 days) – In-clinic or Home Post-delivery Follow-up Visit
At approximately 35 days after birth, all infants will participate in a study visit at home or in-clinic 
for evaluation of any AE, MAE, SNMCs, or SAE experienced since the last delivery; to record 
concomitant medications administered for these events; to report any healthcare provider-confirmed 
episodes of wheezing; symptoms of RSV-suspected illness will be sought and, if onset has been within 
seven (7) days, a sampling of upper respiratory secretions for detection of respiratory viruses will be 
performed; and to report the mode of infant feeding, if a smoker or one or more children < 5 years of 
age reside in the same household, and whether the infant or another child in the household (< 5 years 
of age) is cared for in a group setting with other children (e.g., daycare) for ≥ 3 days per week. Infants 
will have a physical exam performed; weight, length, and FOC measurements will also be recorded. 
A blood sample will be obtained from infants in phlebotomy Cohort 2 for RSV serology.
All procedures, including routine vaccinations that are considered standard of care for a corresponding 
baby-wellness visit may be performed at this visit. Prior to release from the clinic, study staff will 
schedule the next visit and remind the parent or guardian to contact the study staff directly if the infant 
develops a suspect illness (see RSV Surveillance section). A replacement Study Identification Card 
will be offered to the parent/guardian of the infant before dismissal, if needed.
D+60 (± 7 days) – In-clinic or Home Post-delivery Follow-up Visit
At approximately 60 days after birth, all infants will participate in a study visit at home or in-clinic 
for the same procedures performed at the D+35 post-delivery visit, with the exception that the blood 
sample for RSV serology will only be obtained from infants in phlebotomy Cohort 3. Note that all 
procedures, including routine vaccinations that are considered standard of care for a corresponding 
baby-wellness visit, may be performed at this visit.
D+90 (± 7 days) – In-clinic or Home Post-delivery Follow-up Visit 
At approximately 90 days after birth, all infants will participate in a study visit at home or in-clinic 
for the same procedures performed at the D+35 post-delivery visit, with the exception that the blood 
sample for RSV serology will only be obtained from infants in phlebotomy Cohort 1. Note that all 
procedures, including routine vaccinations that are considered standard of care for a corresponding 
baby-wellness visit, may be performed at this visit.
D+120 (± 7 days) – In-clinic or Home Post-delivery Follow-up Visit 
At approximately 120 days after birth, all infants will participate in a study visit at home or in-clinic 
for the same procedures performed at the D+35 post-delivery visit, with the exception that the blood 
sample for RSV serology will only be obtained from infants in phlebotomy Cohort 2. Note that all 

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procedures, including routine vaccinations that are considered standard of care for a corresponding 
baby-wellness visit, may be performed at this visit.
D+180 (± 14 days) – In-clinic or Home Post-delivery Follow-up Visit
At approximately 180 days after birth, all infants will participate in a study visit at home or in-clinic 
for the same procedures performed at the D+35 post-delivery visit, with three exceptions: 1) the blood 
sample for RSV serology will only be obtained from infants in phlebotomy Cohort 3, 2) infant 
subjects will complete the first of two developmental tests and 3) most activities associated with active 
RSV surveillance will conclude, with the exception that infant subjects with ongoing respiratory 
episodes will be followed weekly until symptoms of that episode have resolved or have returned to 
baseline. Parents/guardians of infant subjects will also be reminded to contact the site promptly to 
report any severe, serious, or otherwise concerning AE in the infant. Note that all procedures, 
including routine vaccinations that are considered standard of care for a corresponding baby-wellness 
visit may be performed at this visit.
D+252 (± 14 days) – In-clinic or Home Post-delivery Follow-up Visit
At approximately 252 days after birth, all infants will participate in a study visit at home or in-clinic 
for evaluation of any AEs, MAEs, SNMCs, and SAEs experienced since the last visit and to record 
concomitant medications administered for these events; to report any healthcare provider-confirmed 
episodes of wheezing; and to report the mode of infant feeding, if a smoker or one or more children 
< 5 years of age reside in the same household, and whether the infant or another child in the household 
(< 5 years of age) is cared for in a group setting with other children (e.g., daycare) for ≥ 3 days per 
week. A physical exam may be performed to evaluate any adverse events as needed; weight, length, 
and FOC measurements will be recorded. All procedures, including routine vaccinations that are 
considered standard of care for a corresponding baby-wellness visit, may be performed at this visit. 
Parents/guardians of infant subjects will also be reminded to contact the site promptly to report any 
severe, serious, or otherwise concerning AE in the infant. A replacement Study Identification Card 
will then be offered to the parent/guardian of the infant before dismissal, if needed.
D+364 (± 14 days) – In-clinic or Home Post-delivery Follow-up Visit
At approximately 364 days after birth, all infants will participate in a study visit at home or in-clinic
for evaluation of any AEs, MAEs, SNMCs, and SAEs experienced since the last visit; to record 
concomitant medications taken for these events; to report any healthcare provider-confirmed episodes 
of wheezing; and to report the mode of infant feeding, if a smoker or one or more children < 5 years 
of age reside in the same household, and whether the infant or another child in the household (< 5 
years of age) is cared for in a group setting with other children (e.g., daycare) for ≥ 3 days per week. 
Infants will have a physical exam performed, and weight, length, and FOC measurements will be 
recorded. Developmental testing will be performed for all infant subjects. Note that parents/guardians 
of infant subjects with a positive screen detected at both 6 and 12 months of age (as this is an AE), or 
first appearing at 12 months of age, will be offered repeat Ages and Stages Questionnaire (ASQ)-3 
screening at 15 and 18 months of age as a follow-up procedure. Novavax will collect this information 
as safety data. In addition, appropriate referrals for diagnostic pediatric developmental testing 
(according to local standards of care) will also be advised for infants with a positive screen identified.
All procedures, including routine vaccinations that are considered standard of care for a corresponding 
baby-wellness visit, may be performed at this visit.
Parents/guardians may also be asked to consent to additional infant follow-up for future respiratory 
disease such as severe LRTI syndromes or recurrent wheezing.  Such follow-up, if requested, will be 
voluntary and will be the subject of a separate future protocol and consent document.
Completion of this visit will mark the end of study participation for the infant subject.

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Unscheduled Visits
Parents/guardians will be encouraged to report, or ask the infant’s primary healthcare 
provider/pediatrician to report at any time, any other type of severe, serious, or otherwise concerning 
AE. If symptoms are presented that would require a physical exam to adequately assess potential AEs, 
the exam should be performed and vital signs collected. 
Note the RSV surveillance visits discussed in the RSV Surveillance section below are not considered 
unscheduled visits prior to D+180. Symptoms suggestive of an RSV-suspect illness reported during
passive surveillance, but after D+180, will be captured as AEs and not on the RSV Surveillance page.
Time and Events Schedule - Infant Subject: 
Infant Subject Study Procedures
Visits:
1
2
3
4
5
6
7
8
9
Study Day: Delivery D+14
D+35
D+60
D+90
D+120
D+180
D+252
D+364
Window:
--
±3 
days
±1 
week
±1 
week
±1 
week
±1 
week
±2 
weeks
±2 
weeks
±2 
weeks
Informed consent
x
Physical exam
x
x
x
x
x
x
x
Physical exam, if 
indicated
x
x
Gestational age,  APGAR 
scores
x
Weight, length, FOC
x
x
x
x
x
x
x
x
Phlebotomy, Cohort 1
x[1]
x
x
Phlebotomy, Cohort 2
x[1]
x
x
Phlebotomy, Cohort 3
x[1]
x
x
Time and Events Schedule - Infant Subject (Cont.): 
Infant Subject Study Procedures
Visits:
1
2
3
4
5
6
7
8
9
Study Day: Delivery D+14
D+35
D+60
D+90
D+120
D+180
D+252
D+364
Window:
--
±3 
days
±1 
week
±1 
week
±1 
week
±1 
week
±2 
weeks
±2 
weeks
±2 
weeks
RSV surveillance
Continuous
Distribution of Study 
Identification Card[2]
x
x
x
x
x
x
Query for smokers and 
children < 5 years of age 
in the household; mode of 
infant feeding; whether 
infant or another child (< 5 
years of age) in the 
household is cared for 
outside the home
x
x
x
x
x
x
x
x
x
AEs, MAEs, SNMCs, and 
SAEs 
x
x
x
x
x
x
x
x

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Query for healthcare-
provider confirmed 
wheezing 
x
x
x
x
x
x
x
x
Concomitant medication
x
x
x
x
x
x
x
x
Performance of all routine 
baby-wellness procedures/ 
vaccinations[3]
x
x
x
x
x
x
x
x
x
Developmental testing
x
x[4]
Note: Study visits after Visit #1 may be performed as in-clinic or home visits to facilitate infant subject 
follow-up. 
[1]An infant blood draw should be preferentially obtained within 24 hours of birth if cord blood is not collected 
at delivery, but is permissive up to 72 hours post-delivery. 
[2]The Study Identification Card will be given to the parent/guardian of the infant subject at the delivery visit; 
a replacement card will be offered at all follow-up visits, as needed.
[3]Performed at the Investigator’s discretion.
[4]Infant subjects with a positive screen detected at both 6 and 12 months of age, or first appearing at 12 
months of age, will be offered repeat developmental testing at 15 and 18 months of age as a follow-up 
procedure.
RSV Surveillance - Active and Passive:
Active and Passive Components of Surveillance
RSV surveillance will comprise both active and passive components. All queries for RSV-suspect 
illnesses will be made using an IRB/IEC-approved script, if applicable.

Active Surveillance (applicable to all subjects through the D+180 visit):
o
Study staff will contact the maternal subject and a parent/guardian of the infant subject 
(via telephone call or SMS) on a once weekly interval through the D+180 visit to query 
for an RSV-suspect illness. Newly-discovered RSV-suspect illnesses as assessed by the 
presence of “trigger symptoms” (see Table Signs and (Trigger) Symptoms of RSV-
suspected Illness in Infant and Maternal Subjects) will precipitate a home or clinic visit 
for evaluation (see Section Clinical Study Site Response to Reports of Initial Trigger
Symptoms). 
o
Study staff will re-evaluate (at home or in the clinic) all infant subjects with RSV-suspect 
illnesses between 2 to 3 days after any initial RSV surveillance visit to ascertain 
worsening in the illness. This re-evaluation will include the same procedures outlined in 
Section Clinical Study Site Response to Reports of Initial Trigger Symptoms.

Passive Surveillance (applicable at any time during the study): 
o
If the maternal subject develops any symptom suggestive of an RSV-suspect illness, or 
shows signs of worsening of a previously-evaluated RSV-suspect illness, she should 
contact the study site directly within 3 days of the onset/worsening of symptoms. 
o
If an infant develops symptoms of an RSV-suspect illness while on study, or shows signs 
of worsening of a previously-evaluated RSV-suspect illness, parents or guardians should 
contact study staff directly within 3 days of the onset/worsening of symptoms. 
o
Any newly-discovered RSV-suspect illnesses as assessed by the presence of “trigger 
symptoms” (see Table Signs and (Trigger) Symptoms of RSV-suspected Illness in Infant and 
Maternal Subjects) will precipitate a home or clinic visit for evaluation (see Section 
Clinical Study Site Response to Reports of Initial Trigger Symptoms). 

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o
Study staff will re-evaluate (at home or in the clinic) all infant subjects with RSV-suspect 
illnesses between 2 and 3 days after any initial RSV surveillance visit to ascertain 
worsening in the illness. This re-evaluation will include the same procedures outlined in 
Section Clinical Study Site Response to Reports of Initial Trigger Symptoms. 
o
If the initial evaluation of the maternal or infant subject for an RSV-suspect illness is 
performed by a healthcare provider, not affiliated with the study (e.g., in an urgent care 
clinic, emergency room, or other outpatient clinic), he/she should notify the study staff 
of the maternal or infant subject’s status as per the information provided on the Study 
Identification Card. 
o
Note: symptoms suggestive of an RSV-suspect illness reported during passive 
surveillance but after D+180 will be captured as AEs and not on the RSV Surveillance 
Page. 
Please refer to the Study Operations Manual for additional details regarding the procedures 
performed during the RSV Surveillance.
Trigger Symptoms for RSV-suspected Illness
Surveillance for RSV will be based on the occurrence of “RSV-suspected illnesses” characterized by 
one or more of the following Trigger Symptoms in infant and maternal subjects (shown below) that 
persist for a period of ≥ 24 hours, either in a continuous or intermittent manner, and are assessed as 
“atypical” (by the maternal subject herself, or a parent or other routine caregiver for the infant) in 
nature.
Signs and (Trigger) Symptoms of RSV-suspected Illness in Infant and Maternal Subjects
Symptoms in Infant Subjects
Symptoms in Maternal Subjects

Cough

Cough

Stuffy nose or runny nose

Stuffy nose or runny nose

Trouble breathing or fast breathing when 
resting

Shortness of breath

Trouble feeding or not feeding well 

Sore throat

Less active than normal when awake

Fever 

Sleeps more than normal

New or increasing wheezing

More crying or more fussy than normal

Wheezing (whistling noise when breathing)

New or increasing  sputum production
Note: It is not intended that these triggers for reporting be specific, or diagnostic of RSV, or LRTI; rather the goal is to 
capture acute respiratory illnesses generally. Physician (or qualified clinical designee) evaluation, (including an 
assessment of the infant’s oxygen saturation level via pulse oximetry readings and respiratory rate by observation 
for 1 minute at the time of presentation of the acute illness) will capture those features which characterize LRTI, 
tachypnea, and hypoxemia or severe hypoxemia: molecular diagnosis by reverse transcription-polymerase chain 
reaction (RT-PCR) will detect RSV. These symptoms are intended to be a sensitive, rather than specific, trigger 
for further evaluation.
Clinical Study Site Response to Reports of Initial Trigger Symptoms
In response to a report via active or passive surveillance of Initial Trigger Symptoms, the study site 
staff will:

Arrange for an in-clinic or home visit as soon as possible, but not later than 7 days after 
symptom onset, for evaluation by the study physician/qualified clinical designee of the subject 
(infant or mother) displaying the symptom/s and/or findings in the Signs and (Trigger) 
Symptoms of RSV-suspected Illness in Infant and Maternal Subjects table.

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
Arrange for an in-clinic or home visit by a study physician/qualified clinical designee for 
evaluation as soon as possible within 7 days of symptom(s) onset for maternal or infant 
subjects who received care for trigger symptoms at a non-study, affiliated medical facility. 
Note that this visit would only be applicable to subjects who are receiving outpatient care or 
have been released from inpatient care. 
Procedures to Occur During the Visit
Specific for Symptomatic Infants:

Measure the respiratory rate on room air (if possible) for all symptomatic infants. The 
measurement should be performed first, on a calm, infant, and should be performed by 
observation only (i.e., without stethoscope auscultation) for a full, timed one minute period. 
o
If the result is ≥ 60 bpm in an infant 0 to 59 days age or ≥ 50 bpm in an infant ≥60 days 
of age, a second timed one minute count should be obtained. 
o
If a second count is obtained, the lower of the two observations should be recorded. 

Measure the SpO2 via pulse oximetry (using study-specific pulse oximeter), for all 
symptomatic infants, which is to be performed when the infant is calm and not crying, and 
before administration of oxygen supplementation. The lowest stable SpO2 observed during a 
one minute measure should be recorded. Note that the oxygen should not be removed to 
measure SpO2 in infants already receiving oxygen supplementation at the time of assessment.
Please refer to the Pulse Oximeter Manual for more details. 
For All Symptomatic Subjects (Maternal and Infant):

Review and confirm the history of respiratory illness, including the approximate date of first 
symptom onset. 

Perform an examination of the symptomatic infant subject to ascertain, by observation or 
auscultation, the presence of the LRTI manifestations listed in the Clinical Signs/Symptoms 
to be Clinically Evaluated during an RSV-suspected Illness table.

Collect a respiratory specimen from the symptomatic subject for detection of respiratory 
viruses.
o
Symptomatic maternal subjects will have a nasal and throat specimen collected. The 
nasal secretion will be collected by mid-turbinate swabbing.
o
Symptomatic infant subjects will have a mid-turbinate nasal swab collected. 
o
RT-PCR testing for RSV and other viruses by the study laboratory will be for the 
purposes of this protocol, and not for clinical care. 
o
Respiratory specimens collected from the maternal and infant subject during an RSV 
surveillance visit may be split so that samples are provided for this protocol and for a 
qualified local laboratory supporting clinical care if the attending physician would 
ordinarily regard testing for bacterial and/or viral pathogens as warranted.

Collect vital signs other than respiratory rate (heart rate, blood pressure [if available for the 
infant], and axillary body temperature) for the symptomatic subject. 

Ascertain any medically-attended visit by the subject in response to the respiratory illness.

Ascertain any new concomitant medications resulting from the respiratory illness. 

Notify the infant’s primary healthcare provider of the RSV surveillance visit and outcome, as 
necessary.

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Clinical Signs/Symptoms to be Clinically Evaluated during an RSV-suspected Illness 
Infant Subjects

Cough

Nasal flaring

Difficulty breathing, manifesting in at least 
one of the following clinical signs or 
symptoms:
o
Lower chest wall indrawing 
o
Subcostal retractions Abnormal breath 
sounds, inclusive of: 

Stridor 

Rales

Rhonchi 

Wheezing

Crackles/crepitations 
o
Observed apnea
Maternal Subjects

Cough

Nasal congestion

Fever

Runny nose

Sore throat

Dyspnea

New or increasing wheezing

New or increasing  sputum production
Follow-up of RSV-suspect Illnesses 
Following the evaluation of an RSV-suspect illness outlined in Section Clinical Study Site Response 
to Reports of Initial Trigger Symptoms, the clinical site: 

For symptomatic infant subjects, schedule a follow-up visit in 2 to 3 days to ascertain whether 
the illness is worsening. 
o
The follow-up visit will include the same procedures outlined in Section Clinical Study 
Site Response to Reports of Initial Trigger Symptoms.
o
Parents/guardians will be strongly encouraged to report any worsening after the follow-
up visit, including hospitalizations, which may trigger any number of additional follow-
up visits at the investigator’s discretion. 
o
In the event than an infant is hospitalized, site staff are encouraged to perform a follow-
up visit in-hospital, if permissible under local administrative and ethical review 
procedures. 

For symptomatic maternal subjects, and for symptomatic infant subjects after the first follow-
up visit described above, a weekly contact by telephone/SMS will be performed to ascertain 
respiratory symptom status through to the D+180 visit, and to monitor the status of RSV-
suspect illnesses until symptoms have resolved, or have returned to baseline if after the D+180 
visit.

In the event new and/or worsening symptoms are reported during active or passive follow-up, 
an in-clinic or home RSV surveillance visit may be scheduled at the investigator’s discretion
for an evaluation to occur as soon as possible; a re-evaluation as per Section Clinical Study 
Site Response to Reports of Initial Trigger Symptoms may be performed.
o
At the investigator’s discretion, collection of ONE more respiratory specimen for 
pathogen detection for infant subjects who have developed qualitatively different or 
quantitatively worse symptoms. Note that no more than 3 respiratory specimens should 
be collected from an infant within the same episode.  

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o
If the new or worsening symptom in the maternal subject is associated with a respiratory 
episode for which a specimen has already been obtained, the investigator may exercise 
his/her judgement as the utility of an additional swab.
Definitions and Rules for RSV Surveillance

If possible, study staff should collect symptom data for any RSV-suspected illness for 
maternal and infant subject pairs during the same weekly telephone call or SMS contact. In 
the event the maternal and infant subject pair have independent clinic visits for assessment of 
an RSV-suspected illness within a given surveillance period, the subsequent weekly telephone 
or SMS contact for the next surveillance period can be resynchronized based on the earlier of 
the two contacts. For example, if a maternal subject had a clinic visit to evaluate an illness on 
Monday of surveillance week (SW)-1, this would trigger the next contact for the following 
Monday of SW-2. If the infant subject of the same mother had a clinic visit to evaluate an 
illness on Thursday of SW1, his/her next weekly contact could be rescheduled to coincide
with the maternal subject contact on Monday of SW-2. (The intent of this provision is to 
relieve the need for mother/infant pairs to make multiple follow-up visits in a one-week 
period.)

A new respiratory illness will be deemed to occur any time a one week (7 day) interval elapses 
during which the subject is free of respiratory symptoms. When a subject is determined to 
have a new respiratory illness, the subject should be evaluated at an in-clinic or home visit by 
study staff for this new episode.

A medically-attended visit will be deemed to have occurred whenever the subject or a 
parent/guardian of the infant subject precipitates a visit or home encounter with a physician 
or other healthcare provider for the purpose of evaluation or treatment of a respiratory illness. 
Note that at-home and in-clinic visits undertaken specifically to fulfill the requirements of this 
protocol, for illnesses which would not otherwise cause the parent/guardian to present the 
infant for care, are NOT “medically-attended visits,” with the exception noted immediately 
below.

In the event that the investigator is also the subject’s primary care physician (PCP)/general 
practitioner (GP), any RSV surveillance visit will be counted as a “medically-attended visit.” 

Note that the intent of the evaluation of subjects with Trigger Symptoms is fulfillment of the 
objectives of this protocol. The investigator or study site staff should use their best 
professional judgment to ensure that subjects receive prompt medical care appropriate to their 
clinical condition, if necessary either by referring the subject to their usual physician or 
medical care facility, or providing care if the investigator is the subject’s primary physician 
or if the case is emergent. The collection of the study data to support the primary and 
secondary efficacy endpoints are key objectives of this trial, but when necessary, appropriate 
medical care should supersede this goal. 

Respiratory events captured as efficacy endpoints will NOT be recorded in the AE electronic 
case report form (eCRF) or AE eSource page, with the exception of those that fulfill the 
definition of an SAE. The full particulars of the SAE(s) will also be captured in the SAE report 
form.

Respiratory events ongoing at the 6 months post-delivery visit (D+180) will be followed by 
study staff at weekly intervals until symptoms resolve or return to baseline.

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Laboratory Analyses:
Information regarding the central and local laboratories that will perform clinical laboratory safety 
testing, RSV serology testing, and genotyping of respiratory specimens is provided in the Study 
Operations Manual.
Statistical Methods:  
General:
The analysis populations will include the following: 

Safety Populations
o
Maternal Safety Population (Safety-M) - defined as all maternal subjects who receive any 
test article.  The Safety-M Population will be analyzed as actually treated.
o
Infant Safety Population (Safety-I) – defined as all infants born live to maternal subjects 
who received any test article. The Safety-I Population will be analyzed as actually treated.

Intent-to-treat (ITT) Populations 
o
Intent-to-treat Efficacy (ITT-EFF) Population - defined as all maternal subjects (ITT-
EFF-M) and their infants (ITT-EFF-I) in the Safety Population for whom at least one post-
treatment and post-partum, respectively, efficacy measurement is available for both the 
mother and the infant as evidenced by collection of surveillance observations. The ITT-
EFF Population will be analyzed as randomized. 
o
Intent-to-treat Immunogenicity (ITT-IMM) Population - defined as all maternal subjects 
(ITT-IMM-M) and their infants (ITT-IMM-I) in the Safety Population for whom at least 
one post-treatment immunogenicity measurement is available for both the mother and the 
infant. The ITT-IMM Population will be analyzed as randomized. 

Per-Protocol Efficacy (PP-EFF) Populations
o
The PP-EFF Populations will be the primary analysis populations for the efficacy 
analyses. 
o
PP-EFF for Maternal Subjects (PP-EFF-M) – defined as all maternal subjects who receive 
the test article and regimen to which they were randomized and have at least one post-
treatment encounter documented during which active and/or passive surveillance 
activities for RSV-suspect illness can occur, and have no major protocol deviations 
affecting the primary efficacy outcomes as determined and documented by Novavax prior 
to database lock and unblinding. 
o
The Per-Protocol Population for infant subjects (PP-EFF-I) – defined as all infant subjects 
who: a) are ≥ 37 weeks gestational age at birth, b) are born to maternal subjects who 
received a study injection as randomized and ≥ 2 weeks prior to delivery, c) have not 
received prophylactic treatment with palivizumab between birth and Day 180 after 
delivery, d) have at least one documented post-partum contact during which active and/or 
passive surveillance activities for RSV-suspect illness can occur, and e) have no major 
protocol deviations affecting the primary efficacy outcomes as determined and 
documented by Novavax prior to database lock and unblinding.  

Per-Protocol Immunogenicity (PP-IMM) Populations
o
The PP-IMM Populations will be the primary analysis populations for the 
immunogenicity analyses.

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o
PP-IMM for Maternal Subjects (PP-IMM-M) – defined as all maternal subjects who 
receive the test article and regimen to which they were randomized, provide baseline and 
delivery (up to 72 hours post-delivery) serology data, and have no major protocol 
deviations affecting the primary immunogenicity outcomes as determined and 
documented by Novavax prior to database lock and unblinding. 
o
PP-IMM for Infant Subjects (PP-IMM-I) – defined as all infant subjects who: a) are ≥ 37 
weeks gestational age at birth, b) are born to maternal subjects who received a study 
injection as randomized and ≥ 2 weeks prior to delivery, c) have provided a cord blood 
specimen (or infant blood sample by venipuncture or heel stick within 72 hours of 
delivery as an acceptable substitute), d) have not received prophylactic treatment with 
palivizumab between birth and Day 180 after delivery, and e) have no major protocol 
deviations affecting the primary immunogenicity outcomes as determined and 
documented by Novavax prior to database lock and unblinding.
Demographic parameters and other baseline characteristics (e.g., age, age group, gender, race, 
ethnicity, etc.) will be summarized by treatment group and serology cohort (as applicable) for all 
maternal and infant subjects (separately) in the Safety Population, as well as the number and 
description of protocol deviations. Summary statistics at birth for infant length, weight, FOC, APGAR 
scores, and gestational age will be provided by treatment groups. In addition, a listing will be prepared 
linking, by mother/infant pair, maternal demographic characteristics, maternal treatment, and infant 
length, weight, FOC, APGAR scores, and gestational age at birth.
Analyses of the Efficacy Endpoints:
The primary efficacy endpoint will be analyzed on the ITT-EFF-I and PP-EFF-I (infant) Populations. 
Conclusions concerning stopping for futility, the informational analysis, or declaration of attainment 
of the primary efficacy endpoint at the completion of the study, will only be based on the PP-EFF-I 
Population. In addition, supportive analyses based on the ITT-EFF-I Population will also be 
performed. 
The Vaccine Efficacy (VE) is defined as VE (%) = (1 – RR) x 100, where RR = Relative Risk of 
incidence rates between the two treatment groups (RSV F Vaccine / Placebo). The final analysis will 
be carried out at one-sided Type I error rate of 0.0124 (i.e., the lower bound of 2-sided 97.52% 
confidence interval). This conservative Type I error rate was determined as a part of the original group 
sequential design (GSD) approach and will be retained to guard against a potential Type I error 
inflation resulting from the decision to stop the study at ~4,600 maternal subjects given this decision 
occurred after the informational analysis. Since this change was not part of the original study design 
at the initiation of the study, the agreement on how to implement the change with respect to Type I 
error rate was finalized in consultation with the US-FDA. 
For the original design using the GSD, a simulation of 5,000 trials was performed under a range of 
scenarios (including both varying placebo rates of medically-significant RSV LRTI and endpoint 
event ratios in infants of active vaccinees relative to placebo recipients). A summary of the simulation 
results is provided in the adaptive design report as Appendix 1 in the SAP. 
The RR and its CI will be estimated using Poisson regression with Robust error variance [Zou 2004]. 
The generalized linear model with unstructured correlation matrix (Robust error variances) will be 
used. The explanatory variables in the model will include the treatment group. The dependent variable 
will be the incidence rate of the endpoint of interest. The Robust error variances will be estimated 
using repeated statement and the subject identifier. Poisson distribution will be used with a link 
function logarithm.  
Hypothesis testing of the primary efficacy endpoint will be carried out sequentially for H0: VE ≤0% 
and H0: VE < 30%. Rejection of the first null hypothesis, H0: VE ≤0% demonstrates a statistically 
significant vaccine effect. Rejection of the second null hypothesis, H0: VE < 30% at Type I error rate 

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of 1-sided 0.0124 is required to meet the statistical success criterion pre-specified for the US-FDA.
Should success be declared for the primary endpoint through 0 - 90 days of age, the hierarchical 
sequential analyses of 0 - 120, 0 - 150, and 0 - 180 days of age will be carried out using the Type I 
error rate of 1-sided 0.025 and the same null hypothesis.
Two types of analyses concerning the primary efficacy endpoint will be performed prior to the final 
analysis: recurring futility analyses approximately twice per year after the Northern and Southern 
hemisphere winter virus season, and an informational analysis with approximately 1/3 of projected 
subjects enrolled and followed through at least 90 days.   
For the futility analyses and the informational analysis, a Bayesian approach will be used and the 
analyses will be performed by the Independent Biostatistical Group (IBG) as originally designed. An 
assumption is made that the distribution of the number of events under the vaccine, xv, and the number 
of events under placebo, xp, are binomial:
xv ~Bin(v ,nv)
xp ~Bin(p,np)
where πv and nv, respectively, are the probability of an RSV event and the total number of subjects in 
the vaccine group and πp and np, respectively, are the probability of an event and the total number of 
subjects in the placebo group.  
Furthermore, we assume prior distributions for πv and πp that are flat, non-informative beta 
distributions:
v  ~ Beta(1,1)
p ~ Beta(1,1).
Futility will be demonstrated under the primary hypothesis based on the posterior probability that the 
event ratio, r = πv / πp, is less than or equal to 0.60.
Given xv events out of nv total subjects in the vaccine group and xp events out of np total subjects in the 
placebo group, the posterior distributions of πv and πp are:
v |xv ~ Beta(1xv,1(nv xv))
p |xp ~ Beta(1xp,1(np xp)).
Sampling from the posterior probability distribution for the event ratio is generated by:
1.
Sampling 10 million independent values from the posteriors of πv and πp
2.
Calculating the event ratio, r = πv / πp under each pair-wise sample from the posterior of πv
and πp. 
Futility stopping will be based on the posterior probability of futility that the event ratio is less than or 
equal to 0.60 is less than or equal to 0.05. Furthermore, an additional constraint governing the ability 
to stop the trial early for futility requires that a minimum of 10 events be observed in the vaccine arm. 

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All futility analyses will include all infant subjects who are 90 days old at the time of the data cutoff 
date.
In addition, time to the first medically-significant RSV LRTI event will be analyzed by treatment 
group using Kaplan-Meier methods. Sub-analyses will be performed to evaluate vaccine effects on all 
infections in which RSV is confirmed by RT-PCR, and also infections in which only RSV is found 
(i.e., no co-infections). The incidence rate of medically-significant RSV LRTI may be generated by 
age stratum or co-morbidities present, if sufficient event numbers are available.
Sensitivity analyses for the primary efficacy endpoint will be performed to investigate the impact of 
missing specimens for suspected-RSV illnesses, including RSV-negative specimens collected outside 
the specified collection window, and clinical assessments, including clinical signs/symptoms, 
respiratory rates, and pulse oximetry measurements, obtained by non-study healthcare providers (e.g., 
hospitalization records). Further details regarding the sensitivity analyses will be described in the SAP.
The null hypothesis, H0: VE ≤0%, using the 1-sided Type I error rate (i.e., lower bound of 2-sided 
95% CI) will be used for analyses of all secondary efficacy endpoints in infants. For each endpoint, in 
the event that efficacy is shown through the first 90 days of life, a hierarchical sequence of hypothesis 
tests will be carried out to examine efficacy through 120, 150, and 180 days of life.
Additional efficacy analyses may describe the incidence of symptoms used to define RSV LRTI. 
Percentages of infant subjects with any RSV-confirmed respiratory illness accompanied with the 
following events/complaints will be presented by treatment group through six months postpartum: 
cough, nasal flaring, difficulty breathing, manifesting in any of the following clinical signs or 
symptoms as lower chest wall indrawing, subcostal retractions, abnormal breath sounds (inclusive of 
stridor, rales, rhonchi, wheezing, and crackles/crepitations), and/or observed apnea. Time to the first 
RSV-associated event referenced above will also be analyzed using Kaplan-Meier methods for each 
event category and by treatment group.
Analyses of Safety and Immunogenicity Objectives:
All safety endpoints will be summarized overall and by treatment group for maternal subjects and 
infant subjects based on Percentages of subjects experiencing an adverse event.  Clinical laboratory 
data summaries for maternal subjects will include (by parameter and treatment group) toxicity grade 
shift summaries; absolute means and standard deviations with minima and maxima values, and 
tabulations of changes from baseline. 
For infant subjects, summary statistics will be provided for infant length, weight, FOC, and responses 
to environmental and behavioral queries, through one year post-delivery overall, and by treatment 
group. Results of developmental testing will be summarized by treatment group, and Percentages of 
infants above normal, normal, at-risk at 6 or 12 months, and at-risk at both 6 and 12 months.
Immunogenicity analyses will be descriptive and include tabulations by treatment group for maternal 
subjects and infant subjects based on anti-F IgG, PCA, and RSV/A and RSV/B MN. The transplacental 
transfer of anti-F IgG, PCA, and RSV/A and RSV/B MN antibodies will be examined; first order 
modeling of their decay in infants will be performed for half-life estimations. 
Exploratory Analyses:
Exploratory analysis will be conducted by generating classical two-by-two cross tabulations of all 
RSV respiratory tract infection endpoints detected by active/passive surveillance in infant and 
maternal subjects from immunization through six months after delivery and by treatment group. The 
relative risk (RR) and its 95% CI will be estimated using Poisson regression with robust error variance 
[Zou 2004]. A generalized linear model with unstructured correlation matrix (robust error variances) 

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will be used. The explanatory variables in the model will include the treatment group. The dependent 
variable will be the incidence rate. The Robust error variances will be estimated using repeated 
statement and the subject identifier. Poisson distribution will be used with a link function logarithm. 
The vaccine efficacy, and the corresponding two-sided 95% CI will be calculated.
Similar analysis will be conducted to assess the incidence of non-RSV LRTI in infant subjects as 
detected by active and passive surveillance from vaccination through six months after delivery. 
Percentages of infants and maternal subjects presenting with respiratory symptoms of non-RSV 
respiratory viruses detected by RT-PCR will be summarized.
All exploratory efficacy analyses will be conducted against the null hypothesis of VE ≤0% (i.e., the 
RR ≤1.00). For each endpoint, in the event that efficacy is shown through the first 90 days of life, a 
hierarchical sequence of hypothesis tests will be carried out to examine efficacy through 120, 150, 
and 180 days of life.
Sample Size Calculations:
This study is designed to enroll approximately 4,600 total maternal subjects that include a minimum 
of 3,000 RSV F vaccine recipients over 4 global RSV seasons.  
Assuming a medically-significant RSV LRTI incident rate of 4% in the placebo group and a vaccine 
efficacy of 65%, then the power of the design to claim success is 87%. The table below summarizes 
the power for different placebo attack rates and vaccine efficacies. Power calculations were performed 
using the normal approximation (NCSS PASS 14).  An estimated PP population size of 4,218 total 
evaluable infant subjects (2,786 in the RSV F vaccine group and 1,432 in the placebo group to account 
for 1:1 and 2:1 randomization ratios in Year 1 and the subsequent years, respectively) was used for all 
calculations.  
The target sample size of the safety and efficacy database in third-trimester pregnancy that will be 
required for licensure is at least 3,000 actively-immunized maternal subjects and their infants. 
Therefore, the final analysis for efficacy will commence only after a total of 3,000 subjects have been 
enrolled in the active treatment arm. If no events of a given class are observed among the 3,000 
subjects receiving the RSV F vaccine, an approximation to the one-sided upper 95% confidence bound 
on the rate of SAE occurrence would be 0.1%.
Power Calculations for the Primary Efficacy Endpoint (Medically-Significant RSV LRTI 
Through 90 Days)
Placebo Event Rate
True Event Ratio
Efficacy (1-RR)
Power [1]
0.02
0.5
50%
17%
0.4
60%
41%
0.35
65%
57%
0.3
70%
72%
0.2
80%
92%
0.03
0.5
50%
26%
0.4
60%
59%
0.35
65%
76%
0.3
70%
88%
0.2
80%
99%

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0.04
0.5
50%
34%
0.4
60%
73%
0.35
65%
87%
0.3
70%
96%
0.2
80%
> 99%
0.05
0.5
50%
42%
0.4
60%
83%
0.35
65%
94%
0.3
70%
99%
0.2
80%
> 99%
0.06
0.5
50%
50%
0.4
60%
90%
0.35
65%
97%
0.3
70%
> 99%
0.2
80%
> 99%
[1] Estimated using normal approximation to rule out H0: Vaccine Efficacy < 30% using one-sided Type I error 
rate of 0.0124.

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1
INTRODUCTION
1.1
Respiratory Syncytial Virus (RSV) Background
Respiratory syncytial virus (RSV) is the leading viral cause of severe lower respiratory tract 
disease in infants and young children worldwide. The World Health Organization (WHO) has 
estimated that the global annual burden of infections and mortality due to human RSV are 
64 million and 160,000, respectively [WHO 2009].  In industrialized countries, nearly all 
children have been infected with RSV by 2 years of age. Most infected children present with 
mild upper respiratory tract symptoms, but a subset develops severe lower respiratory tract 
disease characterized by tachypnea, hyperinflation, crackles, and expiratory wheezing (i.e., 
bronchiolitis and pneumonia).  The most severe disease occurs within the first 2 to 8 months of 
life, particularly in infants born prematurely and infants with underlying chronic lung and 
congenital heart diseases. 
Immunity to RSV remains incomplete and frequent reinfections occur throughout life, with the 
frail elderly, immunocompromised, and those with underlying cardiopulmonary disorders being 
among the most susceptible to severe disease in the adult population.  It is estimated that 
between 11,000 to 17,000 elderly adults die of RSV infection or its complications annually in 
the US, with approximately ten-fold more admitted to the hospital with respiratory symptoms 
[Walsh 2012]. Actual attack rates may be higher still, as an RSV diagnosis is often not made in 
adults unless highly sensitive molecular diagnostic tests (i.e., RT-PCR) are performed. Acute 
respiratory illness due to RSV has been documented in previously healthy immunocompetent 
adults as well (e.g., military recruits), although the clinical severity of infection or subsequent 
re-infection is typically diminished [O'Shea 2007].
RSV is a pleomorphic virus belonging to the Paramyxoviridae family, and comprises two major 
subtypes, A and B, that co-circulate. The two major surface glycoproteins of RSV, F and G, are 
the primary targets of neutralizing antibodies, which are associated with protection 
[Graham 2011] The F protein mediates fusion of the viral envelope with the plasma membrane 
and syncytium formation, while the G protein is essential for viral attachment. There is a high 
degree of genetic and antigenic homology in the F proteins across RSV/A and B viruses, and 
among individual isolates, whereas the G protein is much more variable [Johnson 1987]. 
Immunization with vaccinia virus containing the F gene protected animals against homologous 
and heterologous subtype A and B viral challenge; whereas, animals immunized with the G 
gene expressed in the same system were only protected against the homologous virus 
[Olmsted 1986, Stott 1987]. These data demonstrate the ability of anti-F neutralizing antibodies 
to generate immunity across RSV/A and B subtypes.
1.2
Summary of RSV Disease in Various Geographies
1.2.1
High-resource Countries in the Northern and Southern Hemispheres
Data from the United States (US) and Australia suggest that 1.7 to 2.6% of infants are 
hospitalized for RSV infection before 1 year of age [Hall 2009, Iwane 2004, 
Ranmuthugala 2011]. Annually in the US, RSV infection is associated with an estimated 57,527 
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[Centers for Disease Control and Prevention (update May 05 2015), Hall 2009]. In the US, 
Native American children are at increased risk for RSV infection. In 2000-2001, the rate of 
RSV hospitalization among Native American children <1 year of age in the southwest US was 
48 per 1000, nearly double the rate of similarly aged children in the general US population 
(27 per 1000) [Holman 2004]. Among Native American infants in the southwest US, 11% of 
healthy babies were hospitalized with RSV in their first year of life. [O’Brien 2015] The 
elevated risk of admission - roughly six-fold that of infants in the general US population - is 
probably related to socioeconomic and geographic conditions [Bockova 2002].
In the United Kingdom (UK), over the winter seasons from 1989 to 2000, the average annual 
RSV-associated mortality in infants 1 to 12 months of age was 8.4 per 100,000 population 
[Fleming 2005]. The clinical manifestations and morbidity of RSV are similar among infants 
and young children worldwide, regardless of the country of residence. However, the majority 
of deaths due to RSV still occur in developing countries, where burden and risk factors for life-
threatening illness remain the greatest. In fact, mortality rates due to RSV are difficult to 
ascertain in many settings, because children in developing countries, where 99% of fatal cases 
occur [Nair 2010], often die at home [Moisi 2011].
1.2.2
Argentina
Lower respiratory tract infections, in which RSV is a frequent pathogen in children under 
2 years of age [Marguet 2009], are the second leading cause of death in children under 5 years 
of age in Argentina [Marconi 2010]. A recent publication by Ferolla and coworkers confirmed 
the incidence of severe RSV infections as a major burden of respiratory illness among young 
children in Argentina [Ferolla 2013], in agreement with similar studies [Moisi 2011, Nair 2010], 
and stressed the central role of RSV on hospital admissions among children younger than 
2 years. Specifically, this study revealed that over 60% of the respiratory infections in 1,293 
hospitalized children in Buenos Aires within a catchment population of over 360,000 children, 
were due to RSV. Almost 20% of these children had life-threatening disease (as assessed by 
oxygen saturations below 87%), a finding that helps explain the high mortality rates associated 
with RSV in many underdeveloped areas of the world, where access to care is suboptimal. The 
mortality rate attributable to RSV was estimated to be 7% in this study sample. The gravity of 
the RSV disease burden in Argentinean children is exemplified by noting that in the Buenos 
Aires metropolitan area, the burden of RSV illness in 2011 outweighed that of 2009 H1N1 
influenza A virus during the pandemic year: 14-fold in hospitalizations and 4-fold in virus-
confirmed deaths [Libster 2010].
1.2.3
South Africa 
Acute respiratory tract infections due to RSV in South Africa remain a predominant cause of 
morbidity and mortality in young children [Tempia 2014]. A recent surveillance study in South 
Africa by Moyes et al., revealed that acute respiratory tract infections, in which RSV is a 
frequent pathogen, are the cause of approximately 8% of all deaths in children under the age of 
5 years [Moyes 2013]. Results from this study confirm the findings of similar studies 
[Madhi 2006, Moisi 2011, Nair 2010], stressing the central role of RSV on hospital admissions 
among children younger than 2 years. The published hospital-based incidence of RSV infection 
in South Africa is estimated at 3 to 18%, with a mortality rate between 12% and 43% in 

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hospitalized cases [Moisi 2011]. An additional challenge in South Africa is that although a 
seasonal peak in RSV cases is established, with the majority of cases occurring in the winter 
(February-July), a low–level circulation of the virus has been identified outside of the epidemic 
period [Moisi 2011]. 
1.2.4
India, Southern Asia, and the Philippines
As in other geographies, acute lower respiratory tract infections are a major cause of mortality
and hospitalization of young children throughout the region, accounting for an average of 
approximately 29% of hospitalizations for acute lower respiratory illness (ALRI) in children 0 
to 11 months of age in studies from India, Southeast Asia, and the Philippines [Shi 2017].  
Estimates of RSV-associated illness incidence rates for India, Bangladesh, Vietnam, Cambodia, 
and the Philippines are relatively consistent, and range from 35.3 to 59.8 events per 1,000 
children per year [Shi 2017]. In multiple studies from India, respiratory syncytial virus is the 
dominant viral pathogen detected in children under 1 year of age who are hospitalized for lower 
respiratory tract infections, where it appears in cases of both bronchiolitis and 
bronchopneumonia, but especially the former [Chattopadhya 1992, Mishra 2016, Singh 2014,
Kamigaki 2017] estimated incidence rates for severe acute respiratory disease associated with 
RSV ranged from 44.0 to 64.4 events per year per 1,000 children < 6 months old, estimates 
which outstripped the impact of influenza virus in this same age group by 2 to 8-fold.
1.3
Therapeutic and Prophylactic Agents Against RSV
To date, the therapeutic and prophylactic agents for use against RSV are limited. Ribavirin, a 
synthetic nucleoside analog with antiviral activity against both DNA and RNA viruses, is 
recommended for hospitalized children and select adults with severe RSV disease, but is 
difficult to administer and of limited benefit unless given early after symptom onset. Two 
immunoglobulin preparations have been indicated for prophylaxis of RSV infection: one, a 
polyclonal human anti-RSV IgG (RSV-IVIG, Respigam [Groothuis 1995, 1993]), was 
discontinued in 2004; and the other, a humanized monoclonal antibody (palivizumab, Synagis®
[MedImmune, Gaithersburg MD]) therapy, is currently approved for use in high-risk infants in 
the US and worldwide. Palivizumab binds to a neutralizing epitope on the RSV F protein at 
amino acids 254-278, termed antigenic site II [Johnson 1997].  Although the clinical benefits 
of palivizumab have been demonstrated, the monthly administration and high expense make 
this product less-than-ideal for use except in premature infants at highest risk. 
Vaccination is considered a potentially cost-effective approach to limit RSV infection in infants, 
elderly adults, and other high-risk populations, but safety remains a major concern in the field 
of RSV vaccine development. In the 1960s, a formalin-inactivated RSV (FI-RSV) vaccine 
produced by Pfizer (i.e., Lot 100 vaccine), although immunogenic, unexpectedly caused 
exacerbation of pulmonary disease in children who subsequently acquired an RSV infection 
[Kim 1969]. This vaccine-enhanced disease phenotype has been attributed in part to an 
imbalanced T helper cell type 2 biased T cell response [Waris 1996]. Other studies have 
suggested disease exacerbation was due to the development of anti-F antibodies deficient in 
fusion-inhibiting and virus-neutralizing activity post-vaccination [Murphy 1988]. Although the 
precise mechanisms underlying these findings remain open to debate [Blanco 2010], the 
phenomenon of vaccine-enhanced RSV disease has been limited to RSV-naïve infants 

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immunized with FI-RSV. Vaccine-enhanced disease has not been observed either with passive 
antibody prophylaxis (monoclonal or polyclonal) in animal models or humans or in clinical 
trials of various F protein-targeted vaccines in adults or older RSV-seropositive children 
[Groothuis 1998, Munoz 2003, Piedra 2003a].  
1.4
Maternal Immunization
RSV disease is rare in the first two weeks of life, but rapidly appears thereafter, presumably due 
to waning of the maternally-derived, RSV-specific antibodies. The example of palivizumab 
demonstrates that passively-acquired serum antibody alone, if of sufficient titer and appropriate 
specificity, is protective in infants. Passive immunization mediated through placental transfer 
of maternally-derived antibodies elicited by RSV F vaccination of pregnant mothers is an 
attractive strategy to raise or boost anti-F neutralizing titers in infants to “protective” levels that 
persist over the vulnerable first months of infancy. 
Maternal immunization has been successfully implemented by WHO to address neonatal 
tetanus and early estimates are that incidence of that disease has been reduced by 92% since the 
program’s inception [Khan 2013]; and influenza immunization of pregnant women has been 
shown to have efficacy against influenza disease in both the woman and her infant and to lack 
adverse impacts on either the course of the pregnancy or the neonate [Pasternak 2012,
Richards 2013, Steinhoff 2012, Zaman 2008]. A recent published report in an in vivo mouse 
model provides further evidence that maternally-derived antibodies in the offspring of pregnant 
females immunized with FI-RSV are safe and have protective activity. The pups display a 
marked reduction in lung viral loads after RSV challenge, relative to controls pups of 
unimmunized pregnant females, and show no histopathological characteristics of vaccine-
enhanced disease [Kwon 2014].
In humans, maternal immunoglobulin G (IgG) antibodies are transplacentally transferred to the 
fetus by active transcytosis facilitated by IgG Fc receptors expressed on the placenta.  Indeed, 
the active transport of IgG antibodies can result in enhanced antibody concentrations in cord 
blood that accumulate to substantial excess of maternal levels in some instances [Gendrel 1990].  
Accordingly, it is a reasonable expectation that raising anti-F neutralizing titers in a pregnant 
woman will increase titers in infants [Simister 2003], and that such an increase will reduce the 
risks of serious RSV disease in the first months of life. 
1.5
RSV F Vaccine
Novavax’ response to the unmet need for RSV prophylaxis is the development of an RSV F 
vaccine, based on a purified, recombinant near full-length RSV fusion (F) glycoprotein. The 
RSV F is produced using the baculovirus/Spodoptera frugiperda (Sf9) insect cell system, and 
assembles into trimers, which further associate via hydrophobic interactions into nanoparticles 
resembling the previously-described 40 nm protein-protein micelles of isolated RSV F protein 
[Calder 2000].  The purified F protein is adsorbed to aluminum phosphate and contains 120 µg 
of RSV F protein and 0.4 mg of aluminum per 0.5 mL injection.  The vaccine contains no viable 
viruses.  

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1.6
Safety and Immunogenicity of RSV F Vaccine in Animals and 
Humans
A detailed review of the nonclinical and clinical experience with the RSV F vaccine is provided 
in the Investigator’s Brochure (IB).  A brief summary is provided here.
1.6.1
Nonclinical Experience
Results from a Good Laboratory Practice (GLP) three repeat-dose toxicology study in New 
Zealand White rabbits indicated the No-Observed-Adverse-Effect-Level (NOAEL) of the 
RSV F vaccine was ≥ 30 µg (irrespective of adjuvantation with aluminum), a dose that is 
approximately 2.5 to 4.2-fold in excess (on a weight-adjusted basis) of a 120 µg antigen dose 
(the highest proposed human exposure) in a 50 kg human. The single relevant finding observed 
in vaccinated animals was the presence of inflammatory lesions at the injection site, which were 
consistent with immune system activation in response to the vaccine. The reduction in incidence 
and severity of such lesions at the recovery time-point suggested that these events are reversible 
following cessation of treatment.  
A GLP-compliant reproductive toxicity study in New Zealand White rabbits evaluated the 
impact of four (4) doses of RSV F vaccine (120 µg) formulated with aluminum phosphate 
(0.8 mg Al content) in contrast to a saline placebo. Two doses were administered 
intramuscularly at a 21-day interval prior to mating, and two further doses at approximate 
Days 7 and 21 of gestation. F0 does were evaluated for mortality, clinical signs, body weight 
and food consumption, and mating performance. Half of the F0 animals were sacrificed and 
underwent caesarean delivery on approximately Day 29 of gestation for ovarian and uterine 
examinations, and fetal examinations.  The balance of F0 animals were allowed to deliver 
naturally. The F1 kits were assessed for mortality, clinical signs, weight gain and food 
consumption, reflex and physical development, and an observational battery of behavioral 
assessments.  
There was no RSV F vaccine-related effect on mortality or clinical signs in the F0 does, or 
overall impact on mean weights or weight gain before mating, during gestation, or during 
lactation.  Mating occurred in 100% of control animals and 98% of vaccine-treated animals, 
and pregnancy occurred in 98 and 94%, respectively.  One doe in each of the control and 
treatment groups aborted.  In general, there were no clear effects on ovarian/uterine or litter 
observations.  The percentage of pre-implantation losses was slightly, but significantly higher 
in the vaccine group, but there were no significant differences in litter sizes or counts of live 
fetuses.  There were non-statistically significant increases in the number of litters with 
reversible delays in skeletal development (incomplete ossification of the sterna or pubes) in the 
active vaccine group, but these occurred in the smallest fetuses of pregnant animals with 
episodes of body weight loss, an association known in the literature. Pre-weaning and post-
weaning mortality, clinical signs, weight gain, food consumption, and a functional 
observational battery assessing behaviors in post-weaning animals showed no impact of RSV F 
vaccine treatment on the F1 kits.  Immune responses to the vaccine in the F0 does, and placental 
transfer of RSV F-specific maternal antibodies to the fetuses, were documented. It was 
concluded by the study director that RSV F vaccine treatment had no apparent adverse F0 

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maternal effects on mating or fertility and reproduction, and no adverse effects on postnatal 
growth and development of F1 kits of either sex.
In nonclinical studies of immunogenicity, the aluminum-adjuvanted vaccine has proven to be 
immunologically active in all animal models tested (including mice, cotton rats, rabbits, guinea 
pigs, and baboons) and generally superior to unadjuvanted RSV F protein, as indicated by RSV 
neutralizing and anti-F IgG antibody titers, and also the induction of antibodies capable of both 
competing with palivizumab for its binding site on the F protein and binding to an antigenic site 
II linear peptide. When challenged with intranasal RSV, F protein-immunized mice and cotton 
rats were protected from infection (as evidenced by reduced viral replication in lung 
homogenates), and failed to exhibit any evidence of the enhanced pulmonary disease which can 
be elicited in animals vaccinated with FI-RSV and subsequently challenged. In addition, passive 
transfer of sera from cotton rats immunized with RSV F vaccine was able to protect naïve cotton 
rats against RSV challenge in a manner similar to passive palivizumab treatment, indicating that 
a cellular immune response was not required to mediate at least short-term protection. Both 
rabbits and guinea pigs, the latter having placental architecture similar to humans, demonstrate 
vigorous anti-F immune responses after immunization during pregnancy and transplacental 
transfer of vaccine-induced antibodies to their pups. Preliminary data in baboon infants of 
vaccinated mothers indicate that these offspring acquire antibodies to RSV F protein in utero
and show clinically relevant protection against RSV challenge, as demonstrated by improved 
activity levels, reduced tachypnea, and reduced work of breathing relative to infants of 
unimmunized mothers.
1.6.2
Clinical Experience
Novavax’ clinical experience with the RSV F vaccine in young adults and children is based 
upon accumulated data in five randomized, blinded and placebo-controlled clinical trials which 
are complete to date. These completed trials include 1,069 subjects exposed to active vaccine, 
of which 1,022 were healthy young adults ≤49 years of age, and 973 were young women of 
child-bearing age.  Additional active vaccine recipients in completed trials include 22 pregnant 
women between 18 and 40 years of age and 25 children, 2 to 5 years of age. In addition, 
Novavax has treated a total of approximately 6,879 adults 60 years of age and over with a 
different formulation of the RSV F nanoparticle vaccine.  This older adult population has a 
different baseline co-morbidity status than healthy young adults, and a different 
immunogenicity and reactogenicity profile than young adults; therefore it will not be detailed 
further. However, the older adult population has revealed no unusual safety concerns.
Overall, the completed trials in young adults and children have shown that all RSV F vaccine 
formulations tested have produced an acceptable safety profile and were well-tolerated, with no 
significant dose-related toxicities observed. There have been no deaths, serious adverse events
deemed related to the RSV F vaccine by the Sponsor, or subject withdrawals due to an AE 
reported in any of these completed studies. The majority of complaints have been mild to 
moderate solicited injection site events of tenderness/pain and systemic events of headache, 
muscle pain, and fatigue, which have resolved without sequelae during study conduct. The 
active vaccine reactogenicity profile was clearly differentiable from placebo in all studies, but 
did not demonstrate either a strong dose-related increase in the frequency or severity of 

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symptoms or increased reactogenicity after a second dose. The frequency of reports of fever in 
the first seven days after vaccine doses exceeds that in the first seven days after placebo by 
approximately 1%. A small increase in injection site complaints of pain, swelling, and redness, 
and muscle pain and joint pain was attributable to the addition of aluminum adjuvant. A review 
of the clinical laboratory assessments did not indicate any systematic toxicity to the renal or 
hepatobiliary systems, or to the bone marrow or circulating formed elements of the blood. 
The predominant local reactogenicity profile observed across studies in adjuvanted vaccine 
recipients included mild to moderate injection site pain/tenderness reported in approximately 
70% of all aluminum-adjuvanted vaccine recipients versus approximately 20% of placebo 
recipients.  Swelling, redness, and bruising at the injection site occurred at substantially lower 
rates by comparison, reported by 10 to 20% of adjuvanted vaccine recipients compared to 1 to 
3% of placebo recipients. Injection site reactogenicity did not increase notably in frequency or 
severity among subjects who received a second dose.  Additionally, 10% of subjects may report 
residual mild injection site discomfort lasting outside the 7-day active solicitation interval. 
Systemic reactogenicity reports were generally mild to moderate in severity. The predominant 
systemic complaints in adjuvanted vaccine and placebo recipients alike were muscle pain 
(33 and 16%, respectively), headache (36 and 32%), fatigue (30 and 26%); followed by less 
frequent reports of nausea (17 and 19%), chills (12 and 10%), joint pain (12 versus 7%), 
diarrhea (12% in both active and placebo), vomiting (3 and 5%), and fever (2 and 1%). 
Unsolicited adverse event reports of cough, oropharyngeal pain, nasal congestion, upper 
respiratory tract infection, anemia, nasopharyngitis, pharyngitis, contusion, decreased 
hemoglobin, rhinorrhea, toothache, rhinitis, viral infection, and pain in extremity were 
commonly reported (>1 to 10% of subjects) in adjuvanted vaccine recipients. For comparison, 
all except the nasopharyngitis, rhinitis, contusion, and pain in extremity were also commonly 
reported in placebo recipients.  
Considering the 22 pregnant women who received RSV F vaccine in the third trimester 
(concurrently with 28 who received placebo), a review of safety data showed the RSV F 
Vaccine candidate was well-tolerated with no significant risks to overall health identified. Four 
maternal subjects reported a total of 5 serious adverse events (SAEs), but none of the SAEs 
were considered related to treatment and all were judged by the investigator as moderate in 
severity. No maternal deaths or subject withdrawals due to an adverse event (AE) were reported. 
Medical treatment for AEs (ie, medically-attended events or MAEs) was sought by similar 
proportions of placebo and active vaccine recipients. Most MAEs were related to labor and 
delivery, including labor pain (54.5% active and 46.4% placebo), obstructed labor (31.8% and 
39.3%, respectively), postpartum hemorrhage (22.7% and 28.6%, respectively), and afterbirth 
pain (13.6 and 21.4%, respectively).  
More active vaccinees among the pregnant women reported solicited AEs typical of 
intramuscular vaccine reactogenicity as compared to placebo recipients (68 vs 36%, 
respectively). This difference was primarily driven by pain at injection site (59% vs 0%, 
respectively). The local pain was entirely mild or moderate in severity and transient; all events 
resolved within the 7-day solicited period in the active group. The incidence of solicited 
systemic AEs was similar in the active and placebo groups (27% vs 36%, respectively) with 

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headache identified as the most commonly reported event among both groups (18 and 25%, 
respectively). None of the active vaccine recipients reported instances of fever. None of the 
solicited AEs were severe.
There was no difference in the incidence rates of unsolicited AEs through 6 months after 
delivery between the placebo and active vaccine groups, or the proportion that were deemed 
related to the treatment (11 and 9%, respectively), or severe (14% each). None of the severe 
AEs were considered related to treatment. The most commonly reported unsolicited AEs among 
placebo and active subjects (> 10% of subjects) pertained to labor and delivery events, 
hemorrhoids, observed decreased respiratory rate, hypotension, and perineal injury. Lastly, 
administration of the vaccine was not clearly associated with any systemic toxicity pertaining 
to renal or hepatic injury, ability to regulate glucose systemically, or abnormal changes in 
hematological parameters such as hemoglobin, white blood cells, or platelet counts. 
Considering the infants born to mothers treated with vaccine or placebo, there was no evidence 
that administration of the RSV F vaccine to pregnant women posed any safety risk to their 
infants that was apparent in this limited data set.  No clear differences were noted in the pattern 
of adverse events reported among infants born to mothers that received the RSV F vaccine as 
compared to infants of mothers that received placebo. The subject incidence rates of unsolicited 
AE reports in infants were comparable in both groups (93% placebo vs 91% active). 
Gastroesophageal reflux disease, upper respiratory tract infection, acute otitis media, and 
vomiting were the most commonly (> 10%) reported unsolicited events in the placebo group. 
Upper respiratory tract infection, acute otitis, acute, contusions, eczema, gastroesophageal 
reflux disease, conjunctivitis, decreased appetite, and dry skin were the most commonly 
reported unsolicited events in the active group. All events reported in infants in the active group 
were deemed mild or moderate in severity by the investigator (compared with 3 severe events 
reported in the placebo group), and none were considered related to treatment in either group. 
The proportions of infant subjects who reported MAEs were similar in both groups (89% 
placebo vs 82% active) with no systematic association or trend within a particular class of AEs 
noted in infants in the active group. No deaths were reported among the infants in the study. A 
total of 19 SAEs were reported in 11 infant subjects, which included 8 infants (14 SAEs) in the 
placebo group and 3 infants (5 SAEs) in the active vaccine group. All SAEs reported were 
considered unrelated to the test article administered to the maternal subject, and only a single 
event term (failure to thrive in two infants of placebo recipients) was reported more than once.
Health outcomes in both groups of delivered infants were also unremarkable, as mean 
gestational age (~39 weeks), weights (~3.4 kg), heights (~51 cm), FOC (~34 cm), and 1 and 5 
minute APGAR scores (~8-9) were all comparable. All changes in length, weight, FOC, and 
Bayley III developmental screening results for both groups of infants through Day 365 post-
delivery were considered by investigators as within normal limits in both groups. Two infants 
born to mothers that received the RSV F Vaccine had RSV infections at 49 and 87 days post-
delivery during the 1st RSV season; a third infant was diagnosed with RSV at 359 days post-
delivery, which was during the infant’s 2nd RSV season.  In addition, in the placebo group, one 
maternal subject and one infant subject at 33 days post-delivery had RSV disease. Importantly, 
none of the RSV disease in any subject was identified as severe or serious or required 

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hospitalization and thus no findings of enhanced RSV disease or severe RSV disease were 
present.
1.7
Study Rationale
The goal of this clinical development program is to establish efficacy of the RSV F vaccine by 
providing protection against RSV disease in infants during the first three to six months of life 
via active immunization of pregnant women in the third trimester of pregnancy. Passive 
immunization of infants will be achieved through transplacental transfer of maternal IgG 
antibodies from the pregnant mother who has received the RSV F vaccine in the third trimester 
of her pregnancy. Maternally derived, transplacentally-mediated immunity is a physiologic, 
effective, and established means for protecting infants against infectious diseases during the 
first months of life. Active Fc-gamma receptor mediated transport of maternal IgG begins early 
in gestation, but reaches significant levels at 28 weeks gestational age [Palmeira 2012].  By 
≥36 weeks gestational age, antibody levels in the fetus are generally in excess of levels found 
in the mother [Lindsey 2013].  Maternal immunization programs addressing tetanus, pertussis, 
and influenza have all shown benefits to infants. Albeit less well-recognized than influenza, 
anecdotal observations suggest that significant RSV disease may also occur in pregnant women 
themselves, and thus an additional benefit to the mother may also be obtained by immunization 
with an RSV vaccine [Wheeler 2015]. Two recent reports of prospective studies have confirmed 
the existence of a symptomatic RSV disease burden in mothers [Hause 2018, Madhi 2018].
For this global clinical trial of the RSV F vaccine in pregnant women, a 120 μg dose of RSV F 
protein with 0.4 mg aluminum as the phosphate salt, administered as a single injection, was 
selected based on a previous study of women of child-bearing age, where this formulation and 
regimen were well-tolerated and produced the highest peak anti-F antibody responses at 14 days 
post-vaccination when evaluated against other vaccine formulations and regimens. This rapid 
response reflects the fact that all adults are immunologically primed to RSV. The RSV F 
vaccine in general has been shown to elicit high levels of antibodies to the neutralizing RSV F 
protein antigenic site II epitope, based on competition with the globally licensed proven-
efficacious monoclonal antibody palivizumab, as well as assays of direct binding of IgG to the 
antigenic site II linear peptide encompassing amino acid residues 254-278. Levels of these 
antibodies may exceed the trough levels of palivizumab associated with clinical protection by 
10-fold.  This, in turn suggests that, with active placental transfer and possible concentration of 
these antibodies, infant protection extending through at least 3 to 6 months of life might be 
feasible. 
Data from the first-in-pregnant women study (RSV-M-203, N=50) with the RSV F vaccine 
conducted in the United States (US) showed the vaccine was well-tolerated, posing no 
significant safety risk to pregnant women or their infants that was apparent in this limited 
dataset; and was immunogenic, eliciting antibody responses that were analogous in kinetics and 
magnitude to levels observed in non-pregnant women of childbearing age. Results indicated the 
antibody profile achieved with a single dose of the RSV F vaccine in pregnant subjects 
immunized at 33 to 35 weeks gestation was robust, with substantial responses measurable by 
14 days post-vaccination; and diverse, eliciting antibodies with binding activity to the antigenic 
sites I and IV neutralizing epitopes on the F protein in addition to antigenic site II. 

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Transplacental transfer of maternal antibodies with specificity to the RSV F protein in delivered 
infants averaged 90 to 100% of the actively-treated matched mother, but averaged 110 to 120% 
when immunization preceded delivery by ≥ 30 days. This supports immunization of pregnant 
women between 28 to 36 weeks gestation in this study, as widening the window for vaccination 
to include women at the beginning of the third trimester is not expected to result in increased 
safety risk to the woman or fetus [Madhi 2014, Munoz 2014], and may increase the potential 
for higher vaccine-specific antibody titers in the delivered infant due to extended transplacental 
transfer [Abu Raya 2014, Eberhardt 2016, Naidu 2016].
The objectives of the Phase 2 trial were to establish an initial maternal safety database in 
pregnancy, assess the amplitude of transplacental transfer of vaccine-induced antibodies in 
humans, estimate the decay half-life of such antibodies in infants, and detect any signal 
suggestive of “vaccine-enhanced disease” in infants over their first RSV transmission season.
Please refer to the Investigator’s Brochure (IB) for current updates and new findings pertaining 
to the RSV F vaccine. 
1.8
Risk
The most relevant studies to inform the risk of the RSV F vaccine in young pregnant women 
are derived from clinical observations made in 973 female subjects of child-bearing potential 
(the intended study population for this protocol), who were exposed to the RSV F antigen at 
doses up to 120 µg, alone or with up to a 1.2 mg dose of aluminum per injection, and from 
observations made in the 22 RSV F vaccine exposures of third-trimester pregnant women and 
their infants. 
Overall, results have indicated the vaccines were not associated with persistent (based on a six-
month post-second dose and one year post-first dose safety follow-ups) reactogenicity; and 
most short-term reactogenicity events were mild or moderate in severity. Most symptoms were 
transient, resolved without sequelae during study conduct, and did not require medical 
intervention. Adjuvanted-RSV F vaccine recipients were two to three times more likely to 
experience a mild solicited adverse event at the injection site relative to their counterparts 
receiving unadjuvanted vaccines or placebo, with pain/tenderness at the injection site observed 
as the most frequent local complaint. Up to 10% of adjuvanted vaccine recipients may have 
mild local discomfort at the injection site that persists beyond 7 days. Headache, muscle pain, 
and fatigue were the most frequently reported systemic solicited adverse events, followed by 
reports of nausea, chills, joint pain, diarrhea, vomiting, and fever, which all occurred at lower 
frequencies. Of the solicited systemic events reported, only muscle pain and joint pain occurred 
at notably higher rates in adjuvanted vaccinees than placebo recipients. The vaccine-attributable 
rate of fever in the 7 days after immunization among adjuvanted vaccine recipients has been 
1 to 2%. Unsolicited adverse events experienced by >1% of adjuvanted RSV F vaccine 
recipients included cough, oropharyngeal pain, nasal congestion, upper respiratory tract 
infection, anemia, nasopharyngitis, pharyngitis, contusion, decreased hemoglobin, rhinorrhea, 
toothache, rhinitis, viral infection, and pain in extremity. In general, these events were reported 
at similar incidence rates by placebo recipients. SAEs have been infrequent, generally comprise 
common intercurrent illnesses or events that were presaged by prior medical history, and have 
been assessed by investigators as unrelated to the experimental vaccines.

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Results obtained in RSV F vaccine-treated pregnant women suggested the vaccine did not 
appear to pose any increased safety risk to the general health of the woman, to the health and 
progression of the pregnancy, or to the infant. Pregnancy and labor and delivery complications 
noted were unremarkable in terms of the frequency, or severity of events and approximately 
equally distributed between in active vaccinees and placebo recipients. Infants of actively-
immunized women achieved normal marks for all growth and development measures at birth 
through two months of age. 
Because of the limited clinical trial subject numbers, it is not yet possible to evaluate whether 
the adverse events described here are, or are not, causally-related to the RSV F vaccine (with 
or without adjuvant), and other adverse effects may exist which have not yet been detected. In 
common with all vaccines produced in cell culture or other systems, the RSV F vaccine contains 
residual non-vaccine proteins derived from the production system, and sensitization to these 
may theoretically occur. Safety monitoring for hypersensitivity and/or allergic reactions has 
been conducted routinely during study conduct through clinical evaluations and direct 
observations up to 30 minutes post-immunization. While the occurrence of immediate 
hypersensitivity is possible with the parenteral administration of any vaccine, whether licensed 
or in development, no such reactions have been observed in the clinical studies conducted with 
the RSV F vaccine to date. As clinical data become available with increased exposure, it is 
possible that this profile may change. 
As discussed in Section 1.2.4, a formalin-inactivated RSV vaccine trial conducted in the 1960s 
in very young children largely without prior RSV immunity led to an increase in the severity of 
subsequent RSV infections. The exact basis of this result has never been completely clarified.  
However, clinical trials of several RSV vaccines containing F protein, with or without other 
components, and performed in adults and older children, have never resulted in this 
complication. With a mean exposure within the RSV transmission season of 54.5 days among 
infants of actively-immunized women in the RSV-M-203 trial, there were no safety signals 
suggestive of enhanced RSV disease in the infants of actively immunized mothers in the phase 
II trial. While that trial represents a small experience, the signal of enhanced disease noted in 
the Kim (1969) experience was so large that the currently available dataset is inconsistent with 
a finding of similar, or substantially smaller, magnitude.
This study is the second to evaluate the RSV F vaccine in third-trimester pregnant women. 
Currently, there may be adverse effects that may exist that cannot be predicted to occur. Thus, 
the safety of maternal and infant subjects is being carefully monitored throughout the study. 

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2
STUDY OBJECTIVES
2.1
Primary Objective 
The primary objective of this study is:

To determine the efficacy of maternal immunization with the RSV F vaccine against 
medically-significant RSV lower respiratory tract infection (LRTI) with EITHER 
hypoxemia (peripheral oxygen saturation [SpO2] < 95% at sea level or < 92% at altitudes 
> 1800 meters) OR tachypnea (≥ 70 bpm for infants 0 to 59 days of age or ≥ 60 bpm for 
infants ≥ 60 days of age) through the first 90 days of life in infants of maternal RSV F 
vaccinees as compared to placebo recipients. In the event that efficacy is shown through 
the first 90 days of life, a hierarchical sequence of hypothesis tests will be carried out to 
examine efficacy through the first 120, 150, and 180 days of life.
The primary efficacy objective will be evaluated in term infants (≥ 37 weeks gestational age at 
delivery) born to maternal subjects who received a study injection ≥ 2 weeks (14 days) prior to 
delivery. Infants with multiple RSV episodes will be counted only once, using data from the 
first episode of medically-significant RSV LRTI. Success under the primary hypothesis will 
be achieved by demonstration of a lower bound of a two-sided 97.52% confidence interval for 
the Day 90 analysis (lower bound of a 95% confidence interval for later time points) for the 
estimate of vaccine efficacy which equals or exceeds target values agreed with regulatory 
authorities.
2.2
Secondary Objectives
The secondary objectives of this study are:

To determine the efficacy of maternal immunization with the RSV F vaccine in reducing 
the incidence in infants of:
o
RSV LRTI with EITHER severe hypoxemia (SpO2 < 92% at sea level or < 87% at 
altitudes > 1800 meters) OR documented use of oxygen by high flow nasal cannula 
OR a requirement for continuous positive airway pressure (CPAP) OR bilevel 
positive airway pressure (BiPAP) OR Bubble CPAP OR bag-mask ventilation OR 
intubation with subsequent mechanical (or manual) ventilation OR extracorporeal 
membrane oxygenation (ECMO), through the first 90 days of life in infants of 
maternal RSV F vaccinees as compared to placebo recipients. In the event that 
efficacy is shown through the first 90 days of life, a hierarchical sequence of 
hypothesis tests will be carried out to examine efficacy through 120, 150, and 180 
days of life.
o
RSV LRTI leading to hospitalization through the first 90 days of life in infants of 
maternal RSV F vaccinees as compared to placebo recipients. In the event that 
efficacy is shown through the first 90 days of life, a hierarchical sequence of 
hypothesis tests will be carried out to examine efficacy through 120, 150, and 
180 days of life.

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The two secondary efficacy objectives will be evaluated in term infants (≥ 37 weeks gestational 
age at delivery) born to maternal subjects who received a study injection ≥ 2 weeks (14 days) 
prior to delivery. Infants with multiple RSV episodes meeting a given criterion will be counted 
only once, using data from the first episode. Success under the secondary efficacy hypotheses 
will be achieved by demonstration of a lower bound of a two-sided 95% confidence interval for 
the estimate of vaccine efficacy which exceeds 0%.

To describe the immunologic responses to the RSV F vaccine in healthy maternal 
subjects, in the third trimester of pregnancies deemed to be at low risk of obstetrical 
complications, through delivery and six months thereafter.

To describe the transplacental transfer of maternal antibodies specific for RSV and its 
F protein based on the ratio of levels in maternal and cord blood at delivery.  

To estimate the rate of decay of RSV and F protein-specific antibodies in infants through 
the first six months of life. 

To develop an immune correlate of risk of the RSV LRTI syndromes in infants based 
on anti-F protein antibody and/or palivizumab-competitive antibody levels measured in 
the infant and/or cord blood. 

To develop an immune correlate of risk of the RSV LRTI syndromes in infants based 
on anti-F protein antibody and/or palivizumab-competitive antibody levels measured in 
maternal subjects at delivery. 

To describe the safety of third-trimester maternal immunization with the RSV F vaccine 
in infants of vaccinated maternal subjects through their first year of life, which will 
include at least one RSV season.

To describe the safety of the RSV F vaccine in healthy maternal subjects, in the third 
trimester of pregnancies deemed to be at low risk of obstetrical complications, through 
delivery and six months thereafter. 
2.3
Exploratory Objectives
The exploratory objectives of this study are:

To describe the efficacy of maternal immunization with the RSV F vaccine in reducing 
the incidence in infants of medically-significant RSV LRTI defined as per the primary 
objective but with the inclusion of data concerning documentation of RSV infection, 
LRTI symptoms and signs, hypoxemia and/or tachypnea obtained from the observations 
of the clinical site staff OR review and abstraction of medical records for infants 
undergoing hospitalization for a respiratory serious adverse event.

To describe the efficacy of maternal immunization with the RSV F vaccine in reducing 
the incidence of RSV LRTI with EITHER severe hypoxemia (SpO2 < 92% at sea level 
or < 87% at altitudes > 1800 meters) OR the documented use of oxygen by high flow 
nasal cannula OR continuous positive airway pressure (CPAP) OR bilevel positive 
airway pressure (BiPAP) OR Bubble CPAP OR bag-mask ventilation OR intubation 
with subsequent mechanical (or manual) ventilation OR extracorporeal membrane 
oxygenation (ECMO) defined as per the first secondary objective but with the inclusion 

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of data concerning documentation of RSV infection, LRTI symptoms and signs, and 
hypoxemia obtained from the observations of the clinical site staff OR review and 
abstraction of medical records for infants undergoing hospitalization for a respiratory 
serious adverse event. 

To describe the efficacy of maternal immunization with the RSV F vaccine in reducing 
the incidence of RSV LRTI requiring hospitalization defined as per the second 
secondary objective but with the inclusion of data concerning documentation of RSV 
infection, LRTI symptoms and signs obtained from the observations of the clinical site 
staff OR review and abstraction of medical records for infants undergoing 
hospitalization for a respiratory serious adverse event. 

To describe the efficacy of maternal immunization with the RSV F vaccine in reducing 
the incidence in infants of RSV LRTI associated with EITHER hypoxemia (peripheral 
oxygen saturation [SpO2] < 95% at sea level or < 92% at altitudes > 1800 meters) OR
tachypnea (≥ 60 bpm for infants 0 to 59 days of age or ≥ 50 bpm for infants ≥ 60 days 
of age [WHO Handbook, Integrated Management of Childhood Illness criteria for 
tachypnea]) with the inclusion of data concerning documentation of RSV infection, 
LRTI symptoms and signs, hypoxemia and/or tachypnea obtained from the observations 
of the clinical site staff OR review and abstraction of medical records for infants 
undergoing hospitalization for a respiratory serious adverse event. 

To describe the efficacy of maternal immunization with the RSV F vaccine in reducing 
the incidence in infants with RSV LRTI resulting in death.  Evidence of RSV infection 
and LRTI may be based on either or both of the observations of the clinical site staff 
using sponsor-supplied devices and diagnostic tests OR review and abstraction of 
medical records for infants undergoing hospitalization for a respiratory serious adverse 
event. 

To describe the efficacy of maternal immunization with the RSV F vaccine in reducing 
the incidence in infants of all RSV LRTI.
For all of the above exploratory analyses infants, if efficacy is shown through the first 90 
days of life, a hierarchical sequence of hypothesis tests will be carried out to examine 
efficacy through 120, 150, and 180 days of life.

To describe the efficacy of maternal immunization with the RSV F vaccine in reducing 
the incidence of healthcare interventions associated with wheezing through the first year 
of life in infants of maternal RSV F vaccinees as compared to placebo recipients.

To describe the efficacy of maternal immunization with the RSV F vaccine in reducing 
the incidence of all symptomatic RSV respiratory tract infections detected by 
active/passive surveillance in maternal subjects from immunization through six months 
after delivery.

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
To describe the incidence of all-cause LRTI, with and without tachypnea, hypoxemia,
or severe hypoxemia, in infant subjects as detected by active and passive surveillance 
from vaccination through six months after delivery, and the efficacy of maternal 
immunization with the RSV F vaccine in reducing the incidence of these endpoints. 

To describe the epidemiology of non-RSV respiratory viruses detected by RT-PCR in 
infant and maternal subjects presenting with respiratory symptoms, through six months 
after delivery. 

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3
STUDY DESIGN
3.1
Design
This is a randomized, observer-blind, placebo-controlled trial enrolling up to approximately 
4,600
third-trimester pregnant women in the Northern
and Southern hemispheres.
Randomization will be configured to provide approximately 3,000 exposures to the active test 
article. 
Healthy women in the third trimester of a singleton uncomplicated pregnancy, at low risk of 
obstetrical complications, and ≥18 to ≤40 years of age (lower limit of 18 years and 0 days and 
an upper limit of 40 years and 0 days) will be enrolled and randomized, initially in a 1:1 ratio,
into one of two treatment groups, active or placebo, over approximately the three months prior 
to peak RSV season as shown in Table 1. After the first global season of enrollment, the 
randomization scheme will be changed to a 2:1 (active / placebo) ratio to enable more efficient 
accrual of the safety database. Due to the importance of infant RSV exposure in order to 
demonstrate efficacy of the maternal immunization strategy, investigators will be instructed to 
base maternal enrollment on a projected date of delivery for each maternal subject. The 
estimated date of the earliest delivery (EDD-E) will be approximately 6 weeks prior to the 
historic average onset date of increased RSV transmission at each study site. The estimated date 
of the latest delivery (EDD-L) will be calculated based on the historic average end date of RSV 
transmission at each study site, such that participating infants are likely to have a minimum 3 
month exposure to RSV transmission. The Sponsor will assist and provide guidance to each site 
in determining the EDD-E and EDD-L using best available site-specific, local, state/provincial,
or national surveillance data to the extent available. Please refer to the Study Operations 
Manual for further details.
Table 1:
Treatment Assignments
Treatment 
Group
Target Maternal 
Subjects/Group[1]
Test
Article
Dosing 
Volume
Vaccination 
Day
A
~ 1562
Placebo
0.5 mL
Day 0
B
~ 3038
RSV F vaccine
[1] The target number of subjects that may be enrolled over multiple global RSV seasons, based on a 1:1 randomization
for the first season and 2:1 (active / placebo) randomization for all subsequent seasons.
Randomization of maternal subjects will be done at the site level and will be stratified by age 
(i.e., 18 to < 29 years and 29 to ≤ 40 years). No specific proportion in either age group will be 
sought, rather the intent of stratification will be to distribute the proportion of maternal subjects 
presenting for enrollment in each age group equally across the two treatment arms. In addition, 
infant subjects born to randomized maternal subjects will be prospectively and randomly 
assigned to one of three postpartum phlebotomy cohorts, which will differ only in the timing of 
blood sampling (see Appendix 1). It is anticipated that a percentage of the randomized maternal 
subjects and their delivered infant may not complete the study; subjects (maternal and infant) 
who withdraw or are discontinued will not be replaced.

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All maternal subjects will receive a single intramuscular (IM) injection on Day 0 with the 
assigned test article, either the RSV F vaccine or placebo (see Table 1). The procedures to be 
performed in the study are described in detail in Section 6.1 of this protocol. Maternal subjects 
will be monitored for typical vaccine reactogenicity, clinical laboratory impacts, and specified 
adverse pregnancy outcomes, as well as general AEs and SAEs.  In addition, because the 
maternal illness and obstetrical risk burden due to RSV is largely unknown, the occurrence of 
RSV disease in maternal subjects will be monitored before and after delivery. Vaccine impacts 
on markers of infant development and well-being at birth will be monitored, as will growth and 
development through the first year of life.  Infant blood samples will be taken to assess the 
decay half-life of maternally-derived RSV antibodies. Symptomatic infant and maternal RSV 
infections will be monitored through the first RSV season using both active and passive 
surveillance mechanisms; and will be etiologically-confirmed using RSV RT-PCR. Infant RSV 
infections will be characterized based on their symptomatology, associated degree of 
hypoxemia as measured by pulse oximetry, respiratory rate as measured by observation for 
1 minute, and required medical interventions.
For each maternal subject, study participation will span approximately nine (9) months from 
the first dose, ending six (6) months post-delivery. Study follow-up for infant subjects who are 
consented will span approximately one (1) year post-delivery. 
A Data and Safety Monitoring Board (DSMB) will supervise enrollment and monitor subject 
safety throughout the trial (see Section 8.10).  In order to ensure that mothers and infants are 
not placed at risk with scant possibility of success, repeated futility analyses will be performed 
twice per year during the period of the study.  Due to the seasonal nature of RSV disease and 
the occurrence of RSV seasons in a roughly sequential manner across the Northern and Southern 
hemispheres, futility analyses, for detecting situations in which the existing efficacy data is not 
consistent with a predefined minimal clinical benefit, will occur at the approximate end of each 
Northern hemisphere season (data as of approximately 30 May) and each global RSV season 
(data as of approximately 30 September, comprising a Northern hemisphere season and the 
following Southern hemisphere season); and subject to constraint (applied by the DSMB 
statistician) that at least 10 cases will have accrued in the active treatment arm. A determination 
of futility at any futility analysis, will lead to a DSMB recommendation to terminate the trial, 
and stop further enrollment. 
The primary analysis of the trial is an evaluation of the superior efficacy of the RSV F vaccine 
relative to the placebo in reducing the rate of medically-significant RSV LRTI in infants from 
delivery through the first 90 days of life. If successful outcomes are obtained through 90 days 
of life, then additional analyses for efficacy will be performed in a closed hierarchical sequence
considering data from delivery through 120, 150, and 180 days of life (with each sequential 
analysis being enabled by a significant result at the preceding shorter interval).  Multiple 
secondary and exploratory efficacy analyses will also address other infant and maternal RSV 
disease outcomes.
All primary and secondary efficacy endpoints, as well as exploratory efficacy endpoints in 
infants concerning RSV-associated illness, will be reviewed and validated by an independent 
Clinical Endpoint Adjudication Committee (CEAC) prior to unblinding (see Section 10.4.2).  

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Only endpoints validated by the CEAC review will be used for the efficacy analyses.
Section 10.4.3 provides details of the futility and efficacy analyses.
3.2
Study Endpoints
3.2.1
Primary Efficacy Endpoint (In Infant Subjects)

Percentages of infants with medically-significant RSV LRTI from delivery through 90, 
120, 150, and 180 days of life, as defined by:
o
The presence of RSV infection confirmed by detection of RSV genome by 
RT-PCR on respiratory secretions (obtained within the continuous illness 
episode which fulfills the other criteria listed below); AND
o
At least one manifestation of lower respiratory tract infection (LRTI) from 
among the following: cough, nasal flaring, lower chest wall indrawing, subcostal 
retractions, stridor, rales, rhonchi, wheezing, crackles/crepitations, or observed 
apnea; AND
o
Evidence of medical significance as defined by the presence of:
-
EITHER hypoxemia (peripheral oxygen saturation [SpO2] < 95% at sea 
level or < 92% at altitudes > 1800 meters) OR
-
Tachypnea (≥70 breaths per minute [bpm] in infants 0 to 59 days of age 
and ≥60 bpm in infants ≥60 days of age). 
Data elements supporting the three (3) criteria for a primary endpoint case will be 
present within the start and stop dates of a continuous illness episode and derived from 
clinical observations (LRTI signs and symptoms and respiratory rates) made by 
qualified clinical trial site staff, pulse oximetry performed by site personnel using a 
Masimo RAD-5 pulse oximeter supplied by the sponsor, and RSV detection based on 
study-specified RT-PCR performed by the validated GenMark eSensor assay in place 
at the central laboratory (Marshfield Clinic Research Institute, Marshfield, Wisconsin).  
A Clinical Endpoint Adjudication Committee (CEAC) composed of expert pediatricians 
(see Section 10.4.2) will carry out a blinded review of all potential primary endpoint 
cases to determine if they fulfill the primary endpoint criteria in a temporally plausible 
relationship consistent with RSV disease as observed in clinical practice.  Only CEAC-
confirmed cases will be used for the primary endpoint.
3.2.2
Secondary Efficacy Endpoints (In Infant Subjects)

Percentages of infants with RSV LRTI with EITHER severe hypoxemia (SpO2 < 92% 
at sea level or < 87% at altitudes > 1800 meters) OR the documented use of oxygen by 
high flow nasal cannula OR a requirement for continuous positive airway pressure 
(CPAP) OR bilevel positive airway pressure (BiPAP) OR Bubble CPAP OR bag-mask 
ventilation OR intubation with subsequent mechanical (or manual) ventilation OR 
extracorporeal membrane oxygenation (ECMO) from delivery through 90, 120, 150,
and 180 days of life. An event is considered RSV LRTI with severe hypoxemia if all 
parameters outlined below are present during a continuous symptomatic illness episode:

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o
RSV infection as confirmed by detection of the RSV genome by RT-PCR, AND
o
At least one manifestation of lower respiratory tract infection (LRTI) from 
among the following: cough, nasal flaring, lower chest wall indrawing, subcostal 
retractions, stridor, rales, rhonchi, wheezing, crackles/crepitations, or observed 
apnea, AND
o
Evidence of severe hypoxemia or the requirement for respiratory support as 
defined by the presence of:
-
EITHER severe hypoxemia (peripheral oxygen saturation [SpO2] < 92% at 
sea level or < 87% at altitudes > 1800 meters) OR
-
The documented use of oxygen by high flow nasal cannula OR continuous 
positive airway pressure (CPAP) OR bilevel positive airway pressure 
(BiPAP) OR Bubble CPAP OR bag-mask ventilation OR intubation with 
subsequent mechanical (or manual) ventilation OR extracorporeal 
membrane oxygenation (ECMO).

Percentages of infants with RSV LRTI with hospitalization from delivery through 90, 
120, 150, and 180 days of life. An event is considered RSV LRTI hospitalization if all 
parameters outlined below are present during a continuous symptomatic illness episode:
o
RSV infection as confirmed by detection of the RSV genome by RT-PCR, AND
o
At least one manifestation of lower respiratory tract infection (LRTI) from 
among the following: cough, nasal flaring, lower chest wall indrawing, subcostal 
retractions, stridor, rales, rhonchi, wheezing, crackles/crepitations, or observed 
apnea, AND
o
Documented hospitalization.  
Data elements supporting the criteria for secondary endpoint cases will be present within 
the start and stop dates of a continuous illness episode and derived from clinical 
observations (LRTI signs and symptoms and respiratory rates) made by qualified 
clinical trial site staff, pulse oximetry performed by site personnel using a Masimo 
RAD-5 pulse oximeter supplied by the sponsor, and RSV detection based on study-
specified RT-PCR performed by the validated GenMark eSensor assay in place at the 
central laboratory (Marshfield Clinic Research Institute, Marshfield, Wisconsin). 
Evidence of hospitalization and/or in-hospital use of high-flow nasal cannula, CPAP, 
BiPAP, bubble CPAP, intubation, or mechanical/manual ventilation or ECMO will be 
supported by hospital records obtained by the clinical site staff.
A Clinical Endpoint Adjudication Committee (CEAC) composed of expert pediatricians 
(see Section 10.4.2) will carry out a blinded review of all potential secondary endpoint 
cases to determine if they fulfill the relevant endpoint criteria in a temporally plausible 
relationship consistent with RSV disease as observed in clinical practice.  Only CEAC-
confirmed cases will be used for secondary endpoints.
3.2.3
Immunogenicity Endpoints (In Maternal and Infant Subjects as Stated)

Serum immunoglobulin G (IgG) antibody concentrations specific for the F protein 
antigen measured by enzyme-linked immunosorbent assay (ELISA) and serum 
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protein.  Derived/calculated endpoints based on these data will include geometric mean 
concentrations as ELISA Units (GMEU) or µg/mL as appropriate, geometric mean fold-
rise (GMFR), proportion of subjects with ≥ 2-fold and ≥ 4-fold increases in 
concentration from baseline (seroconversion rate, SCR [maternal subjects only]), and 
seroresponse rate (SRR). Analyses will be used to evaluate:
o
Immunogenicity through six months post-delivery in maternal subjects.
o
Transplacental transfer of maternal antibodies specific for RSV described as a ratio 
of levels in maternal and cord blood at delivery.
o
Infant RSV-specific antibody decay during the first six months of life relative to 
cord blood levels. 
o
Immune correlates of risk of RSV LRTI in infants based on anti-RSV F protein IgG 
or palivizumab-competitive antibody responses in the infant and/or cord blood, and 
maternal subjects at delivery.

Serum microneutralization (MN) titers against RSV/A and B in maternal and infant 
subjects at select time-points may be generated for a subset of the population using the 
derived/calculated endpoints previously referenced, based on geometric mean titer 
(GMT). An external laboratory, whose personnel are blinded to study treatment, will 
perform RSV/A and B MN testing during study conduct and after Day 180 unblinding.  
Final MN results, because of their time-consuming nature, may be provided as one or 
more sequential addenda to the main study report.
3.2.4
Safety Endpoints
3.2.4.1
In All Infant Subjects

Percentages of term (≥ 37 weeks gestational age), healthy infants appropriate for 
gestational age (as determined by ultrasound gestational age assessment), APGAR 
scores, length, birth weight, frontal-occipital head circumference (FOC), and physical 
examination at birth. 

Percentages of infants with AEs and SAEs (with special attention to congenital 
anomalies; respiratory failure other than RSV-associated hospitalization; neonatal 
death; infant death; sudden infant death syndrome; asphyxia; neonatal or hypoxic-
ischemic encephalopathy; or other adverse events or complications of adverse events 
that necessitate hospitalization) during the neonatal period and through the first year of 
life.

Percentages of infants with unsolicited adverse events (including abnormalities detected 
in routine metabolic screening blood and neonatal hearing tests), unscheduled medical 
visits for adverse events, and serious adverse events through the first year of life.

Percentages of infants with developmental delay, as measured by the outcome of testing 
using a validated developmental scale at six months and at one year, in infants of RSV F 
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3.2.4.2
In Maternal Subjects

Percentages of subjects with solicited injection site and systemic reactogenicity within 
seven days of vaccination.

Percentages of subjects with unsolicited (local and systemic) adverse events (AEs), 
unscheduled medically-attended adverse events (MAEs), significant new medical 
conditions (SNMCs), and serious adverse events (SAEs) through delivery and six (6) 
months thereafter. 

Clinical safety laboratory assessments of select serum chemistry and hematology 
parameters through delivery.

Percentages of subjects with Caesarean, vaginal, or instrument-assisted vaginal modes 
of delivery.

Percentages of subjects with post-immunization onset of specific complications of third-
trimester pregnancy and delivery including:
o
Pregnancy complications: 
-
Stillbirth, 
-
Preterm birth (moderate to late preterm: 32 to < 37 weeks of gestation; very 
preterm: 28 to < 32 weeks of gestation),
-
Preterm premature rupture of membranes, 
-
Placental abruption,
-
Hypertensive disorders of pregnancy including: gestational hypertension, pre-
eclampsia/eclampsia, 
-
Third-trimester hemorrhage, and
-
Gestational diabetes.
o
Labor and delivery complications: 
-
Emergency Caesarean (C)-section for maternal or fetal indications,
-
Postpartum hemorrhage, 
-
Chorioamnionitis, and
-
Maternal fever or infection. 
3.2.5
Exploratory Endpoints (In Maternal and Infant Subjects as Stated)

Percentages of infants with medically-significant RSV LRTI from delivery through 90, 
120, 150 and 180 days of life defined as per the primary efficacy endpoint with the 
exception that evidence of RSV infection, LRTI, hypoxemia, and/or tachypnea may be 
based on either or both of the observations of the clinical site staff using sponsor-
supplied devices and diagnostic tests OR review and abstraction of medical records for 
infants undergoing hospitalization for a respiratory serious adverse event. 

Percentages of infants with RSV LRTI with EITHER severe hypoxemia (SpO2 < 92% 
at sea level or < 87% at altitudes > 1800 meters) OR the documented use of oxygen by 
high flow nasal cannula OR continuous positive airway pressure (CPAP) OR bilevel 
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intubation with subsequent mechanical (or manual) ventilation OR extracorporeal 
membrane oxygenation (ECMO) from delivery through 90, 120, 150, and 180 days of 
life defined as per the corresponding secondary efficacy endpoint with the exception 
that evidence of RSV infection, LRTI, severe hypoxemia, and/or respiratory support 
may be based on either or both of the observations of the clinical site staff using sponsor-
supplied devices and diagnostic tests OR review and abstraction of medical records for 
infants undergoing hospitalization for a respiratory serious adverse event. 

Percentages of infants with RSV LRTI requiring hospitalization from delivery through 
90, 120, 150, and 180 days of life defined as per the corresponding secondary efficacy 
endpoint with the exception that evidence of RSV infection and LRTI may be based on 
either or both of the observations of the clinical site staff using sponsor-supplied devices 
and diagnostic tests OR review and abstraction of medical records for infants 
undergoing hospitalization for a respiratory serious adverse event. 

Percentages of infants with RSV LRTI associated with EITHER hypoxemia (peripheral 
oxygen saturation [SpO2] < 95% at sea level or < 92% at altitudes > 1800 meters) OR 
tachypnea (≥ 60 bpm for infants 0 to 59 days of age or ≥ 50 bpm for infants ≥ 60 days 
of age [WHO Handbook, Integrated Management of Childhood Illness criteria for 
tachypnea]) from delivery through 90, 120, 150, and 180 days of life. Data concerning 
documentation of RSV infection, LRTI symptoms and signs, hypoxemia and/or 
tachypnea may be obtained from the observations of the clinical site staff OR review 
and abstraction of medical records for infants undergoing hospitalization for a 
respiratory serious adverse event. 

Percentages of infants with RSV LRTI resulting in death from delivery through 90, 120, 
150, and 180 days of life. Evidence of RSV infection and LRTI may be based on either 
or both of the observations of the clinical site staff using sponsor-supplied devices and 
diagnostic tests OR review and abstraction of medical records for infants undergoing 
hospitalization for a respiratory serious adverse event. 

Percentages of infants with RSV LRTI (all severities) from delivery through 90, 120, 
150, and 180 days of life.  Evidence of RSV infection and LRTI may be based on either 
or both of the observations of the clinical site staff using sponsor-supplied devices and 
diagnostic tests OR review and abstraction of medical records for infants undergoing 
hospitalization for a respiratory serious adverse event. 

Counts and incidence rates of infant healthcare interventions associated with wheezing 
through the first year of life.

Percentages of maternal subjects with RSV-related respiratory illness as observed by 
the clinical study staff and detected by active and passive surveillance from vaccination 
through six months after delivery, overall and by pathogen(s).

Percentages of infant subjects with all-cause LRTI, with or without tachypnea, 
hypoxemia, or severe hypoxemia, as detected by active and passive surveillance from 
vaccination through six months after delivery, overall and by pathogen(s). 

Percentages of infant and maternal subjects with non-RSV respiratory viruses, overall 
and by pathogen(s), through six months after delivery.

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A Clinical Endpoint Adjudication Committee (CEAC) composed of expert pediatricians 
(see Section 10.4.2) will carry out a blinded review of all potential exploratory endpoint 
cases involving RSV LRTI in infants to determine if they fulfill the relevant endpoint
criteria in a temporally plausible relationship consistent with RSV disease as observed in 
clinical practice.  Only CEAC-confirmed cases will be used for exploratory endpoints.
3.3
Study Duration
The approximate maximum duration of the maternal subject’s participation in the study conduct 
is nine months. The maximum duration of the infant subject’s participation in the study conduct 
is approximately one year. The duration of the entire study is estimated to be approximately 
four years.   
3.4
Study Population
Maternal subjects for the study will be healthy (as determined by physical examination, medical 
history, and clinical laboratory parameters), third-trimester pregnant subjects deemed to be at 
low-risk for obstetrical complications, between the ages of ≥18 to ≤40 years, who meet all of 
the inclusion criteria and none of the exclusion criteria (see Section 5). 
3.5
Randomization Scheme
The sample size for this trial will be approximately 4,600 third-trimester pregnant subjects in 
the Northern and Southern hemispheres and their infants. Randomization of maternal subjects 
will be done at the site level and will be stratified by age (i.e., 18 to < 29 years and 29 to ≤ 40 
years). No specific proportion in either age group will be sought, rather the intent of 
stratification will be to distribute the proportion of maternal subjects presenting for enrollment 
in each age group equally across the two treatment arms. Infant subjects born to randomized 
maternal subjects will be prospectively and randomly assigned to one of three postpartum 
phlebotomy cohorts, which will differ only in the timing of blood sampling (see Appendix 1).
3.6
Randomization and Blinding Procedure
Maternal subject randomization will be conducted using an Interactive Web Randomization 
System (IWRS). The system will ensure proper distribution of maternal subjects across group 
assignments. Stratification will be based on study site and age (18 to < 29 years and 29 to 40 
years), in order to distribute the proportion of such subjects in each age group equally across 
treatment groups. At maternal randomization, the infant of that mother-infant pair will also be 
randomized to one of three phlebotomy cohorts.
Preparation and administration of the RSV F vaccine and placebo will be performed by an 
unblinded vaccine administrator(s), with masking of the syringe content. Administration of the 
RSV F vaccine and placebo will be performed by designated site personnel.
Maternal subjects and the main study team clinical staff will remain blinded as to treatment 
assignment for the duration of the study unless emergency unblinding is necessary. Refer to 
Section 3.7 for information regarding the process for emergency unblinding. However, 

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assignment with regard to the infant’s phlebotomy cohort will be transmitted immediately to 
site personnel. 
All treatment assignments, vaccine and placebo storage and accountability, and/or dosing 
related matters, will be monitored by a designated “unblinded monitor.” Any deviations will be 
discussed, documented and resolved by the unblinded monitor and the unblinded site personnel. 
The unblinded monitor will be responsible for escalating issues to the clinical project team in a 
blinded manner. The Clinical Supplies Manager at Novavax will be responsible for determining 
whether the team will be unblinded in order to adequately resolve issues.  Any unblinding of 
the project team will be clearly documented in the Trial Master File (TMF). No reports from 
the unblinded monitor will be released to the TMF until database lock for the final analysis and 
official declaration of unblinding is given by Novavax.  
3.7
Procedure for Unblinding Individual Subject Treatment 
Assignments
In the event of a medical emergency, when knowledge of the maternal subject’s treatment 
assignment may influence her or her infant’s clinical care, the investigator or designee may 
request that the blind be broken for the maternal subject-infant subject pair experiencing the 
emergency. If feasible, the investigator is asked to notify the Medical Monitor or designee prior 
to unblinding; however, the investigator may unblind without consulting the Medical Monitor,
if it is deemed to be in the best interest of the subject. The investigator will be expected to 
provide a rationale for the necessity of unblinding, based on a meaningful change to the 
maternal or infant subject’s immediate and short-term medical care which will result from 
knowledge of the treatment assignment. Novavax also retains the right to initiate the unblinding 
of treatment allocation for serious adverse events (SAEs) that are unexpected and are suspected 
to be causally related to the test article and that potentially require expedited reporting to 
regulatory authorities.
If unblinding is deemed necessary, the unblinded vaccine administrator will utilize information 
from IWRS to obtain treatment details for the maternal subject-infant subject pair. The date and 
time of breaking the blind as well as the reason must be documented and placed in the Study 
Pharmacy Manual by unblinded staff. The investigator should not otherwise divulge the 
treatment assignment of the maternal subject-infant subject pair to site staff, and should provide 
the information only to those individuals involved in the direct care of the subject. The date and 
reasons for breaking the blind must be submitted to the Medical Monitor within 24 hours. 
Additional instructions for unblinding will be contained in the Study Operations Manual and 
the Study Pharmacy Manual.
If treatment assignment of a maternal subject-infant subject pair is unblinded, both subjects 
should remain in the study and continue the protocol-specified follow-up evaluations if 
possible.

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4
TEST ARTICLES
4.1
Overview of Product and Manufacturing Process for Clinical Trial 
Material
The RSV F vaccine candidate is based on a purified, recombinant near full-length RSV F 
glycoprotein that self-assembles into protein-protein nanoparticle structures of approximately 
30 to 60 nm. The baculovirus/Sf9 insect cell system was used to clone and express the 
recombinant human RSV F gene. In the vaccine construct, one of two subtilisin-like protease 
cleavage sites in the RSV F sequence is deleted, as well as approximately half of the fusion 
domain, to mitigate toxicity of the protein to the expression system. In Sf9 insect cells, 
recombinant F is produced as a precursor (F0) that is modified by N-linked glycans and, like 
the native F fusion protein, assembles into homo-oligomers as trimers [Collins 1991]. The F0 
precursor is processed into F2 and F1 chains that remain predominantly covalently linked by 
disulfide bond(s) in the product.
4.1.1
Production and Purification of RSV F Protein
The recombinant human RSV F gene was cloned via Escherichia coli (E. coli) into a FlashBac 
GOLD expression vector baculovirus DNA with v-acth and chitinase genes deleted (Oxford 
Expression Technologies). The F gene is under transcriptional control of the baculovirus 
Autographa californica multiple nuclear polyhedrosis virus (AcMNPV) polyhedrin promoter 
at the 5' end and includes a poly (A) sequence at the 3' end.  A single recombinant baculovirus 
expressing the F gene was identified, plaque-purified, and amplified for use in the manufacture 
of the bulk RSV F antigen.
Manufacture of the RSV F protein antigen is initiated by infecting Sf9 cells in exponential 
growth with baculovirus containing the RSV F gene. After infection, cells are collected by 
centrifugation, washed with sterile buffer, and then lysed in the presence of detergent to release 
membrane-bound RSV F protein.  Leupeptin hemi-sulfate salt is added to the lysis buffer to 
protect the RSV F protein from cellular proteases, which are also inactivated by low pH 
treatment. The supernatant containing the RSV F protein is separated from cell debris by 
filtration before it is purified on an anion exchange column. The flow-through fraction is first 
nanofiltered through a virus removal filter and then loaded on an affinity chromatography 
column, which binds the RSV F protein. After washing, the RSV F protein is eluted from the 
column with buffer containing methyl-α-D-mannopyranoside (MMP) and Polysorbate (PS)-80, 
and exposed to a second low pH treatment. Eluted fractions are further purified with a cation 
exchange chromatography step that removes MMP and transfers the product into a sodium 
phosphate buffer with sodium chloride and PS-80. The product is then filtered through a 
sterilizing filter (0.20 μm) to produce the bulk drug substance that is clear and colorless, and 
contains no preservatives.  The bulk drug substance is stored at -70°C until it is adsorbed onto 
aluminum phosphate and filled as drug product. 
4.1.2
Aluminum Adjuvant
The aluminum phosphate salt is supplied as a sterile suspension in unbuffered isotonic saline 
(4.8 mg/mL of aluminum as a phosphate salt in 0.15 M NaCl without buffer) by Brenntag 
Biosector (Frederikssund, Denmark).  

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4.1.3
Final Drug Product
The F protein content in the purified drug substance is determined by an F protein-specific 
binding ELISA. To produce the adjuvanted vaccine, the bulk RSV F protein and aluminum 
phosphate are diluted to a specified concentration and then combined to yield a final 
concentration of 240 μg/mL RSV F and 0.8 mg/mL aluminum, in a final buffer of 18 mM 
sodium phosphate, pH 6.2, with 0.15 M NaCl, 0.8% histidine, 0.03% PS-80. The RSV F vaccine 
is filled into single-use glass vials. The final product appears as a white opalescent suspension. 
No antibiotics or preservatives are present. 
4.1.4
Formulation Buffer Placebo
The placebo treatment is comprised of 22 mM sodium phosphate, pH 6.2, with 150 mM NaCl, 
1.0% histidine, and 0.03% PS-80; is manufactured by Althea Technologies (San Diego, 
California); and is supplied in single-use 2 mL glass vials. 
4.2
Investigational Product Packaging, Storage, and Handling
The RSV F vaccine and placebo will be packaged in a validated shipping container for 
distribution to the investigational sites under refrigerated conditions. The investigational 
product will be labeled with the following information: manufacturer’s name and address, 
product name, manufacture date, storage requirements (2 - 8°C), directions for use, and any 
other investigational product labeling appropriate to the jurisdiction in which the trial is 
conducted. 
The RSV F vaccine and placebo will be stored at 2 - 8°C in a temperature monitored refrigerator.  
Access to this refrigerator will be limited to designated site personnel.  
Additional information on the packaging, storage, and handling procedures for the RSV F 
vaccine and placebo is provided in the Study Pharmacy Manual.
4.3
Compliance and Drug Accountability
It is the responsibility of the investigator at each site to ensure that all test articles (RSV F 
vaccine and placebo) received at the site are inventoried and tracked throughout the study and 
the result recorded on the product accountability form maintained in the Study Pharmacy 
Manual. 
All quantities of the test articles must be reconciled at the termination of the study and a written 
explanation provided for any discrepancies.  Unless specific written instructions to the contrary 
are provided by Novavax (or designee), all unused vials containing the RSV F vaccine and 
placebo, and packaging materials, will be inventoried and maintained at the clinical site until 
further notice by Novavax or (designee). The site is not permitted to return or destroy used or 
unused test articles or packaging materials unless specifically authorized by Novavax (or 
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5
SELECTION OF STUDY SUBJECTS
5.1
Inclusion Criteria
Pregnant women must meet all of the following to be eligible for participation in the study:
1) ≥ 18 and ≤ 40 years-of-age (which connotes a lower limit of 18 years and 0 days and an 
upper limit of 40 years and 0 days). 
2) Singleton pregnancy of 28 to 360/7 weeks gestation on the day of planned vaccination.
Documentation of gestational age will be based on one of the following composite criteria
(Note: The investigator should use the earliest ultrasound data available to establish the 
study-specific gestational age dating):
(a) Gestational Age Dating Based on First Trimester Data (data obtained ≤ 136/7 weeks):
The date of the first day of the reported last menstrual period (LMP) may be used to 
establish the gestational age if corroborated by a first trimester ultrasound. If the 
gestational age estimation derived using the LMP and the first trimester ultrasound are 
discrepant by > 7 days, the ultrasound will be used to establish the gestational age. 
If LMP is uncertain or unknown, the ultrasound-established gestational age estimation
will be used to establish the gestational age of the pregnancy. 
(b) Gestational Age Dating Based on Early Second Trimester Data (data obtained 140/7 to 
216/7 weeks):  
The date of the first day of the reported LMP may be used to establish the gestational 
age if corroborated by an early second trimester ultrasound (that estimates the 
gestational age between 140/7 and 216/7 weeks). If the gestational age estimation derived 
using the LMP and the early second trimester ultrasound are discrepant by > 10 days, 
the ultrasound will be used to establish the gestational age. 
If LMP is uncertain of unknown, the ultrasound-established gestational age estimation 
will be used to establish the gestational age of the pregnancy. 
(c) Gestational Age Dating Based on Later Second Trimester Data (data obtained 220/7 to 
276/7 weeks)
The date of the first day of the reported LMP may be used to establish the gestational 
age if corroborated by a later second trimester ultrasound (that estimates the gestational 
age between 220/7 to 276/7 weeks). If the gestational age estimation derived using the 
LMP and the later second trimester ultrasound are discrepant by > 14 days, the 
ultrasound will be used to establish the gestational age. 
If LMP is uncertain or unknown, the ultrasound-established gestational age estimation 
will be used to establish the gestational age of the pregnancy. 

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(d) Gestational Age Dating When the LMP is Uncertain or Unknown AND No Prior  First 
or Second Trimester Ultrasound Has Been Performed:
An ultrasound performed at screening, within the second trimester (≤ 276/7 weeks) will 
be used to establish the gestational age. 
3)
Documentation of a second or third (between 180/7 weeks and prior to randomization) 
trimester ultrasound with no major fetal anomalies identified. 
4) Good general maternal health as demonstrated by:

Medical history (including history of clinically significant adverse reactions to prior 
vaccines and allergies). 

Physical examination including at least vital signs (blood pressure, pulse, respirations, 
and axillary body temperature); weight; height; examination of the HEENT, 
cardiovascular, pulmonary, gastrointestinal (abdominal), musculoskeletal, lymphatic, 
and dermatologic organ systems; and documentation of fetal heart tones.  Note that 
abnormal vital signs may be repeated at the investigator’s discretion since these 
measures may be labile.  Vital signs should be assessed in the context of normal values 
for the third trimester of pregnancy (see the Study Operations Manual).

Clinical laboratory parameters that include:
o
For the first year of study conduct in any country, normal/clinically insignificant 
blood urea nitrogen (BUN), creatinine, alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), total bilirubin, alkaline phosphatase (ALP), hemoglobin, 
white blood count, and platelet count. Note that normal ranges for clinical 
laboratory parameters will be based on reference ranges appropriate for the third 
trimester of pregnancy, specified in the toxicity grading scale (TGS, provided in 
the Study Operations Manual) and should be referenced to assess for any 
abnormalities. This testing should be performed by the central laboratory.
o
For all subjects, serologic exclusion of infection with hepatitis B (HBV) and C 
(HCV) viruses, syphilis and HIV as documented by testing (performed at the
central or local laboratory) at screening or by medical records during the current 
pregnancy.
5) Able to understand, and both willing and physically able to comply with study procedures.  
This includes anticipation of reasonable geographic proximity to the study clinic and 
adequate transportation to comply with scheduled and unscheduled study follow-up visits. 
6) Able and willing to provide written informed consent for themselves and infant.
5.2
Exclusion Criteria
Pregnant women will be excluded if there is historical, physical examination, or laboratory 
evidence of any of the following:
1)
Symptomatic cardiac or pulmonary disease requiring chronic drug therapy, including 
hypertension and asthma. Asthma will be exclusionary if the subject is receiving chronic 

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systemic glucocorticoids at any dose or inhaled glucocorticoids at any dose > 500 µg per 
day of beclamethasone or fluticasone, or > 800 μg per day of budesonide.
2)
Pregnancy complications (in the current pregnancy) such as preterm labor, hypertension 
(blood pressure [BP] > 140/90 in the presence of proteinuria or BP > 150/100 with or 
without proteinuria) or currently on an antihypertensive therapy or pre-eclampsia; or 
evidence of intrauterine growth restriction.
3)
Grade 2 or higher clinical laboratory or vital sign abnormality. Exclusion of subjects with 
grade 1 abnormalities will be based on the subject’s prior medical history and the 
investigator’s clinical judgment that the abnormality is indicative of a meaningful 
physiologic event. 
4)
Receipt of any licensed vaccine (e.g., Tdap, inactivated influenza vaccine) within 14 days 
of study vaccination. 
5)
Received any RSV vaccine at any time. 
6)
Body mass index (BMI) of ≥ 40, at the time of the screening visit. 
7)
Hemoglobinopathy (even if asymptomatic) or blood dyscrasias.
8)
Hepatic or renal dysfunction. 
9)
Established diagnosis of seizure disorder, regardless of therapy.
10)
Known, active auto-immune disease or immunodeficiency syndrome.
11)
Endocrine disorders, including (but not limited to) untreated hyperthyroidism, untreated 
hypothyroidism (unless due to auto-immune disease), and glucose intolerance (e.g., 
diabetes mellitus type 1 or 2) antedating pregnancy, or occurring during pregnancy and 
requiring interventions other than diet for control. 
12)
History of major gynecologic or major abdominal surgery, including bariatric surgery 
(previous Caesarean section is not an exclusion).
13)
Known HIV, syphilis, HBV, or HCV infection, as assessed by serologic tests conducted 
during the current pregnancy or as a procedure during the screening period of the study.
14)
Primary genital Herpes simplex virus (HSV) infection during the current pregnancy.
15)
Current alcohol or drug abuse based on the investigator’s knowledge of present or recent 
(within the last 2 years) use/abuse of alcohol or illegal or non-prescription drugs.
16)
Documentation that the current pregnancy results from in vitro fertilization (IVF).
17)
Documentation that the current pregnancy results from rape or incest.
18)
Documentation that the infant will be a ward of the state or be released for adoption.
19)
History/presence of deep venous thrombosis or thromboembolism, or the use of 
anticoagulants during pregnancy (use of low-dose aspirin as prophylaxis [e.g., for the 
prevention of morbidity and mortality from preeclampsia] is acceptable in dosages 
consistent with local standards of care).
20)
Red blood cell allo-immunization.

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21)
Prior stillbirth or neonatal death, or multiple (≥ 3) spontaneous abortions. 
22)
Prior preterm delivery ≤ 34 weeks gestation or having ongoing intervention 
(medical/surgical) in current pregnancy to prevent preterm birth.
23)
Greater than five (5) prior deliveries.
24)
Previous infant with a known genetic disorder or major congenital anomaly.
25)
Receipt of investigational drugs or immune globulins (with the exception of prophylactic 
anti-Rho D immune globulin) within six (6) months prior to the administration of the 
study vaccine.
26)
Chronic 
administration 
(defined 
as 
more 
than 
14 
continuous 
days) 
of 
immunosuppressants or other immune-modifying drugs within 6 months prior to the 
administration of the study vaccine. An immunosuppressant dose of glucocorticoid will 
be defined as a systemic dose ≥ 10 mg of prednisone per day or equivalent. The use of 
topical, inhaled, and nasal glucocorticoids will be permitted except for the limit 
established in exclusion criterion #1.
27)
Neuro-psychiatric illness, including a history of severe post-partum depression, deemed 
likely to interfere with protocol compliance, safety reporting, or receipt of pre-natal care; 
or requiring treatment with psychotropic drugs (excluding treatment for depression and 
anxiety).
28)
Any other physical, psychiatric or social condition which may, in the investigator’s 
opinion, increase the risks of study participation to the maternal subject or the fetus/infant; 
or may lead to the collection of incomplete or inaccurate safety data.
29)
Acute disease within 72 hours of the day of the planned vaccination (defined as the 
presence of a moderate or severe illness with or without fever, or an axillary body 
temperature > 38.0°C).
30)
History of a serious adverse reaction (e.g., anaphylaxis) to any prior vaccine.

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6
STUDY ASSESSMENTS AND PROCEDURES
A study schematic flowchart is provided in Appendix 1 for maternal and infant subjects, 
separately. A detailed description of procedures performed at each in-clinic visit is described in 
this section. 
6.1
Study Visit Procedures
This study contemplates a two-staged design with study procedures for maternal subjects 
provided in Section 6.1.1, and infant subjects in Section 6.1.2. Study visits were designed to 
coincide approximately with pregnancy, postpartum, and baby wellness visits. 
6.1.1
Maternal Subject Study Visit Procedures
6.1.1.1
Up to Two (2) Months Prior to Study Start – Pre-Screening 
Obstetrical investigators may, at their discretion, introduce the concept of participation in a 
third-trimester RSV vaccine trial to women who they regard as potentially fulfilling the 
inclusion/exclusion criteria.  If required by the Institutional Review Board (IRB)/Independent 
Ethics Committee (IEC) having authority, interested women may be asked to provide informed 
consent in order for the investigator to collect information regarding their general health history, 
obstetrical history, and results of screening testing performed for the current pregnancy. The 
screening consent will be for collection of existing data only, and will not provide for any 
invasive procedure (including phlebotomy). Screening consent may be withdrawn at any time, 
and will not bind the prospective subject to enroll in the clinical trial or the investigator to offer 
enrollment.
6.1.1.2
Day -28 to 0 – Screening (up to four weeks before the planned day of 
vaccination)
The healthy pregnant subjects, who are considered to be at low-risk of obstetrical complications, 
≥18 to ≤40 years of age (18 years and 0 days to 40 years and 0 days), have provided written 
Informed Consent for themselves and their infants to participate in the main study, and are able 
to comply with study requirements, will have the following procedures performed:

Review of medical history, including history of clinically significant adverse reactions 
to prior vaccines and allergies. 

Review of the parameters by which the gestational age dating of the current pregnancy 
was established, to include the LMP (if known), physical examination, and the results 
of a first or second trimester ultrasound.

Performance of a second trimester (≤ 276/7 weeks) ultrasound (if not previously done) 
that establishes gestational age dating.

Performance of a second or third trimester ultrasound (if not previously done) that 
confirms there are no major fetal anomalies.

Review of obstetrical history to include the following outcomes of previous 
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fetal/neonatal outcomes, complications of pregnancy, including history of fetal losses 
and elective abortions.

Review of surgical history including prior gynecologic, abdominal, or uterine surgery. 

Document results of any Group B streptococcus (GBS) screening (urine or recto-vaginal 
swab as applicable), or other infectious disease screening (i.e., for syphilis, gonorrhea, 
Herpes simplex, chlamydia, HBV, HCV, and HIV).

Administration of a licensed vaccine recommended during pregnancy, if indicated. 
Note: This dose should be administered at least 14 days before or at least 14 days after 
the Day 0 vaccination.

Document current smoking, alcohol, and recreational drug use.

Document results of gestational diabetes screen.

Vital signs (blood pressure, pulse, respirations, and axillary body temperature [Note that 
repeat testing may be performed for subjects with any abnormality]), height, and weight; 

Physical examination including the following body systems: HEENT, cardiovascular, 
pulmonary, 
gastrointestinal 
(abdominal), 
musculoskeletal, 
lymphatic, 
and 
dermatologic; and confirmation of fetal heart tones.  

Blood draw:
o
For RSV baseline serology (20 mL).
o
For subjects participating in the first year in any country: Clinical laboratory 
assessments (10 mL) for select serum chemistry (i.e., blood urea nitrogen, 
creatinine, alanine aminotransferase [ALT], aspartate aminotransferase [AST], 
alkaline phosphatase [ALP], total bilirubin) and hematology (i.e., hemoglobin, 
white blood cell [WBC], and platelet counts) parameters by central laboratory
testing; and HIV, syphilis, HBV, and HCV antigen tests/serologies as required by 
central or local laboratory testing (i.e., if screening results are not available in prior 
data collected during the course of the current pregnancy). Since results of the 
clinical laboratory testing are needed to confirm subject eligibility, it is 
recommended this phlebotomy be performed at least two days before the planned 
Day 0 vaccination. 
o
For subjects participating in all other years in any country: HIV, syphilis, HBV, and 
HCV antigen tests/serologies (10 mL, as required) by central or local laboratory if 
screening results are not available in prior data collected during the course of the 
current pregnancy.

Medication history, including concomitant medications. 

Query for any AE experienced since informed consent was obtained. 
Note that further procedures may be performed at the investigator’s discretion in order to 
adequately screen subjects against eligibility criteria and/or to confirm medical history. 
Potential subjects who meet all inclusion criteria and none of the exclusion criteria (see 
Section 5) may be enrolled.

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6.1.1.3
Day 0 – Vaccination (gestational week 28 to 360/7)
On Day 0, all subjects who have vital signs taken, fetal heart tones checked, and eligibility re-
confirmed will be randomized to a treatment group and infant serology cohort. The following 
procedures will then be performed:

Query for any AE (and SAE specifically) experienced by the subject since informed 
consent was obtained. 

Alcohol swab or cleanse the area of vaccination (following the local standard of care), 
followed by IM injection into the deltoid with the designated study treatment.

Monitoring for any AEs for approximately 30-60 minutes following vaccination.

Vital sign (heart rate, blood pressure, respiratory rate, and axillary body temperature) 
and a fetal heart tone check performed at approximately 30 minutes (range 30-60 
minutes) post-vaccination.

Distribution of the subject diary and oral thermometer for documentation of any AEs 
(solicited and unsolicited), oral temperature and concomitant medications taken; and 
documentation of any unscheduled physician visit or hospitalization associated with an 
adverse event, occurring from the time of discharge through to Day 6 (inclusive).  
Diaries will provide a telephone number for 24-hour contact to the study staff in the 
event of concerns, solicited or unsolicited AEs, new obstetrical complications, or 
symptoms suggestive of an RSV infection. 

Issuance of a Study Identification Card that indicates the maternal subject is part of an 
investigational vaccine trial and provides the contact number(s) of the obstetrical 
investigator’s study staff. The identification card will also include a list of the clinical 
signs and symptoms of an RSV infection in adults and infants.

Instruction for subjects to inform the study site promptly of any severe (grade 3) 
solicited or unsolicited AE, obstetrical complication, or symptoms suggestive of an RSV 
infection. 

Verify subject locator information and the delivery center to be utilized. 

Schedule the next visit.
6.1.1.4
Day 7 (+ 2 days) – In-clinic or Home Follow-up Visit
In addition to normal obstetrical follow-up including confirmation of fetal heart tones, all 
subjects will return to the clinic or will be evaluated by study staff at a home visit on Day 7 for 
the following procedures:

Vital sign collection (heart rate, blood pressure, respiratory rate, and axillary body 
temperature). 

Review and collection of subject diary.

Query for any unsolicited AEs, MAEs, SNMCs, and SAEs occurring since the last study 
visit, and any concomitant medications taken for these events. A physical exam may also 
be performed to evaluate any adverse event reported. Subjects will also be queried 
regarding symptoms suggestive of RSV infection and, in the event onset is within seven 

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(7) days, will undergo a sampling of upper respiratory secretions for detection of 
respiratory viruses (see RSV Illness Surveillance procedures in Section 6.2).

Reminder for subjects to contact the site promptly to report any severe or serious AE or 
obstetrical complication, or symptom(s) suggestive of an RSV infection. 

Distribution of a memory aid for subjects to record any medical events experienced in 
between clinic visits. (Note that the memory aid is considered a tool that subjects may 
or may not choose to use, and as such is NOT considered a source document and WILL 
NOT be collected.) A replacement Study Identification Card will also be provided to all 
subjects, as needed.

Schedule the next visit.
6.1.1.5
Day 14 (± 2 days) – In-clinic or Home Follow-up Visit
In addition to normal obstetrical follow-up including confirmation of fetal heart tones, all 
subjects will return to the clinic or will be evaluated by study staff at a home visit on Day 14 
for the procedures listed below. 

Vital sign collection (heart rate, blood pressure, respiratory rate, and axillary body 
temperature). 

Query for any unsolicited AEs, MAEs, SNMCs, and SAEs occurring since the last study 
visit, and any concomitant medications taken for these events. A physical exam may also 
be performed to evaluate any adverse event reported. Subjects will also be queried 
regarding symptoms suggestive of RSV infection and, in the event onset is within seven 
(7) days, will undergo a sampling of upper respiratory secretions for detection of 
respiratory viruses (see RSV Illness Surveillance procedures in Section 6.2).

Blood draw (10 mL) for post-vaccination clinical safety laboratory assessments (if 
applicable) and (20 mL) RSV serology. Subjects will be reminded to contact the site to 
report any severe or serious AE, obstetrical complication, or symptoms suggestive of an 
RSV infection.

A replacement Study Identification Card will be offered to all subjects, as needed. 

Schedule the Day 28 visit. 
If a subject delivers prior to the Day 14 visit, the procedures discussed above will not be 
performed and no missed Day 14 visit protocol deviation will be captured. The single exception 
is the blood draw for the clinical safety laboratory assessment [which only applies to subjects 
enrolled in the first year of study conduct in any country] that should be obtained at the Delivery 
visit.
6.1.1.6
Day 28 (± 2 days) – Telephone/SMS Contact, In-clinic or Home Visit 
Safety Follow-up
Subjects who have not yet delivered will have a safety follow-up performed as a telephone/SMS
contact visit using an IRB/IEC-approved script (if applicable), an in-clinic visit, or a home visit.  
At this visit, whether conducted in-clinic or at home, study staff will assess the general health 
of the subject and query for any severe unsolicited AEs, SAEs, MAEs, SNMCs, clinical 
symptoms or signs of a suspected RSV illness, or any new obstetrical complications occurring 

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since the last visit, and any concomitant medications taken for these events. Subjects 
participating in this visit via telephone or SMS and who report any severe or serious adverse 
event or symptoms suggestive of an RSV infection, may be asked to return to the clinic or to 
schedule a home visit for evaluation of the event(s) to assess any effect(s) it may have on the 
pregnancy, and to potentially undergo a sampling of upper respiratory secretions for detection 
of respiratory viruses if symptom onset is within seven (7) days (see RSV Illness Surveillance
procedures in Section 6.2). The same procedures will be performed for subjects participating in 
this follow-up as an in-clinic or home visit with the exception that a replacement Study 
Identification Card will be offered to all subjects, if needed.
6.1.1.7
Delivery (D) – Hospital Follow-up Visit
Subjects will be counselled to notify the obstetrician of the start of labor and will go to the 
registered hospital or delivery center for delivery where the following procedures will be 
performed:

For applicable subjects (i.e., those enrolled in the first year of study conduct in any 
country) who deliver prior to the Day 14 visit, collection of a venous blood sample (10 
mL) for the clinical safety laboratory assessment.  

Collection of a venous blood sample (20 mL) for RSV serology at any time from 
admission to the hospital and optimally up to 12 hours post-delivery. Note: In 
extenuating circumstances such as a delivery on a holiday or weekend, the venous blood 
sample may be obtained up to 72 hours post-delivery.

Collection of a cord blood sample (at least 5 mL) by the obstetrician or designee 
immediately upon delivery. If cord blood is not obtained, then this information should 
be conveyed to the study staff responsible for the infant, so that infant sera may be 
collected in lieu of cord blood (see Section 6.1.2, Infant Study Procedures at the 
Delivery Day visit for details).

Record vital sign data at admission from the subject’s medical chart.

Query for all unsolicited AEs experienced and concomitant medications taken by, or 
administered to, the subject since the last clinic visit. (Note: Routine medications for the 
management of labor and delivery do not need to be recorded.)

Documentation of perinatal management including antibiotic therapy and any medical 
or surgical interventions for cause.

Documentation of any GBS screening result and treatment.

Study staff notification of the infant’s primary healthcare provider of the child’s 
anticipated participation in the study before or immediately after delivery.

Reminder of subjects to contact the site promptly to report any symptoms suggestive of 
an RSV infection.

Distribution of a replacement Study Identification Card to all subjects, as needed.
6.1.1.8
D+35 (± 7 days) – In-clinic or Home Post-delivery Follow-up Visits
Maternal subjects will return to the clinic or will be evaluated by study staff at a home visit on 
approximately 35 days post-delivery for the following procedures:

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
Vital sign collection (heart rate, blood pressure, respiratory rate, and axillary body 
temperature).

Query for any unsolicited AEs (including MAEs, SNMCs, and SAEs) experienced and 
concomitant medications taken for these events since the last visit. Note that a physical 
exam may also be performed at the investigator’s discretion to evaluate any adverse 
event reported. Maternal subjects will also be queried regarding symptoms suggestive 
of RSV infection and, if symptom onset is within seven (7) days, will undergo a 
sampling of upper respiratory secretions for detection of respiratory viruses if specific 
events are present (see RSV Illness Surveillance procedures in Section 6.2).

Blood draw (20 mL) for post-vaccination RSV serology. 

Reminder of subjects to contact the site promptly to report any symptoms suggestive of 
an RSV infection and replacement of the Study Identification Card to all subjects, as 
needed. 

Schedule the Day 180 visit.
6.1.1.9
D+180 (± 14 days) – In-clinic or Home Post-delivery Follow-up Visit
Maternal subjects will return to the clinic or will be evaluated by study staff at a home visit on 
approximately 180 days post-delivery for the following procedures:

Vital sign collection (heart rate, blood pressure, respiratory rate, and axillary body 
temperature).

Pregnancy testing. Note that a positive result will trigger additional follow-up to monitor 
the outcome of this pregnancy.  

Query for any unsolicited AEs (including MAEs, SNMCs, and SAEs) experienced and 
concomitant medications taken for these events since the last visit. Note that a physical 
exam may also be performed at the investigator’s discretion to evaluate any adverse 
event reported. Maternal subjects will also be queried regarding symptoms suggestive 
of RSV infection and, if symptom onset is within seven (7) days, will undergo a 
sampling of upper respiratory secretions for detection of respiratory viruses if specific 
events are present (see RSV Illness Surveillance procedures in Section 6.2).

Blood draw (20 mL) for post-vaccination RSV serology. 
This visit will mark the end of study participation for the maternal subject. However, maternal 
subjects with ongoing respiratory episodes will be contacted weekly by telephone/SMS contact
and followed until symptoms have resolved or have returned to baseline. In addition, maternal 
subjects with a positive pregnancy result will be followed for safety through the time of delivery 
to determine the outcome of this pregnancy.  
6.1.1.10
Unscheduled Visits
Maternal subjects will be encouraged to notify the investigator if any severe (grade 3) local or 
systemic solicited AE occurs during the 7-day post-immunization period, or if any severe, 
serious, or otherwise concerning AE occurs at any time following vaccination. If symptoms are 

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presented that would require a physical exam to adequately assess potential AEs, the exam 
should be performed and vital signs collected. 
Note the RSV surveillance visits discussed in Section 6.2 are not considered unscheduled visits. 
6.1.2
Infant Subject Study Visit Procedures
6.1.2.1
Visit 1: Delivery – Hospital Follow-up Visit
All procedures, including routine vaccinations that are considered standard of care for the 
newborn infant may be performed at any study visit which coincides with the usual timing for 
such procedures. Before any of the following study-specific procedures are performed, 
informed consent for the infant subject and release of medical records will be reviewed with the 
maternal subject (i.e., mothers will not be re-consented) or will be obtained from the other 
parent or guardian if not captured under the institution’s policy.

If cord blood is not collected at the time of delivery (see delivery procedures for 
maternal subjects in Section 6.1.1.7), a blood sample from the infant (2 mL by 
venipuncture preferred; 1 mL by heel stick acceptable) should be obtained within 72 
hours of birth for RSV serology. (Note: Cord blood is markedly preferred and all efforts 
should be directed to obtaining this specimen.  A phlebotomy/heel stick within 72 hours 
is a fall back procedure only.  The volume of a postpartum phlebotomy/heel stick must 
be accounted for within the phlebotomy limits as per the investigator’s institution, 
whereas a cord blood sample need not.)

The investigator or a trained designee will perform the following procedures: collection 
of results from the physical exam, weight, length, frontal-occipital circumference 
(FOC), and APGAR measurements performed following birth and used to assess the 
overall health of the infant; and documentation of the mode of infant feeding (e.g.,   
exclusively breastfed, exclusively formula fed, breast milk and supplemented with 
formula, expressed breast milk, wet nurse, receiving solids), if a smoker or one or more 
children < 5 years of age will reside in the same household, and whether the infant or 
another child in the household (< 5 years of age) will be/is cared for in a group setting 
with other children (e.g., daycare) for ≥ 3 days per week. 

Issue a Study Identification Card to parents and/or guardians of each infant that indicates 
that he/she is part of an investigational vaccine trial and provides the contact number to 
the investigator and study staff responsible for the study-related follow-up of the infant, 
along with a list of the signs and symptoms of RSV infection in adults and infants. 

Provide instruction to parents and/or guardians to contact the study staff promptly if the 
infant develops an “RSV-suspect illness” listed in Section 6.2.2, but to seek appropriate 
medical care for the infant first. This is especially important in instances when the initial 
evaluating physician providing care to the infant is not affiliated with the study.
6.1.2.2
Visit 2: D+14 (± 3 days) – In-clinic or Home Follow-up Visit
On approximately 14 days post-delivery, all infants will participate in a study visit at home or 
in-clinic and the following procedures will be performed:

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
Query and evaluation of any AEs, MAEs, SNMCs, and SAEs experienced since 
delivery and concomitant medications taken for these events. Note that a physical exam 
may be performed to evaluate any adverse events as needed.  Symptoms of RSV-suspect 
illness will be sought and, if onset has been within seven (7) days, a sampling of upper 
respiratory secretions for detection of respiratory viruses will be performed.

Collection of all healthcare provider-confirmed episodes of wheezing experienced by 
the infant since the last visit.

Documentation of the mode of infant feeding, if a smoker or one or more children < 5 
years of age reside in the same household, and whether the infant or another child in the 
household (< 5 years of age) is cared for in a group setting with other children (e.g., 
daycare) for ≥ 3 days per week.

A blood sample (1 to 2 mL) will be obtained from infants in phlebotomy Cohort 1 for 
RSV serology by venipuncture or heel stick and the method used will be documented. 

Prior to release from the clinic, parent(s) and/or guardians will be reminded to contact 
the study staff promptly if the infant develops a suspect illness (see RSV Illness 
Surveillance procedures in Section 6.2). The Study Identification Card will also be 
offered to the parent/guardian, if needed.

Schedule the next visit.
Note that all procedures, including routine vaccinations that are considered standard of care for 
a corresponding baby-wellness visit may be performed at this visit.
6.1.2.3
Visit 3: D+35 (± 7 days) – In-clinic or Home Follow-up Visit
At approximately 35 days after birth, all infants will participate in a study visit at home or in-
clinic and the following procedures will be performed:

Query and evaluation of any AEs, MAEs, SNMCs, and SAEs experienced since birth 
and concomitant medications taken for these events. Note that a physical exam may be 
performed to evaluate any adverse events as needed.  Symptoms of an RSV-suspected 
illness will be sought and, if onset has been within seven (7) days, a sampling of upper 
respiratory secretions for detection of respiratory viruses will be performed.

Documentation of the mode of infant feeding, if a smoker or one or more children < 5 
years of age reside in the same household, and whether the infant or another child in the 
household (< 5 years of age) is cared for in a group setting with other children (e.g., 
daycare) for ≥ 3 days per week.

Collection of all healthcare provider-confirmed episodes of wheezing experienced by 
the infant since the last visit.

Physical exam and collection of weight, length, and FOC measurements.   

A blood sample (1 to 2 mL) will be obtained from infants in phlebotomy Cohort 2 for 
RSV serology by venipuncture or heel stick and method used will be documented. 

Prior to release from the clinic, parent(s) and/or guardians will be reminded to contact 
the study staff directly if the infant develops a suspect illness (see RSV Illness 

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Surveillance procedures in Section 6.2). The Study Identification Card will also be 
offered to the parent/guardian, if needed.

Schedule the next visit.
Note that all procedures, including routine vaccinations that are considered standard of care for 
a corresponding baby-wellness visit may be performed at this visit.
6.1.2.4
Visit 4: D+60 (± 7 days) – In-clinic or Home Follow-up Visit
At approximately 60 days after birth, all infants will participate in a study visit at home or in-
clinic for the same procedures performed at the D+35 post-delivery visit, with the exception 
that the blood sample for RSV serology will only be obtained from infants in phlebotomy 
Cohort 3. Note also that all procedures, including routine vaccinations that are considered 
standard of care for a corresponding baby-wellness visit may be performed at this visit.
6.1.2.5
Visit 5: D+90 (± 7 days) – In-clinic or Home Follow-up Visit
At approximately 90 days after birth, all infants will participate in a study visit at home or in-
clinic for the same procedures performed at the D+35 post-delivery visit, with the exception 
that the blood sample for RSV serology will only be obtained from infants in phlebotomy 
Cohort 1. Note also that all procedures, including routine vaccinations that are considered 
standard of care for a corresponding baby-wellness visit may be performed at this visit.
6.1.2.6
Visit 6: D+120 (± 7 days) – In-clinic or Home Follow-up Visit
At approximately 120 days after birth, all infants will participate in a study visit at home or in-
clinic for the same procedures performed at the D+35 post-delivery visit, with the exception 
that the blood sample for RSV serology will only be obtained from infants in phlebotomy 
Cohort 2. Note that all procedures, including routine vaccinations that are considered standard 
of care for a corresponding baby-wellness visit may be performed at this visit.
6.1.2.7
Visit 7: D+180 (± 14 days) – In-clinic or Home Follow-up Visit
At approximately 180 days after birth, all infants will participate in a study visit at home or in-
clinic for the same procedures that were performed at the D+35 post-delivery visit, with three 
exceptions: 

The blood sample for RSV serology will only be obtained from infants in phlebotomy 
Cohort 3.

Infant subjects will complete the first of two developmental tests. 

Most activities associated with active RSV surveillance will conclude at this visit, 
except for the weekly follow-up of infant subjects with respiratory episodes that are 
ongoing. 
Note that all procedures, including routine vaccinations that are considered standard of care for 
a
corresponding baby-wellness visit
may be performed at this visit. In addition, 
parents/guardians of infant subjects will be reminded to contact the site promptly to report any 
severe, serious, or otherwise concerning AE.

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6.1.2.8
Visit 8: D+252 (± 14 days) – In-clinic or Home Follow-up Visit
At approximately 252 days after birth, all infants will participate in a study visit at home or in-
clinic and the following procedures will be performed:

Query and evaluation of any AEs, MAEs, SNMCs, and SAEs experienced since the last 
visit and to record concomitant medications administered for these events, and reports 
of any healthcare provider-confirmed episodes of wheezing. Note that a physical exam 
may be performed to evaluate any adverse events as needed. 

Documentation of the mode of infant feeding, if a smoker or one or more children < 5 
years of age reside in the same household, and whether the infant or another child in the 
household (< 5 years of age) is cared for in a group setting with other children (e.g., 
daycare) for ≥ 3 days per week.

Collection of weight, length, and FOC measurements.  

The Study Identification Card will also be offered to the parent/guardian, if needed.

Reminder for parents/guardians of infant subjects to contact the site promptly to report 
any severe, serious, or otherwise concerning AE.

Schedule the next visit.
Note that all procedures, including routine vaccinations that are considered standard of care for 
a corresponding baby-wellness visit may be performed at this visit. 
6.1.2.9
Visit 9: D+364 (±14 days) – In-clinic or Home Follow-up Visit
At approximately 364 days after birth, all infants will participate in a study visit at home or in-
clinic and the following procedures will be performed:

Query and evaluation of any AEs, MAEs, SNMCs, and SAEs experienced since 
delivery and concomitant medications taken for these events, and reports of any 
healthcare provider-confirmed episodes of wheezing. 

Documentation of the mode of infant feeding, if a smoker or one or more children < 5 
years of age reside in the same household, and whether the infant or another child in the 
household (< 5 years of age) is cared for in a group setting with other children (e.g., 
daycare) for ≥ 3 days per week.

Physical exam and collection of weight, length, and FOC measurements. 

Developmental testing for all infant subjects. Parents/guardians of infant subjects with 
a positive screen detected at both 6 and 12 months of age (as this is an AE), or first 
appearing at 12 months of age, will be offered repeat Ages and Stages Questionnaire 
(ASQ)-3 screening at 15 and 18 months of age as a follow-up procedure. Novavax will 
collect this information as safety data. In addition, appropriate referrals for diagnostic 
pediatric developmental testing (according to local standards of care) will also be 
advised for infants with a positive screen identified.

Parents/guardians may be asked to consent to additional infant follow-up for future 
respiratory disease such as severe LRTI syndromes or recurrent wheezing.  Such follow-

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up, if requested, will be voluntary and will be the subject of a separate future protocol 
and consent document.
Completion of this visit will mark the end of study participation for the infant subject. Note that 
all procedures, including routine vaccinations that are considered standard of care for a 
corresponding baby-wellness visit may be performed at this visit.
6.1.2.10
Unscheduled Visits
Parents/guardians will be encouraged to report, or ask the infant’s primary healthcare 
provider/pediatrician to report at any time, any other type of severe, serious, or otherwise 
concerning AE. If symptoms are presented that would require a physical exam to adequately 
assess potential AEs, the exam should be performed and vital signs collected. 
Note the RSV surveillance visits discussed in Section 6.2 are not considered unscheduled visits
prior to D+180. Symptoms suggestive of an RSV-suspect illness reported during passive 
surveillance but after D+180, will be captured as AEs and not on the RSV Surveillance page.
6.2
RSV Surveillance: Active and Passive
6.2.1
Active and Passive Components of Surveillance
RSV surveillance will comprise both active and passive components. All queries for RSV-
suspect illnesses will be made using an IRB/IEC-approved script, if applicable. 

Active Surveillance (applicable to all subjects through the D+180 visit): 
o
Study staff will contact the maternal subject and a parent/guardian of the infant 
subject via telephone call or SMS on a once weekly interval through the D+180 
visit to query for an RSV-suspect illness. Newly-discovered RSV-suspect illnesses 
as assessed by the presence of “trigger symptoms” (see Section 6.2.2 and Table 2) 
will precipitate a home or clinic visit for evaluation (see Section 6.2.3). 
o
Study staff will re-evaluate (at home or in the clinic) all infant subjects with RSV-
suspect illnesses between 2 and 3 days after any initial RSV surveillance visit to 
ascertain worsening in the illness. This re-evaluation will include the same 
procedures outlined in Section 6.2.3. 

Passive Surveillance (applicable at any time during the study): 
o
If the maternal subject develops any symptom suggestive of an RSV-suspect 
illness, or shows signs of worsening of a previously-evaluated RSV-suspect illness, 
she should contact the study site directly within 3 days of the onset/worsening of 
symptoms.  
o
If an infant develops symptoms of an RSV-suspect illness while on study, or shows 
signs of worsening of a previously-evaluated RSV-suspect illness, parents or 
guardians should contact study staff directly within 3 days of the onset/worsening
of symptoms. 
o
Any newly-discovered RSV-suspect illnesses as assessed by the presence of 
“trigger symptoms” (see Section 6.2.2 and Table 2) will precipitate a home or clinic 
visit for evaluation (see Section 6.2.3).  

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o
Study staff will re-evaluate (at home or in the clinic) all infant subjects with RSV-
suspect illnesses between 2 and 3 days after any initial RSV surveillance visit to 
ascertain worsening in the illness.  This re-evaluation will include the same 
procedures outlined in Section 6.2.3. 
o
If the initial evaluation of the maternal or infant subject for an RSV-suspect illness 
is performed by a healthcare provider, not affiliated with the study (e.g., in an 
urgent care clinic, emergency room, or other outpatient clinic), he/she should notify 
the study staff of the maternal or infant subject’s status as per the information 
provided on the Study Identification Card. 
o
Note: symptoms suggestive of an RSV-suspect illness reported during passive 
surveillance but after D+180 will be captured as AEs and not on the RSV 
Surveillance page.
Please refer to the Study Operations Manual for additional details regarding the procedures 
performed during the RSV Surveillance. 
6.2.2
Trigger Symptoms for RSV-suspected Illness
Surveillance for RSV will be based on the occurrence of “RSV-suspected illness” characterized 
by one or more of the following Trigger Symptoms in infant and maternal subjects (Table 2) 
that persist for a period of ≥ 24 hours, either in a continuous or intermittent manner, and are 
assessed as “atypical” (by the maternal subject herself, or a parent or other routine caregiver for 
the infant) in nature.
Table 2:
Signs and (Trigger) Symptoms of RSV-suspected Illness in Infant and Maternal 
Subjects
Symptoms in Infant Subjects
Symptoms in Maternal Subjects

Cough

Cough

Stuffy nose or runny nose

Stuffy nose or runny nose

Trouble breathing or fast breathing when 
resting

Shortness of breath

Trouble feeding or not feeding well 

Sore throat

Less active than normal when awake

Fever 

Sleeps more than normal

New or increasing wheezing

More crying or more fussy than normal

Wheezing (whistling noise when breathing)

New or increasing  sputum production
Note: It is not intended that these triggers for reporting be specific, or diagnostic of RSV, or LRTI; rather the goal is to 
capture acute respiratory illnesses generally. Physician (or qualified clinical designee) evaluation, (including an 
assessment of the infant’s oxygen saturation level via pulse oximetry readings and respiratory rate by observation 
for 1 minute at the time of presentation of the acute illness) will capture those features which characterize LRTI, 
tachypnea, and hypoxemia or severe hypoxemia; molecular diagnosis by reverse transcription-polymerase chain 
reaction (RT-PCR) will detect RSV. These symptoms are intended to be a sensitive, rather than specific, trigger for 
further evaluation.

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6.2.3
Clinical Study Site Response to Reports of Initial Trigger Symptoms
In response to a report via active or passive surveillance of Initial Trigger Symptoms, the 
study site staff will:

Arrange for an in-clinic or home visit as soon as possible, but not later than 7 days after
symptom onset, for evaluation by the study physician/qualified clinical designee of the 
subject (infant or mother) displaying the symptom/s and/or findings listed in Table 2. 

Arrange for an in-clinic or home visit by a study physician/qualified clinical designee 
for evaluation as soon as possible within 7 days of symptom(s) onset for maternal or 
infant subjects who received care for trigger symptoms at a non-study, affiliated medical 
facility. Note that this visit would only be applicable to subjects who are receiving 
outpatient care or have been released from inpatient care.
Procedures to Occur During the Visit:

Specific for Symptomatic Infants:Measure the respiratory rate on room air (if possible) 
for all symptomatic infants. This measurement should be performed first, on a calm 
infant, and should be performed by observation only (i.e., without stethoscope 
auscultation) for a full, timed one minute period.  
o
If the result is ≥60 bpm in an infant 0 to 59 days of age or ≥50 bpm in an infant 
≥60 days of age, a second timed one minute count should be obtained.
o
If a second count is obtained, the lower of the two observations should be recorded.

Measure the SpO2 via pulse oximetry (using study-specific pulse oximeter) for all 
symptomatic infants, which is to be performed when the infant is calm and not crying, 
and before administration of oxygen supplementation. The lowest stable SpO2 observed 
during a one minute measure should be recorded. Note that the oxygen should not be 
removed to measure SpO2 in infants already receiving oxygen supplementation at the 
time of assessment. Please refer to the Pulse Oximeter Manual for more details. 
For all Symptomatic Subjects (Maternal and Infant):

Review and confirm the history of respiratory illness, including the approximate date of 
first symptom onset. 

Perform an examination of the symptomatic infant subject to ascertain, by observation 
or auscultation, the presence of the LRTI manifestations listed in Table 3 below.

Collect a respiratory specimen from the symptomatic subject for detection of respiratory 
viruses.
o
Symptomatic maternal subjects will have a nasal and throat specimen collected. The 
nasal secretion will be collected by mid-turbinate swabbing.
o
Symptomatic infant subjects will have a mid-turbinate nasal swab collected. 
o
RT-PCR testing for RSV and other viruses by the study laboratory will be for the 
purposes of this protocol, and not for clinical care. 
o
Respiratory specimens collected from the maternal and infant subject during an RSV 
surveillance visit may be split so that samples are provided for this protocol and for 

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a qualified local laboratory supporting clinical care if the attending physician would 
ordinarily regard testing for bacterial and/or viral pathogens as warranted.

Collect vital signs other than respiratory rate (heart rate, blood pressure [if available for 
the infant], and axillary body temperature) for the symptomatic subject. 

Ascertain any medically-attended visit by the subject in response to the respiratory 
illness.

Ascertain any new concomitant medications resulting from the respiratory illness.

Notify the infant’s primary healthcare provider of the RSV surveillance visit and 
outcome, as necessary.
Table 3:
Clinical Signs/Symptoms to be Clinically Evaluated during an RSV-suspected
Illness 
Infant Subjects
Maternal Subjects

Cough

Nasal flaring

Difficulty breathing, manifesting in at least one of the 
following clinical signs or symptoms:
o
Lower chest wall indrawing 
o
Subcostal retractions 
o
Abnormal breath sounds, inclusive of: 

Stridor, 

Rales,

Rhonchi, 

Wheezing,

Crackles/crepitations 
o
Observed apnea

Cough

Nasal congestion

Fever

Runny nose

Sore throat

Dyspnea

New or increasing wheezing

New or increasing  sputum production
6.2.4
Follow-up of RSV-Suspect Illnesses
Following the evaluation of an RSV-suspect illness outlined in Section 6.2.3, the clinical site 
will:

For symptomatic infant subjects, schedule a follow-up visit in 2 to 3 days to ascertain 
whether the illness is worsening.
o
The follow-up visit will include the same procedures outlined in 6.2.3.
o
Parents/guardians will be strongly encouraged to report any worsening after the 
follow-up visit, including hospitalizations, which may trigger any number of 
additional follow-up visits at the investigator’s discretion.
o
In the event that an infant is hospitalized, site staff are encouraged to perform a 
follow-up visit in-hospital, if permissible under local administrative and ethical 
review procedures.

For symptomatic maternal subjects, and for symptomatic infant subjects after the first 
follow-up visit described above, a weekly contact by telephone/SMS will be performed 
to ascertain respiratory symptom status through to the D+180 visit, and to monitor the 

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status of RSV-suspect illnesses until symptoms have resolved, or have returned to 
baseline if after the D+180 visit. 

In the event new and/or worsening symptoms are reported during active or passive 
follow-up, an in-clinic or home RSV-surveillance visit may be scheduled at the 
investigator’s discretion for an evaluation to occur as soon as possible, and a re-
evaluation as per Section 6.2.3 may be performed.
o
At the investigator’s discretion, collection of ONE more respiratory specimen for 
pathogen detection for infant subjects who have developed qualitatively different or 
quantitatively worse symptoms. Note that no more than 3 respiratory specimens should
be collected from an infant within the same episode.  
o
If the new or worsening symptom in the maternal subject is associated with a respiratory 
episode for which a specimen has already been obtained, the investigator may exercise 
his/her judgement as to the utility of an additional swab. 
6.2.5
Definitions and Rules for RSV Surveillance

If possible, study staff should collect symptom data for any RSV-suspected illness for 
maternal and infant subject pairs during the same weekly telephone call or SMS contact. 
In the event the maternal and infant subject pair have independent clinic visits for 
assessment of an RSV-suspected illness within a given surveillance period, the 
subsequent weekly telephone or SMS contact for the next surveillance period can be 
resynchronized based on the earlier of the two contacts. For example, if a maternal 
subject had a clinic visit to evaluate an illness on Monday of surveillance week (SW)-
1, this would trigger the next contact for the following Monday of SW-2. If the infant 
subject of the same mother had a clinic visit to evaluate an illness on Thursday of SW1, 
his/her next weekly contact could be rescheduled to coincide with the maternal subject 
contact on Monday of SW-2. (The intent of this provision is to relieve the need for 
mother/infant pairs to make multiple follow-up visits in a one-week period.)

A new respiratory illness will be deemed to occur any time a one week (7 day) interval 
elapses during which the subject is free of respiratory symptoms. When a subject is 
determined to have a new respiratory illness, the subject should be evaluated at an in-
clinic or home visit by study staff for this new episode (as described in Section 6.2.3).

A medically-attended visit will be deemed to have occurred whenever the subject or a 
parent/guardian of the infant subject precipitates a visit or home encounter with a 
physician or other healthcare provider for the purpose of evaluation or treatment of a 
respiratory illness. Note that at-home or in-clinic visits undertaken specifically to fulfill 
the requirements of this protocol, for illnesses which would not otherwise cause the 
parent/guardian to present the infant for care, are NOT “medically-attended visits,” 
with the exception noted immediately below.

In the event that the investigator is also the subject’s primary care physician 
(PCP)/general practitioner (GP), any RSV surveillance visit will be counted as a 
“medically-attended visit.” 

Note that the intent of the evaluation of subjects with Trigger Symptoms is fulfillment 
of the objectives of this protocol. The investigator or study site staff should use their 

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best professional judgment to ensure that subjects receive prompt medical care 
appropriate to their clinical condition, if necessary either by referring the subject to their 
usual physician or medical care facility, or providing care if the investigator is the 
subject’s primary physician or if the case is emergent. The collection of the study data 
to support the primary and secondary efficacy endpoints are key objectives of this trial, 
but when necessary, appropriate medical care should supersede this goal. 

Respiratory events captured as efficacy endpoints will NOT be recorded in the AE
electronic case report form (eCRF) or AE eSource page, with the exception of those that 
fulfill the definition of an SAE. Full particulars of the SAE(s) will also be captured in 
the SAE report form.

Respiratory events ongoing at the 6 months post-delivery visit (D+180) will be followed 
by study staff at weekly intervals until symptoms resolve or return to baseline.
6.3
Concomitant Therapy
Maternal and infant subjects may receive all concomitant medications and procedures deemed 
necessary to provide adequate healthcare during the study, with the exception of those specified 
in the exclusion criteria. Routine medical standards of care are permitted, including vaccines 
needed for emergent indications (e.g., tetanus booster in response to a penetrating injury and 
palivizumab prophylaxis during RSV season of infants born prior to 35 weeks). Routine 
vaccination is permitted at all times for the infant (e.g., well-baby vaccinations). 
Concomitant medications, procedures, and hospitalizations will be recorded throughout the 
study including the period from the day Informed Consent Form (ICF) is signed through the 
end of study follow-up. All new or changed concomitant medications taken through the entire 
study period for both maternal and infant subjects will be recorded (excluding routine 
medications administered for the management of labor and delivery). The investigator will 
document whether the concomitant medication was provided for either a solicited systemic or 
an injection site adverse event.
6.4
Declining Study Treatments or Procedures
The maternal subject and parents/guardians of the infant subject have the right to decline study 
treatment or other study procedures for themselves or their infants for any reason at any time 
during the study. If a maternal subject declines study procedures subsequent to receipt of a 
treatment dose or if a parent/guardian of the infant declines study procedures at any time during 
the study, it should be recorded as a protocol deviation and the reason should be clearly 
documented in the source document. The maternal subject and/or parent/guardian of the infant 
will be asked to complete all other study procedures for herself and infant, as applicable. If the 
maternal subject or parent/guardian of the infant does not wish for herself or the infant to remain 
in the study, either can choose to withdraw consent and discontinue at any time as outlined in 
Section 6.5.
The investigator may, at his/her discretion, restrict a maternal or infant subject from receiving 
a specific study procedure if he or she consider it to be in the maternal or infant subject’s best 
interest to do so, but can suggest that both remain in the study to be followed for safety if the 
maternal subject has received a test article. In this situation, the reason for not performing the 

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study treatment and/or procedure should also be recorded as a protocol deviation and clearly 
documented in the source document. 
6.5
Premature Discontinuation from Study
Pregnant subjects who provide consent but are found to be ineligible on screening will be 
informed of the reason for ineligibility and may be provided with local medical referral by the 
investigator as appropriate, but will receive no further study follow-up.
Maternal and infant subject participation in the study is strictly voluntary. Maternal subjects 
and/or parents/guardians of infants have the right to withdraw themselves and/or the infant from 
the study at any time and for any reason, without penalty. The investigator may, at his/her 
discretion, discontinue subjects from the study if he/she considers it to be in the participants' 
best interest to do so, or if the maternal subject or the infant’s parent or guardian is not willing 
or able to comply with the study requirements. Novavax will be notified immediately by the 
investigator if a subject prematurely ends study participation. The reason for early 
discontinuation will be clearly documented in the electronic Case Report Form (eCRF) or 
eSource. A withdrawal due to an AE will initiate additional reporting requirements as outlined 
in Section 8.7. 
In the event of early termination, investigators will make every reasonable effort to perform 
study completion procedures. Study completion procedures will include a query for any MAEs, 
SNMCs, or SAEs occurring since the last study visit, and any concomitant medications taken 
to treat these events, as well as:

For maternal subjects: a blood draw for serology testing (20 mL) at any time and for 
clinical laboratory safety assessments (10 mL) in applicable subjects (i.e., those subjects 
with safety labs performed at screening) if before the Day 14 visit. 

For infant subjects: a blood draw for serology testing (1 to 2 mL by venipuncture or heel 
stick with documentation of the method used, but not within two weeks of a prior 
phlebotomy) if prior to the:
o
Day 90 visit for Cohort 1 subjects, 
o
Day 120 visit for Cohort 2 subjects, and
o
Day 180 visit for Cohort 3 subjects. 
Additionally any SNMC or SAE that continues beyond the duration of the study is to be 
followed to resolution or until the event becomes stable.  Maternal and infant subjects who 
terminate from the study early will not be replaced.
6.6
Study Termination
Novavax reserves the right to terminate the study at any time for any reason. When the study is 
terminated (either prematurely or as scheduled), the investigator will notify the IRB/IEC for the 
study, and other authorities as required by local regulatory requirements. 
The scheduled end of the study will be the completion of the last post-delivery Day 364 follow-
up visit with the last infant enrolled in the study.

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7
LABORATORY REQUIREMENTS
Appendix 3 specifies the maximum amount of blood that will be drawn from maternal (120 mL) 
and infant (from 3 to 6 mL, depending on the collection method) subjects, and from the cord 
blood at delivery (a minimum of 5 mL) for clinical safety and/or immunogenicity laboratory 
procedures to be completed throughout the study. This amount may increase for maternal 
subjects if repeat laboratory safety assessments are performed (see Section 8.2.3 for more 
details).   
Specific information regarding the central or local laboratories that will perform clinical 
laboratory safety testing, RSV serology testing, and genotyping of respiratory specimens is 
provided in the Study Operations Manual.
7.1
Clinical Laboratory Testing
The following laboratory tests will be performed by a qualified central laboratory (unless 
otherwise stated) designated by Novavax on blood samples collected from maternal subjects 
enrolled in the first year of study conduct in any country at the screening visit (Days -28 to 0) 
and on Day 14 (unless the subject delivers prior to this visit at which time the blood sample will 
be obtained at delivery):

Serum chemistry – alanine aminotransferase (ALT), aspartate aminotransferase (AST), 
total bilirubin, alkaline phosphatase (ALP), creatinine, and blood urea nitrogen (BUN). 

Hematology – hemoglobin, platelet count, and white blood cell (WBC) count. 
Additional clinical laboratory antigen tests/serologies for HIV, syphilis, HBV, and HCV 
detection will be performed by a central or local laboratory at the screening visit, if results are 
not available in prior data collected during the course of the current pregnancy.
A urine pregnancy test will be administered to all maternal subjects at the D+180 visit; a positive 
result will trigger additional follow-up to determine the outcome of the pregnancy.
7.2
Assessments of Immunogenicity
Anti-F IgG antibody levels in EU, PCA concentrations, and neutralizing antibody titers to 
RSV/A and RSV/B will be determined at protocol-specified time points for all subjects. 
Completion of microneutralization testing may be staged, due to its cumbersome nature, and 
results may be reported in addenda to the primary clinical study report. Serological 
immunogenicity parameters will include GMEU, geometric mean concentration (GMC), or 
GMT (as appropriate); GMFR, SCR, and SRR by treatment group for most analyses. 
Comparisons across groups will be performed as described in the statistical analysis plan and 
briefly in Section 10.5. Blood samples from maternal subjects will be drawn for RSV serology 
testing at screening (Day -28 to 0) and on Day 14 prior to delivery, at delivery, and on Days 35 
and 180 post-delivery. Blood samples from infant subjects will be drawn for RSV serology 
testing at post-delivery study Days 14 and 90 for Cohort 1 infants, on Days 35 and 120 for 
Cohort 2 infants, and on Days 60 and 180 for Cohort 3 infants. Infant subjects may also have 
blood drawn within 72 hours of birth if cord blood is not collected at delivery. 

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7.2.1
Anti-F IgG ELISA
For the anti-F IgG ELISA, 96-well microtiter plates are coated overnight with the RSV F 
antigen, then blocked with an irrelevant protein to reduce non-specific binding. Serial dilutions 
of subject sera are added starting minimally at 1:10. Serial three-fold dilutions of an anti-F IgG 
reference standard as well as negative and positive controls are also included. After incubation, 
wells are washed extensively and an anti-human IgG peroxidase conjugated antibody is added 
to detect the presence of anti-RSV F IgG specific antibodies in the wells. Following secondary 
antibody incubation and extensive washing, substrate is added to the plates, color is allowed to 
develop, and the plate is read at an optical density (OD) of 450 nm with subtraction at 630 nm 
to account for background. A four-parameter logistic (4-PL) curve fit is applied to the reference 
standard and the reported titer is determined from the mean calculated from serial dilutions, 
interpolated from the reference standard concentrations. A full description of the validated 
method can be found in Novavax standard operating procedure (SOP) numbered 
P_SOP_00659.
7.2.2
Palivizumab-Competitive Antibody (PCA) ELISA 
In the PCA ELISA, 96-well microtiter plates are coated overnight with the RSV F antigen, then 
blocked with an irrelevant protein to reduce non-specific binding.  Serial dilutions of test sera,
diluted minimally at 1:4, are incubated with a fixed amount of biotin-labeled palivizumab in the 
RSV F-coated plates. Reference standards as well as negative and positive controls are also 
included. After incubation to reach binding equilibrium, the plates are washed and then 
incubated with avidin-conjugated horseradish peroxidase. After additional washing, substrate 
is added to the plates, color is allowed to develop, and the plate is read at OD450 with subtraction 
at 630 nm to account for background. Palivizumab-like antibodies in the test serum are 
quantitated based on OD values corresponding to 50% binding of unlabeled palivizumab. The 
final concentration is obtained by linear interpolation/extrapolation of the reference curve 
adjusted by dilution factor using a 4-PL curve fit analysis. The binding of biotinylated 
palivizumab to the antigen on the plate reflects the competition of palivizumab-like antibodies 
from human serum.  A full description of the validated method can be found in Novavax SOP 
numbered P_SOP_01066.
7.2.3
RSV/A and B Microneutralization (MN)
Tests for serum neutralizing antibodies against a minimum of one RSV/A and B group viruses 
are performed using a MN assay developed by P.A. Piedra and colleagues at the Baylor College 
of Medicine. This assay is well-controlled and has been extensively tested for over 20 years, in 
both seroepidemiology and vaccine studies, and has been used to estimate potential protective 
titers [Piedra 2003b].  The RSV/A and B MN assay is qualified.
In brief, RSV/A and RSV/B stocks are prepared in HEp-2 monolayers, divided into aliquots, 
and stored at -70ºC as previously described [Piedra 2003b, Suara 1996]. Duplicate serial two-
fold dilutions of sera are added to a constant virus inoculum in a 96-well microtiter plate. HEp-
2 cells are then added to each well and plates are incubated for 6 to 7 days. Positive (no test 
serum) and negative (no virus) controls are included. Multiple standard control sera with 
established titers across the dynamic range of the assay are included in each assay run, and their 
titers must conform to pre-specified acceptance criteria in order for results of that run to be 

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valid. The viral cytopathic effect (CPE), defined as tissue destruction, is determined visually 
after the cells are fixed with formalin and stained with crystal violet. The neutralizing antibody 
titer is defined as the reciprocal of the serum dilution at which > 50% reduction in viral CPE 
was observed.
7.3
Detection of RSV and Other Pathogens by RT-PCR
A respiratory specimen will be collected as soon as possible after onset of illness in maternal or
infant subjects with an RSV-suspected illness that is accompanied with the symptoms listed in 
Table 2. The specimen will be processed and subjected to a commercially available multiplex 
RT-PCR for identification of a range of common viral pathogens in addition to RSV. 
Instructions on how to obtain the respiratory specimen are provided in the Study Operations 
Manual. Note that the testing described in this section will be for research purposes and the 
protocol does not contemplate use of these data for clinical care; which will be the 
responsibility of the subjects’ primary physicians and their local laboratory services.
7.4
Retention and Use of Archived Specimens
Serum specimens may be archived by Novavax or its contractors for a period not to exceed 25 
years. The archived sera, which will not contain information that can identify a subject, may be 
used for repetition of the assays listed above (Section 7.2) using different RSV antigens, or for 
other exploratory assays of RSV immunity in development. Archived sera may also be used for 
clinical laboratory testing for safety if needed to evaluate an adverse event, provided that a) 
sample storage falls within conditions previously validated by the clinical laboratory to yield 
interpretable results (or an appropriate control strategy can be used to evaluate potential storage 
impacts), and b) such testing will not include either assays to detect HIV infection, or any 
genetic testing.  Archived samples may also be used to create positive or negative panels for 
quality control or for assay development related to other infectious diseases (excluding HIV), 
in which case they will be anonymized. The above uses will be outlined in the Informed Consent 
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8
ASSESSMENT OF SAFETY
The safety assessments performed in this study will include a seven-day solicited AE profile in 
the vaccinated maternal subject, as well as an extended unsolicited AE profile through six (6) 
months after delivery. Additionally, vaccine safety will include measures that assess for 
potential pregnancy/labor and delivery complications for the maternal subject, and for potential 
safety concerns for the infant exposed to anti-F antibodies in utero via transplacental 
immunization. The infant’s health status will be assessed for any adverse events including 
physical and/or developmental impairments, as well as increased severity of RSV illness upon 
natural exposure. Because safety outcomes are different based on the subject population (i.e., 
maternal subjects vs. infant subjects) under evaluation, AE assessments specific to the maternal 
or infant subject are indicated in this section. 
8.1
Adverse Events
Adverse events (AEs) are defined as any unfavorable or unintended change in the physical, 
psychological, or biochemical condition of the subject. An AE temporally related to 
participation in the study or due to a procedure performed in the trial will be documented 
whether or not considered related to the test article. This definition includes intercurrent 
illnesses and injuries, and exacerbations of pre-existing conditions. Stable pre-existing 
conditions which do not change in nature or severity during the study are not considered AEs; 
however, these should be collected as part of the medical history. AEs will be considered 
treatment emergent from the date and time of the first administration of the investigational 
product. 
Data concerning ALL adverse events will be collected at all scheduled visits for the entire study 
period for maternal subjects (i.e., from the time informed consent is obtained though post-
delivery study Day 180) and through one year of life for infant subjects. 

In addition to the scheduled visits, maternal subjects will be encouraged to return to the 
clinic or notify the investigator if any severe (grade 3) local or systemic solicited AE 
occurs during the 7-day post-immunization period, or if a severe AE, a serious AE, or 
any other AE worrisome to the subject occurs at any time following vaccination. 

Parents/guardians will also be encouraged to report, or ask the infant’s primary 
healthcare provider/pediatrician to report at any time, any other type of severe, serious, 
or otherwise concerning AE. 

If at a scheduled or unscheduled visit, symptoms are presented that would require a 
physical exam to adequately assess potential AEs, the exam should be performed and 
vital signs collected.  
Adverse events will be recorded as observed by the investigator, designated personnel, or as 
provided by the maternal subject on the diary card or during a face-to-face visit with the 
maternal subject or the infant’s parent/guardian.  Full details of the AE (i.e., nature, date of 
onset and recovery as well as an assessment of severity, relationship to study agent, seriousness, 
treatment and outcome) will be recorded in the source documentation and captured in the eCRF

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or entered into the eSource directly, and will generally require the investigator(s) causality 
assessment, except as discussed in subsequent sections.
8.2
Maternal Adverse Events 
8.2.1
Solicited Adverse Events Collected by Subject Diary 
Maternal subjects will be provided with a diary for the documentation of solicited and 
unsolicited AEs, daily recording of their oral temperature, and concomitant medications and 
procedures starting on vaccination day and for six days following vaccination (i.e., from Day 0 
to Day 6, inclusive, or 7 days total).  A series of local injection site and systemic reactions that 
are reasonably likely to occur in vaccine programs (Table 4) will be solicited daily in the diary 
and standardized severity grades offered to the subject. A standard tool for the measurement of 
visible local reactions will be provided (see example provided in Appendix 4) as will a digital 
oral thermometer. Maternal subjects will also be asked to record any physician visits or 
hospitalizations, and any unsolicited AEs experienced during Day 0 through Day 6. In addition 
to reporting grade 3 solicited adverse events in the diary card, subjects should be encouraged to 
contact the Investigator by telephone if these occur. The investigator may request an ad hoc
clinic visit at his/her judgment, and should enter any grade 3 solicited adverse events reported 
by telephone in the solicited AE eCRF or AE eSource Page promptly, even if the balance of 
diary data is not yet available.
Table 4:
Listing of Diary Solicited Events  
Injection Site (Local) Events
Systemic Events
Pain
Body temperature (oral)
    Nausea
Bruising
Chills
Vomiting
Redness 
Muscle pain 
Headache
Swelling 
Joint pain 
Fatigue
Diarrhea
Note: All events listed will be solicited by diary for seven days following vaccination (i.e., from Day 0 to Day 6, inclusive) 
and will be categorized as solicited events.  Events reported outside this window will be categorized and reported as 
unsolicited AEs.
Standard severity grading definitions will be provided in the diary. Grading of visible, 
measurable injection site reactions will be based on the Food and Drug Administration (FDA) 
Guidance for Industry, Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers 
Enrolled in Preventive Vaccine Clinical Trials (September 2007). Definitions are summarized 
in Table 6. Body temperature (for assessment of fever) during pregnancy will be collected as a 
continuous variable and graded by the investigator based on third-trimester values published in 
Sheffield et al. [2013] (see Table 7) and also provided in the Toxicity Grading Scale (TGS) 
located in the Study Operations Manual.  
Investigators will not be required to assess causality of solicited adverse events specifically 
named in the diary if onset is during the solicitation period (these will be presumed to be 
treatment-related). Adverse events consistent with the solicited adverse events listed in the 
diary, but with onset after the solicitation period (i.e., post-Day 6), will be captured as 
unsolicited AEs and are subject to all procedures for unsolicited AE data.

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Solicited AEs, collected from the subject diary, which continue after the collection period (i.e., 
post-Day 6) will be followed to resolution. The continuing, solicited AE will be captured by 
verbatim term, on the AE eCRF or AE eSource page. Investigators will be required to assess 
severity of the continuing solicited adverse event(s) starting from the day after the last diary 
entry until resolution.
8.2.2
Unsolicited Adverse Events 
Any AEs reported by maternal subjects will be categorized as unsolicited events and Medical 
Dictionary for Regulatory Activities (MedDRA) coded by system organ class (SOC) and 
preferred term (PT). Solicited events with an onset after the solicitation period will also be 
classified as unsolicited AEs. Unsolicited events that occur within 7 days following vaccination 
should also be recorded in the subject diary. If any grade 3 unsolicited event is reported during 
this period, maternal subjects should be encouraged to contact the investigator by telephone. 
The investigator may request an ad hoc clinic visit at his/her judgment, and should enter any 
grade 3 unsolicited adverse event reported by telephone in the unsolicited AE eCRF or eSource
page promptly, even if the balance of diary data is not yet available. 
All unsolicited AEs occurring in maternal subjects will be assessed for severity (as defined in 
Section 8.8) and for causality (as discussed in Section 8.9), and will be documented in the source 
documents and captured in the eCRFs or entered into the eSource directly.  
8.2.3
Clinical Laboratory Findings as Adverse Events 
Clinical laboratory parameters will be tabulated in study reports by grades using the Toxicity 
Grading Scale (TGS) provided in the Study Operations Manual, which is based on third-
trimester values published in Sheffield et al. [2013]. Note that normal ranges for these 
parameters are based on reference ranges appropriate for women in the third trimester of a 
pregnancy. 
Laboratory values that show an increase in the toxicity grade relative to baseline values in the 
same subject, and attain at least grade 2 (e.g., normal or grade 1 to grade 2 or higher) will be 
reported as AEs (along with the severity grade). Repeat testing will be conducted as defined 
below until the laboratory parameter returns to baseline, becomes stable, or an explanatory 
diagnosis is available: 

Grade 2 events - weekly, from the time the investigator becomes aware of the abnormal 
laboratory parameter.

Grade 3 events - every 72 hours from the time the investigator becomes aware of the 
abnormal laboratory parameter. 
The investigator may also elect to report less severe abnormalities as AEs (e.g., grade 1 events), 
at his/her discretion, if the abnormality is of sufficient concern to trigger, or should have 
triggered, a diagnostic evaluation (including repeat testing). 

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8.2.4
Vital Sign Abnormalities as Adverse Events 
Severity grades for vital signs are provided in the TGS located in the Study Operations 
Manual. These ranges are adopted directly from the third-trimester values in Sheffield et al.
[2013], and are summarized in Table 7 for fever. The toxicity grade range for a fetal heart tone 
abnormality is also provided in Table 7. For the purposes of reporting vital sign abnormalities 
as AEs, those values that show an increase in the toxicity grade relative to the baseline values 
(in the same subject) and attain at least a grade 2 (e.g., normal or grade 1 to grade 2, or grade 2 
to grade 3) must be reported as an AE. Investigators may report lesser abnormalities as AEs if 
indicated based on clinical judgment. Abnormal vital signs may be repeated at the investigator’s 
discretion, and because these measures are highly labile, they should only be reported as AEs 
when the investigator believes there is a meaningful physiologic change. An exception is made 
for the fetal heart tones measure, which may be repeated, but should also be reported as an AE 
if an abnormality is consistently observed (i.e., present on more than one observation) with 
repeat testing.   
8.3
Infant Subject Safety Assessments
Any AEs reported in infants will be categorized as unsolicited events and MedDRA coded by 
SOC and PT.  These can include, but are not limited to, abnormalities in vital signs, metabolic 
screening and developmental tests, neonatal hearing, congenital anomalies, respiratory failure, 
perinatal infections, neonatal death, complications that result in extended hospitalization; as 
well as any other SAE (as defined in Section 8.5), MAE, or SNMC (as defined in Section 8.4). 
All unsolicited AEs will be assessed for severity (as defined in Section 8.8) and for causality 
(as discussed in Section 8.9), and will be documented in the source documents and captured in 
the eCRFs or entered into the eSource directly. Severity for all unsolicited events, including 
those for which numerical values may be available (e.g., vital signs or clinical laboratory 
parameters) will be based on interference with daily-activities and/or whether medical 
intervention/therapy is required, according to the investigator’s medical judgment. 
Events that meet the threshold for SAEs (as discussed in Section 8.5), will be designated as 
such, and are associated with enhanced reporting requirements (see Section 8.7). 
8.3.1
Ages and Stages Questionnaire
The Ages & Stages Questionnaires®, Third Edition (ASQ-3™) consists of a brief (10-15 
minute) parent questionnaire that is then scored by health professionals. It is designed as a 
screening tool to pinpoint developmental progress in children between the ages of one month 
to 5 ½ years. One of the strengths of the ASQ is that it employs a parent-centric approach, 
although assistance by site staff is permissible (http://agesandstages.com/). Developmental 
assessments will be performed at 6 and 12 months (assessment for infants born prematurely 
may use age-appropriate adjusted scoring) of age for all infant subjects. For purposes of 
reporting the developmental screening as AEs, only abnormalities observed at both 6 and 12 
months of age will be reported as an AE. Parents/guardians of infant subjects with a positive 
screen detected at both 6 and 12 months of age, or first appearing at 12 months of age, will be 
offered repeat ASQ screening of their infant at 15 and 18 months of age as a follow-up 
procedure. In addition, appropriate referrals for diagnostic pediatric developmental testing 

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(according to the local standards of care) will also be advised for infants with a positive screen 
identified.
As a guidance, and solely for the purposes of consistency within this protocol, it is suggested 
that investigators report ASQ abnormalities which persist at 6 and 12 months in a given infant 
as an AE that is “moderate” in severity. If diagnostic developmental testing is undertaken, the
event should be further classified as a medically-attended event (MAE, see Section 8.4). If 
diagnostic evaluation, during the trial or afterward, leads to the diagnosis of a persistent 
developmental disability, the event then also becomes a serious adverse event (SAE, see 
Section 8.5) and should be reported as such.
8.4
Medically-Attended Events and Significant New Medical Conditions
Medically-attended events (MAEs) are adverse events which result in an unscheduled visit to a 
healthcare provider (e.g., physician, midwife, or other provider as per local standards of care) 
due to symptomatic illness or injury.  These may include office visits, clinic visits, home 
consultations, 
emergency 
room 
evaluations 
for 
non-life-threatening 
events, 
and 
hospitalizations.  
Significant new medical conditions (SNMCs) are adverse events that are new (that is, not 
present at baseline), clinically significant (meaning that they imply an important change in the 
subject’s long-term health status), and typically chronic (requiring an ongoing change in the 
subject’s medical management). This category is not meant to include minor or transient 
diagnoses or age-related changes.  For example, while new diagnoses of presbyopia or tinea 
versicolor are chronic conditions, they are not SNMCs because no significant change in health 
status is implied. Similarly, adverse events which are isolated, treatable events that resolve and 
do not require chronic therapy are also not SNMCs (examples could include an uncomplicated 
acute urinary tract infection or a simple fracture resolved with conservative treatment and with 
no residual disability). In contrast, new diagnoses of rheumatoid arthritis or coronary artery 
disease are SNMCs because they imply a long-term change in health status and require ongoing 
medical management.   
The eCRF/eSource will provide a field in which the investigator may designate AEs as MAEs, 
SNMCs, or both. Because of the significance of the designation for the subject’s health, long-
term medical management, and for evaluation of vaccine safety, SNMCs are expected to be 
substantiated diagnoses, not isolated symptoms which might or might not be an SNMC, and the 
Investigator should record sufficient data in the source document to support the diagnosis.
Full details of MAEs and SNMCs (i.e., nature, date of onset and recovery (if applicable) as well 
as an assessment of severity, relationship to study agent, seriousness, treatment, and outcome) 
will be recorded in the source documentation and captured in the eCRF or entered into the 
eSource directly, and will require the Investigator(s) causality assessment. 

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8.5
Serious Adverse Events
An SAE is defined as an AE that results in any of the following outcomes: 

Death,

An immediate threat to life, 

In-patient hospitalization or prolongation of an existing hospitalization. 
o
Hospitalization is defined as an actual admission, not a 24-hour stay or emergency 
room visit. 
o
Admissions for elective surgeries, undertaken for conditions present prior to receipt 
of study drug and without complication, should not be considered SAEs, 
o
Hospitalization for delivery represents normal obstetrical care and is not an SAE 
unless precipitated by an unanticipated adverse fetal or maternal event.

A persistent or significant disability/incapacity (substantial disruption of an ability to 
conduct normal life functions), or 

A congenital anomaly or birth defect. 
An important medical event that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical judgment, it 
may jeopardize the patient or subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition. Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, and 
blood dyscrasias or convulsions that do not result in in-patient hospitalization. Events which 
could have led to the above outcomes had they occurred with greater severity are not SAEs, but 
should be reported as AEs, MAEs, or SNMCs, as appropriate. 
The eCRF or eSource will provide a field for designating an AE as an SAE. SAEs are associated 
with enhanced reporting requirements (see Section 8.7).   
8.6
Maternal/Fetal/Neonatal Adverse Events of Special Interest
Table 5 summarizes and defines a series of maternal, fetal, and neonatal adverse events that are 
of special interest in the evaluation of maternal immunization strategies.  The majority of these 
events will fulfill one or more of the criteria listed above for SAEs.  In the event that one of 
these events does not meet the criteria for an SAE (e.g., “Small for Gestational Age” might not), 
it will nonetheless be reported as an SAE using the same reporting requirements as an SAE.  
The majority of these terms and definitions are derived from the Brighton Collaboration 
Definitions of Key Terms (WHO meeting July 2014).  Investigators should strive to collect the 
same level of data as for any SAE, and are encouraged to use the exact terms in Table 5 to report 
events meeting these definitions (see Table 5 footer for exceptions for reporting of neonatal and 
infant death).  Note that the SAE eCRF/eSource will provide a field for designating an SAE 
report as a Maternal/Fetal/Neonatal Adverse Event of Special Interest (MFNAESI).  Some 
MFNAESIs are open to interpretation as to which subject should be recorded as sustaining the 
event. Table 5 also designates to which subject each class of event should be assigned; solely 
as a uniform data collection convention. Since there are multiple potential sources to determine 
the GA at birth, the study defined EDD and the birth date will be used to determine the 

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gestational age (GA) at birth for the summary of the preterm birth categories (Very preterm and 
Moderate to late preterm).
Table 5:
Maternal/Fetal/Neonatal Adverse Events of Special Interest
Term
Definition
Reported as an Event In
Stillbirth:
Delivery of a dead fetus of > 22 weeks gestation, 
subcategorized as:

Antepartum 

Intrapartum
Mother
Placental 
Abruption:
Placental separation from the uterus with bleeding 
(concealed or vaginal) before fetal birth, with or without 
maternal/fetal compromise
Mother
Preterm Birth:
Delivery of a live newborn child, subcategorized as:

Very preterm: 28 to < 32 weeks gestation

Moderate to late preterm: 32 to < 37 weeks gestation
Mother
Gestational 
Hypertension/
Pre-Eclampsia/ 
Eclampsia:
Gestational Hypertension: New onset elevations of blood 
pressure after 20 weeks of gestation, in the absence of 
accompanying proteinuria.  
Pre-Eclampsia: A hypertensive disorder of pregnancy 
with:

A blood pressure ≥ 140/≥ 90 on 2 occasions, at least 
4 hours apart after 20 weeks of gestation, or a blood 
pressure ≥ 160/≥ 110 and
the presence of 
proteinuria (≥ 300 mg of urinary protein / 24 hours; 
or protein/ creatinine ratio ≥ 0.3, dipstick reading of 
1+), or 

In 
the 
absence 
of 
proteinuria, 
new-onset 
hypertension with the new onset of any of the 
following:
o Thrombocytopenia (platelet count <100,000/ 
µL), 
o Renal 
Insufficiency 
(serum 
creatinine 
concentrations > 1.1 mg/dL or a doubling of the 
serum creatinine concentration in the absence of 
other renal disease), 
o Impaired liver function, 
o Pulmonary edema, 
o Cerebral or visual symptoms. 
Eclampsia: All components of Pre-Eclampsia, with 
convulsions. 
Mother
Third Trimester 
Hemorrhage:
Any third trimester bleeding with the etiology specified 
and may include, but not limited to, placenta previa, vasa 
previa, placental abruption. 
Mother
Neonatal Death*:
Death of a live newborn child at any time from birth to 28 
days of life, regardless of gestational age based on the 
following subgroups: 

Very early neonatal death: < 24 hours 

Early neonatal death: birth to < 7 days 

Late neonatal death: 7 to < 28 days
Infant

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Table 5:
Maternal/Fetal/Neonatal Adverse Events of Special Interest
Term
Definition
Reported as an Event In
Infant Death*:
A post-neonatal death that occurs between 28 days and 1 
year of life.
Infant
Low Birth 
Weight:
Subcategorized as:

Low birth weight: < 2,500 grams 

Very low birth weight: < 1,500 grams  

Extremely low birth weight: < 1,000 grams
Infant
Intrauterine 
Growth Restriction 
or Retardation 
(IUGR):
A fetus whose estimated weight is below the 10th
percentile for gestational age and whose abdominal 
circumference is below the 2.5 percentile.
Infant
Small for 
Gestational Age 
(SGA):
Defined as a birth weight < 10% for infants of the same 
gestational age and gender, in the same population.
Infant
Asphyxia:
Insufficient oxygen supply to organs at birth resulting 
from inadequate ventilation or perfusion.
Infant
Neonatal 
Encephalopathy:
A disturbance of neurological function manifested by 
difficulty 
initiating 
and 
maintaining 
respiration, 
depression of tone and reflexes, abnormal level of 
consciousness and often seizures. Categories of neonatal 
encephalopathy include:

Due to hypoxic insult (intrapartum),

Due to another cause.
Infant
Hypoxic-Ischemic 
Encephalopathy:
A syndrome of abnormal neurological behavior in the 
neonate, which is frequently associated with multi-system 
dysfunction and follows severe injury before or during 
delivery associated with hypoxic and/or ischemic event.
Infant
Sudden Infant 
Death Syndrome 
(SIDS):
Sudden death of any child under 12 months of age which 
remains unexplained after excluding other causes of death. 
Infant
*Neonatal and infant deaths should be reported whenever possible as the underlying medical condition which results in 
death, with death captured as the outcome of the SAE.  This allows the capture of more granular information about the 
incidence of specific diagnostic entities leading to death, and prevents confusion with SIDS in analysis.   
8.7
Safety Reporting Requirements and Timelines for SAEs and
Certain Other Events
Any SAE must be reported (using the SAE Report Form) to Novavax Product Safety within 
24 hours of the investigator’s first knowledge of the event, regardless of the presumed 
relationship to the investigational product. The investigator or qualified designee must complete 
the SAE Report Form, sign, and transmit the completed form to Novavax Product Safety. 
Initial reports of SAEs may be reported via fax or e-mail. Initial reports via telephone must be 
supported by transmission of documentation (paper or electronic) signed (physically or 
electronically) by the investigator or a qualified sub-investigator within 24 hours of 
notification. When additional follow-up information becomes available, a written follow-up 
SAE report (depending on the qualified event) must be completed, signed by the investigator or 
a qualified sub-investigator and transmitted as soon as possible. The investigator is responsible 

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for obtaining detailed information to support all SAE reports, including records of inpatient and 
outpatient care, laboratory reports, and autopsy or medical examiner reports.   
The following events must be reported to the Medical Monitor within 24 hours of the 
investigator’s first knowledge of the event:

Any withdrawal of consent after dosing due to an AE.

Any SAE.

Any pregnancy occurring after the birth of the planned child enrolled in the current 
study AND before the maternal subject has completed the Day 180 post-delivery visit
(Note however that such pregnancies will not be captured as an AE).

Overdose (of a test article as specified in the protocol with or without an AE).

Inadvertent or accidental exposure to the test article with or without an AE.

Medication error (includes the administration of an incorrect treatment, an expired test 
article, a test article that has deviated from its required storage or refrigeration 
requirements, or any test article prior to documentation of informed consent).
Novavax or its designee will be responsible for notifications of SAEs and other qualifying 
events that are considered by the Sponsor to be unexpected and related to study agent as 
expedited (e.g., 7- or 15-Day) reports to the relevant regulatory authorities and to all 
participating investigators. In addition, Novavax or its designee will follow all applicable local 
and national regulatory requirements regarding safety reporting, including reporting to Ethics 
Committees (in jurisdictions where this is a sponsor responsibility). Each investigator must also 
comply with the applicable local and national regulatory requirements related to the reporting 
of SAEs to the IRBs/IECs responsible for reviewing the trial at their site, as well as the 
regulatory authority(ies) (where applicable).
The contact information for the study’s Medical Monitor is provided during site training and is 
specified in the Study Operations Manual. 
8.8
Severity
All AEs experienced by maternal and infant subjects will be assigned severity according to the 
TGS provided in the Study Operations Manual. 
8.8.1
Maternal Subjects 
Maternal subjects will be able to indicate severity for any AEs experienced and record this in 
their diary according to the same scale. For quick reference, an abbreviated grading scale is 
provided in Table 6 for visible and non-visible local AEs and for systemic AEs for which 
severity is based on interference with daily activities and not numeric ranges, and in Table 7 for 
adverse events of nausea, vomiting, diarrhea, fever, and fetal heart tones.  
The severity of visually-evaluated local AEs will be a function of size. During the diary period, 
maternal subjects will monitor the size of visible local AEs at the injection site using the Subject 
Measurement Tool (Appendix 4) which has concentric circles that correspond to the diameters 

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specified in Table 6. For the purposes of reporting during the solicitation period (i.e., Days 0 to 
6), the maternal subjects’ observations will form the primary data. During clinic visits, 
investigators may measure any persistent local AEs with a ruler, documenting the size of the 
reaction at its widest diameter and use the numeric scale provided in Table 6 to assess for 
severity.
Non-visible local AEs (e.g., pain), solicited systemic AEs (except for those listed in Table 7), 
and unsolicited AEs will be assigned a severity based primarily on interference with daily 
activities (Table 6). Medical care-seeking is typically absent for grade 1 (mild) and often present 
for grade 3 (severe) events, but is not the primary determinant, since individuals behave 
differently in this regard.
Severity of clinical laboratory and vital sign abnormalities (including oral or axillary body 
temperature, which is captured as a continuous variable) will be graded based on established 
ranges provided in the TGS, located in Study Operations Manual.  
Table 6:
Severity Grade Definitions for Adverse Events, Maternal Subjects
Definitions for Local Adverse Events
(primarily used for Solicited AEs)
Definitions for Systemic 
Adverse Events
(used for Solicited and Unsolicited AEs)
Severity 
Grade
Visual Local AE Size 
Grading Description
Non-Visual Local AE
Grading Description
Systemic AE Description 
(Interference with Daily Activities)
0 – Normal
Reaction size
(greatest single 
diameter) < 2.5 cm
No noticeable 
symptom
No noticeable symptom or finding
1 – Mild
Reaction size 
(greatest single 
diameter) 2.5 to 5.0 cm
Discomfort or 
tenderness noticeable, 
but does not interfere 
with normal daily 
activities
Mild symptoms or diagnostic 
observations; Intervention not indicated; 
No interference with normal activity
2 – Moderate
Reaction size 
(greatest single 
diameter) 
>5.0 to 10.0 cm
Moderate discomfort 
or tenderness on firm 
pressure; Causes some 
limitation of normal 
daily activities
Moderate symptoms or diagnostic 
observations; Some interference with 
normal activity, not requiring medical 
intervention
3 – Severe
Reaction size (greatest 
single diameter) >10.0
cm
Severe pain at rest, 
pain (including 
tenderness) 
immobilizes the 
injected limb and 
prevents normal daily 
activities
Severe symptoms, significantly disrupts or 
prevents normal daily activities; Generally 
requires medical attention/intervention
Note: Vital sign and laboratory abnormalities reported as unsolicited AEs should represent increases of at least one 
severity grade over prior observations and attain at least a grade 2 severity as per the Toxicity Grading Scale 
provided in the Study Operations Manual.

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Table 7:
Severity Grade Definitions for Solicited Gastrointestinal Adverse Events, Fever, 
and Fetal Heart Tones, Maternal Subjects
Severity 
Grade
Nausea
Vomiting
Diarrhea
Fever
Fetal Heart 
Tones[1]
0 – Normal
No noticeable 
symptom
No noticeable 
symptom
No noticeable 
symptom
< 38.0˚C
120 to 160 
beats/min 
1 – Mild
No interference 
with activity, or 1 –
2 episodes/
24 hour period
No interference with 
activity, or 1 – 2 
episodes/
24 hour period
1 – 3 unformed 
(loose) stools/24 
hour period
38.0 to 
38.4˚C
--
2 – Moderate
Some interference 
with activity, or > 2 
episodes/
24 hour period
Some interference 
with activity, or > 2 
episodes/
24 hour period
4 – 5 unformed 
(loose) stools/24 
hour period
38.5 to 
38.9˚C
--
3 – Severe
Prevents daily 
activity, or requires 
intravenous 
hydration
Prevents daily 
activity, or requires 
intravenous 
hydration
≥ 6 loose stools/24 
hour period, or 
requires 
intravenous 
hydration
> 38.9˚C
< 120 
beats/min 
or
> 160 
beats/min
[1], Fetal heart tone abnormalities may be repeated at the investigator’s discretion as these measures are highly labile.  
Severe abnormalities (i.e., < 120 beats/min or > 160 beats/min) should be reported as AEs and should warrant 
additional evaluation and monitoring. 
8.8.2
Infant Subjects
The investigator is to use his/her best medical judgment to assign severity for adverse events 
occurring in infants based on interference with daily-activities and/or whether medical 
intervention/therapy is required (Table 8). This will involve assessment of activities that are age 
and culturally appropriate (e.g., social interactions, play activities, learning tasks, sleeping, etc.) 
for infants. In addition, medical care-seeking is typically absent for grade 1 (mild) and often 
present for grade 3 (severe) events. 
Table 8:
Severity Grade Definitions for Adverse Events Occurring in Infant Subjects
AE Category
1 – Mild
2 – Moderate
3 - Severe
Unsolicited 
Events
No interference with 
normal activities; 
Transient or mild 
discomfort; No 
medical 
intervention/therapy 
required
Some limitation of normal daily 
activities; No or minimal medical 
intervention/therapy required; May 
require monitoring
Prevents normal daily 
activities; Medical 
intervention/therapy 
required

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8.9
Relationship (Causality)
The relationship of all unsolicited AEs to the test article must be assessed and documented by 
the investigator or a qualified sub-investigator, and classified according to the categories shown 
in Table 9.  The investigator should use his/her best medical judgment to consider whether the 
temporal sequencing of treatment and event, the existence (or lack thereof) of a biologically 
plausible mechanism (which is consistent with the temporal sequence), and the existence (or 
lack thereof) of likely alternative explanations support the causality assessment given. (Note 
that Investigators will not be required to assess causality for solicited AEs reported during the 
solicitation period as these are presumed to be treatment-related.)
Table 9:
Definition of Relationship for Adverse Events
Relationship
Relationship Description
Unrelated / Unlikely 

May or may not follow a reasonable temporal sequence from administration of 
the test article;

No plausible mechanism based on known or suspected actions of the test article 
or product class;

Readily explained by known characteristics of the maternal or infant subject’s 
(as applicable) clinical state, common intercurrent illnesses, or other treatments 
administered to the maternal subject.
Possibly

Follows a reasonable temporal sequence from administration of the test article;

Based on known or suspected actions of the test article or product class, a 
plausible mechanism could exist;

May be reasonably explained by known characteristics of the maternal or infant 
subject’s (as applicable) clinical state, common intercurrent illnesses, or other 
treatments administered to the maternal subject; but the Investigator deems this 
less likely than test article effect.
Probably

Follows a reasonable temporal sequence from administration of the test article;

Based on known or suspected actions of the test article or product class, a 
plausible mechanism could exist;

Cannot be reasonably explained by known characteristics of the maternal or 
infant subject’s (as applicable) clinical state, common intercurrent illnesses, or 
other treatments administered to the maternal subject.
Definitely

Follows a reasonable temporal sequence from administration of the test article;

Consistent with known actions of the test article or product class;

Cannot be reasonably explained by known characteristics of the maternal or 
infant subject’s (as applicable) clinical state, common intercurrent illnesses, or 
other treatments administered to the maternal subject.

May be confirmed by re-challenge (if applicable).

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8.10
Data and Safety Monitoring Board (DSMB)
A Data and Safety Monitoring Board (DSMB) will be assembled for this study to perform 
ongoing assessments of the risks of vaccination in pregnant women through delivery, and in the 
delivered infant through the first year of life. In addition, the DSMB will review all 
recommendations from the unblinded statistician to stop enrollment in the trial for futility.  The 
DSMB will consist of at least five clinicians to include not less than two obstetricians (at least 
one with expertise in high-risk obstetrics or maternal-fetal medicine), and not less than two 
pediatricians (at least one neonatologist), and the unblinded DSMB statistician. These 
individuals will not be employees of the Sponsor; and will operate under a charter agreed prior 
to study start which will define responsibilities and authority (including authority to halt 
enrollment or require changes in safety assessments), frequency of meetings, triggers of ad hoc
meetings, access to data and treatment codes, and  communication pathways. The Novavax Sr. 
Director of Pharmacovigilance and Product Safety, or designee, will serve as the sponsor’s 
liaison to the Project Manager of the DSMB. The Study Physician will serve as the medical 
liaison to the DSMB and will be responsible for all presentations to the DSMB during the open 
sessions of the DSMB meetings. 
In general, the DSMB will meet not less than monthly during periods of active maternal 
enrollment and every two months outside these periods, or as required by triggering safety 
events to be identified by the DSMB Charter. The DSMB may elect, based on a vote of the 
members, to meet less frequently (e.g., quarterly), after the first year of the study.

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9
DATA MANAGEMENT
9.1
Recording and Collection of Data
Novavax will provide sites with template source documents for the recording and collection of 
maternal and infant subject data. Data will be entered into an electronic data capture (EDC) 
system by site staff. All EDC entries will be completed as soon as possible after each visit for 
maternal and infant subjects. 
Corrections to data in the EDC or eSource system will be documented in the electronic audit 
trail that is compliant to US-FDA regulations (21 Code of Federal Regulations [CFR] Part 11) 
or equivalent. The investigator will review data resident in the EDC or eSource system and 
indicate by electronic signature that, to his/her knowledge, the data are complete and accurate. 
If further changes are made after this, the investigator will need to again sign the Investigator 
Signature Page electronically. Designated source documents will be signed and dated by the 
appropriate study personnel. The investigator must agree to ensure completion and maintenance 
of source documents for each subject participating in the study.
9.2
Data Quality Assurance
All trial data will be entered by clinical study site staff with study-specific EDC or eSource 
training into a computerized data management system.  Statistical analyses of data will only be 
performed after all clinical monitoring and data queries have been resolved.
9.2.1
Monitoring
Novavax, as the Sponsor of this study, is responsible for ensuring the proper conduct of the 
study, in accordance with the Declaration of Helsinki (Amended Fortaleza, Brazil, 2013) and 
Good Clinical Practices (GCP) including, but not limited to, protocol adherence and the validity 
of the data recorded in the database. For the purposes of this study, Novavax may transfer 
responsibility for the clinical monitoring to Independent clinical monitors who may monitor on-
site or remotely. Novavax and/or independent clinical monitors are responsible for ensuring that 
the site(s) prepare complete, accurate, legible and well-organized clinical study data. On-site 
monitoring inspections will be routinely performed in order to review data entry of source 
documentation directly captured on paper and transcribed into the system, to ensure protocol 
adherence, to assess site operational capabilities, and to perform other monitoring activities that 
cannot be performed remotely. In addition, clinical monitors will provide ongoing support to 
ensure the investigator’s continued understanding of all applicable regulations concerning the 
clinical evaluation of the investigational vaccine, and the proper execution of the protocol, as 
well as the investigator’s reporting responsibilities.
The clinical study sites will be monitored periodically for database accuracy and completeness, 
adherence to the protocol, regulatory compliance, safety reporting, clinical trial material 
accountability, and the maintenance of comprehensive source documents. Where applicable, 
the database will be checked against applicable source documents to verify completeness and 
accuracy. When data entry has been completed by the appropriate study staff, source document 
verified and monitored
by Novavax and/or contract research organization (CRO) 

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representatives, and reviewed by the investigator, the investigator should sign and date the 
Investigator Signature Page.
9.2.2
Audit and Inspection
Novavax Clinical Quality Assurance (CQA) will develop a Quality Assurance plan to ensure 
the integrity of the conduct of the clinical study. CQA visits may be performed pre-study, during 
the study and post-study by Novavax CQA or other personnel authorized by Novavax. 
Regulatory authorities reserve the right to audit study sites following submission of data in 
regulatory applications. By signing this protocol, the investigator acknowledges that these 
inspection procedures may take place and agrees to provide access to the required subject 
records and other study documentation. Further, the investigator agrees to inform Novavax and 
the IRB/IEC immediately of any scheduled or unscheduled inspection by regulatory authorities.
9.3
Adherence to and Changes to the Protocol
Any change or addition to this protocol will only be made when a protocol amendment has been 
written, approved, and signed by Novavax and the investigator before the change or addition 
can be considered effective, unless immediate implementation of a change is necessary to 
ensure the safety of subjects. This amendment must also be submitted to the IRB/IEC for 
approval and, when necessary, regulatory authority approval before implementation. Protocol 
amendments may affect consent forms of current and future subjects. Novavax will clearly 
specify when a protocol amendment includes safety, procedural, and/or efficacy information 
that will require specific Informed Consent text changes.
9.4
Retention of Records
It is the responsibility of the investigators and study staff to maintain a comprehensive and 
centralized filing system of all study-related documentation, which is suitable for inspection at 
any time by Novavax, its designees, and regulatory agencies. These should minimally include:

Subject files including the completed eCRFs/eSource (based on output from clinical 
database) on compact disc (CD), supporting source documentation, and the Informed 
Consent and any other subject information.

Study files (essential documents and regulatory files) including the protocol with all 
amendments, the Investigator’s Brochure, safety and protocol deviations meeting
IRB/IEC reportable criteria, copies of all regulatory documentation, and all 
correspondence with the IRB/IEC, regulatory authority, and Novavax.

Pharmacy files including all investigational vaccine shipment, receipt, storage, 
dispensing, and accountability records, and pharmacy-related correspondence.
In addition to the eCRF/eSource, the investigator will maintain adequate records that fully 
document the progress of the trial. Copies of these trial records and related documents must be 
kept on file by the investigator for a period of no less than 15 years (or longer if mandated by 
relevant local regulations). ALL DOCUMENTATION AND MATERIAL PROVIDED BY 
NOVAVAX OR A NOVAVAX REPRESENTATIVE FOR THIS TRIAL (CASE REPORT 
FORMS, PROTOCOL, ETC.) ARE TO BE RETAINED IN A SECURE PLACE AND 
TREATED AS CONFIDENTIAL MATERIAL.

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10
STATISTICAL CONSIDERATIONS
The planned statistical analyses for this study are briefly outlined below.  A detailed statistical 
analysis plan (SAP) will be created and finalized in tandem to the protocol. 
10.1
Subject Populations
The following subject populations will be used in all analyses:

Safety Populations
o
Maternal Safety Population (Safety-M) - defined as all maternal subjects who 
receive any test article.  The Safety-M Population will be analyzed as actually 
treated.
o
Infant Safety Population (Safety-I) – defined as all infants born live to maternal 
subjects who received any test article. The Safety-I Population will be analyzed as 
actually treated.

Intent-to-treat (ITT) Populations 
o
Intent-to-treat Efficacy (ITT-EFF) Population - defined as all maternal subjects 
(ITT-EFF-M) and their infants (ITT-EFF-I) in the Safety Population for whom at 
least one post-treatment and post-partum, respectively, efficacy measurement is 
available for both the mother and the infant as evidenced by collection of 
surveillance observations. The ITT-EFF Population will be analyzed as randomized. 
o
Intent-to-treat Immunogenicity (ITT-IMM) Population - defined as all maternal 
subjects (ITT-IMM-M) and their infants (ITT-IMM-I) in the Safety Population for 
whom at least one post-treatment immunogenicity measurement is available for both 
the mother and the infant. The ITT-IMM Population will be analyzed as randomized. 

Per-Protocol Efficacy (PP-EFF) Populations
o
The PP-EFF Populations will be the primary analysis populations for the efficacy 
analyses. 
o
PP-EFF for Maternal Subjects (PP-EFF-M) – defined as all maternal subjects who 
receive the test article and regimen to which they were randomized and have at least 
one post-treatment encounter documented during which active and/or passive 
surveillance activities for RSV-suspect illness can occur, and have no major 
protocol deviations affecting the primary efficacy outcomes as determined and 
documented by Novavax prior to database lock and unblinding. 
o
The Per-Protocol Population for infant subjects (PP-EFF-I) – defined as all infant 
subjects who: a) are ≥ 37 weeks gestational age at birth, b) are born to maternal 
subjects who received a study injection as randomized and ≥2 weeks prior to 
delivery, c) have not received prophylactic treatment with palivizumab between 
birth and Day 180 after delivery, d) have at least one documented post-partum 
contact during which active and/or passive surveillance activities for RSV-suspect 
illness can occur, and e) have no major protocol deviations affecting the primary 
efficacy outcomes as determined and documented by Novavax prior to database lock 
and unblinding.  

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
Per-Protocol Immunogenicity (PP-IMM) Populations
o
The PP-IMM Populations will be the primary analysis populations for the 
immunogenicity analyses.
o
PP-IMM for Maternal Subjects (PP-IMM-M) – defined as all maternal subjects who 
receive the test article and regimen to which they were randomized, provide baseline 
and delivery (up to 72 hours post-delivery) serology data, and have no major 
protocol deviations affecting the primary immunogenicity outcomes as determined 
and documented by Novavax prior to database lock and unblinding. 
o
PP-IMM for Infant Subjects (PP-IMM-I) – defined as all infant subjects who: a) are 
≥ 37 weeks gestational age at birth, b) are born to maternal subjects who received a 
study injection as randomized and ≥ 2 weeks prior to delivery, c) have provided a 
cord blood specimen (or infant blood sample by venipuncture or heel stick within 
72 hours of delivery as an acceptable substitute), d) have not received prophylactic 
treatment with palivizumab between birth and Day 180 after delivery, and e) have 
no major protocol deviations affecting the primary immunogenicity outcomes as 
determined and documented by Novavax prior to database lock and unblinding.  
10.2
General
All analysis populations will be defined and full descriptions of each population will be 
provided. Continuous variables will be presented by summary statistics (e.g., mean and standard 
deviation for the non-immunogenicity endpoints, and geometric means and their 95% CIs for 
the immunogenicity endpoints), and the categorical variables will be presented by frequency 
distributions (percentages) for the non-immunogenicity endpoints, and percentages and their 
95% confidence intervals for the immunogenicity endpoints.
10.3
Demographics and Protocol Compliance
Demographic parameters and other baseline characteristics (e.g., age, age group, gender, race, 
ethnicity, etc.) will be summarized by treatment group and serology cohort (as applicable) for 
all maternal and infant subjects (separately) in the Safety Population, as well as the number and 
description of protocol deviations. Summary statistics at birth for infant length, weight, FOC, 
APGAR scores, and gestational age will be provided by treatment groups.  In addition, a listing 
will be prepared linking, by mother/infant pair, maternal demographic characteristics, maternal 
treatment, and infant length, weight, FOC, APGAR scores, and gestational age at birth. 

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10.4
Efficacy Analyses
10.4.1
Study Definitions for Efficacy Determination
10.4.1.1
Infant Subjects 
RSV LRTI:
Confirmed RSV LRTI will feature detection of RSV in respiratory secretions by 
RT-PCR and at least one of the following clinical manifestations observed and 
documented by appropriately-trained study staff: cough, nasal flaring, lower chest 
wall indrawing, subcostal retractions, abnormal breath sounds (inclusive of 
stridor, rales, rhonchi, wheezing, and crackles/crepitations); and/or observed 
apnea.
Medically-
significant RSV 
LRTI:
An RSV LRTI episode with EITHER a resting SpO2 < 95% at sea level or < 92% 
at altitudes > 1800 meters by pulse oximetry on room air OR tachypnea defined 
as ≥70 bpm in an infant 0 to 59 days of age, or ≥60 bpm in an infant ≥60 days 
of age.
RSV LRTI 
with Severe 
Hypoxemia:
An RSV LRTI episode with a resting SpO2 < 92% at sea level or SpO2 < 87% at 
altitudes > 1800 meters by pulse oximetry on room air OR documented use of 
oxygen by high flow nasal cannula OR a requirement for continuous positive 
airway pressure (CPAP) OR bilevel positive airway pressure (BiPAP) OR Bubble 
CPAP OR bag-mask ventilation OR intubation with subsequent mechanical (or 
manual) ventilation OR extracorporeal membrane oxygenation (ECMO).
Correlate of 
Risk:
An immune marker statistically correlated with risk, either absolute or relative to 
a control population, of meeting an RSV infection clinical endpoint.
10.4.1.2
Maternal Subjects
Symptomatic 
RSV Infection:
An acute, clinical study site-observed RSV infection, manifesting as one or more 
of cough, stuffy nose, runny nose, dyspnea, sore throat, fever, new or increasing 
wheezing, or new or increasing sputum production; with detection of RSV in 
respiratory secretions by RT-PCR.
10.4.2
Clinical Endpoint Adjudication Committee (CEAC)
A clinical endpoint adjudication committee (CEAC) comprising an odd number of three or more 
clinically-experienced voting pediatricians, a non-voting chair who will oversee meetings of the 
CEAC, and a non-voting coordinator for administrative support will be empaneled to review all 
primary, secondary, and exploratory efficacy endpoints relative to infant subjects. The 
operations of the CEAC will be carried out according to a charter which will be collaboratively 
drafted by the CEAC and the sponsor, and will be adopted prior to any review CEAC activities.  
The CEAC will review each potential infant efficacy endpoint event to determine whether the 
protocol-specified criteria have been fulfilled in a plausible temporal relationship. All 
deliberations of the CEAC will be carried out in blinded manner with regard to treatment 
assignment and the determination of the CEAC with regard to each endpoint event will be final 
and binding on the sponsor.

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10.4.3
Analysis of Primary and Secondary Efficacy Endpoints
The primary efficacy endpoint will be analyzed on the ITT-EFF-I and PP-EFF-I (infant)
Populations. Conclusions concerning stopping for futility, the informational analysis, or 
declaration of attainment of the primary efficacy endpoint at the completion of the study, will 
only be based on the PP-EFF-I Population. In addition, supportive analyses based on the ITT-
EFF-I Population will also be performed.
The Vaccine Efficacy (VE) is defined as VE (%) = (1 – RR) x 100, where RR = Relative Risk 
of incidence rates between the two treatment groups (RSV F Vaccine / Placebo). The final 
analysis will be carried out at one-sided Type I error rate of 0.0124 (i.e., the lower bound of 2-
sided 97.52% confidence interval). An estimate of vaccine efficacy will be reported using a 
two-sided 95% confidence interval. This conservative Type I error rate was determined as a 
part of the original group sequential design (GSD) approach and will be retained to guard 
against a potential Type I error inflation resulting from the decision to stop the study at ~4,600 
maternal subjects given this decision occurred after the informational analysis. Since this 
change was not part of the original study design at the initiation of the study, the agreement on 
how to implement the change with respect to Type I error rate was finalized in consultation with 
the US-FDA. 
For the original design using the GSD approach, a simulation of 5,000 trials was performed 
under a range of scenarios (including both varying placebo rates of medically-significant RSV 
LRTI and endpoint event ratios in infants of active vaccinees relative to placebo recipients). A 
summary of the simulation results is provided in the adaptive design report as Appendix 1 in 
the SAP. 
The RR and its CI will be estimated using Poisson regression with Robust error variance 
[Zou 2004]. The generalized linear model with unstructured correlation matrix (Robust error 
variances) will be used. The explanatory variables in the model will include the treatment group. 
The dependent variable will be the incidence rate of the endpoint of interest. The Robust error 
variances will be estimated using repeated statement and the subject identifier. Poisson 
distribution will be used with a link function logarithm.  
Hypothesis testing of the primary efficacy endpoint will be carried out sequentially for H0: VE 
≤0% and H0: VE < 30%. Rejection of the first null hypothesis, H0: VE ≤0% demonstrates a 
statistically significant vaccine effect. Rejection of the second null hypothesis, H0: VE < 30%
at Type I error rate of 1-sided 0.0124 is required to meet the statistical success criterion pre-
specified for the US-FDA. Should success be declared for the primary endpoint through 0 - 90 
days of age, the hierarchical sequential analyses of 0 - 120, 0 - 150, and 0 - 180 days of age will 
be carried out using the Type I error rate of 1-sided 0.025 and the same null hypothesis.
Two types of analyses concerning the primary efficacy endpoint will be performed prior to the 
final analysis: recurring futility analyses approximately twice per year after the Northern and 
Southern hemisphere winter virus season, and an informational analysis with approximately 1/3 
of projected subjects enrolled and followed through at least 90 days.   

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For the futility analyses and the informational analysis, a Bayesian approach will be used and 
the analyses will be performed by the independent biostatistical group (IBG) as originally 
designed. An assumption is made that the distribution of the number of events under the vaccine, 
xv, and the number of events under placebo, xp, are binomial:
xv ~Bin(v ,nv)
xp ~Bin(p,np)
where πv and nv, respectively, are the probability of an RSV event and the total number of 
subjects in the vaccine group and πp and np, respectively, are the probability of an event and the 
total number of subjects in the placebo group.  
Furthermore, we assume prior distributions for πv and πp that are flat, non-informative beta 
distributions:
v  ~ Beta(1,1)
p ~ Beta(1,1).
Futility will be demonstrated under the primary hypothesis based on the posterior probability 
that the event ratio, r = πv / πp, is less than or equal to 0.60.
Given xv events out of nv total subjects in the vaccine group and xp events out of np total subjects
in the placebo group, the posterior distributions of πv and πp are:
v |xv ~ Beta(1xv,1(nv xv))
p |xp ~ Beta(1xp,1(np xp)).
Sampling from the posterior probability distribution for the event ratio is generated by:
3. Sampling 10 million independent values from the posteriors of πv and πp
4.
Calculating the event ratio, r = πv / πp under each pair-wise sample from the posterior 
of πv and πp. 
Futility stopping will be based on the posterior probability of futility that the event ratio is less 
than or equal to 0.60 is less than or equal to 0.05. Furthermore, an additional constraint 
governing the ability to stop the trial early for futility requires that a minimum of 10 events be 
observed in the vaccine arm. All futility analyses will include all infant subjects who are 90 days 
old at the time of the data cutoff date.
In addition, time to the first medically-significant RSV LRTI event will be analyzed by 
treatment group using Kaplan-Meier methods. Sub-analyses will be performed to evaluate 
vaccine effects on all infections in which RSV is confirmed by RT-PCR, and also infections in 
which only RSV is found (i.e., no co-infections). The incidence rate of medically-significant 

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RSV LRTI may be generated by age stratum or co-morbidities present, if sufficient event 
numbers are available.
Sensitivity analyses for the primary efficacy endpoint will be performed to investigate the 
impact of missing specimens for suspected-RSV illnesses, including RSV-negative specimens 
collected outside the specified collection window, and clinical assessments, including clinical 
signs/symptoms, respiratory rates, and pulse oximetry measurements, obtained by non-study 
healthcare providers (e.g., hospitalization records). Further details regarding the sensitivity 
analyses will be described in the SAP.
The null hypothesis, H0: VE ≤0%, using the 1-sided Type I error rate (i.e., lower bound of 
2-sided 95% CI) will be used for analyses of all secondary efficacy endpoints in infants. For 
each endpoint, in the event that efficacy is shown through the first 90 days of life, a hierarchical 
sequence of hypothesis tests will be carried out to examine efficacy through 120, 150, and 
180 days of life.
Additional efficacy analyses may describe the incidence of symptoms used to define RSV 
LRTI. Percentages of infant subjects with any RSV-confirmed respiratory illness accompanied 
with the following events/complaints will be presented by treatment group through six months 
postpartum: cough, nasal flaring, difficulty breathing, manifesting in any of the following 
clinical signs or symptoms as lower chest wall indrawing, subcostal retractions, abnormal breath 
sounds (inclusive of stridor, rales, rhonchi, wheezing, and crackles/crepitations), and/or 
observed apnea. Time to the first RSV-associated event referenced above will also be analyzed 
using Kaplan-Meier methods for each event category and by treatment group.
10.5
Immunogenicity Analyses
Immunologic analyses will be conducted using the ITT and PP Populations, with primary 
conclusions drawn from the PP Population. The primary variable of interest for assessment of 
immune response to the RSV F vaccine will be anti-F IgG EU and PCA concentration, and 
testing by these methodologies will have the highest priority. The secondary variables will be 
RSV/A and B MN titers, which will be determined on all blood samples, but with priority testing 
assigned to samples collected at the following time-points: at delivery for the maternal subject, 
and at delivery, D+14, D+35, D+60, D+90, D+120, and D+180 for the infant subject.   
The following immunogenicity outcome measures and their 95% CI will be summarized by 
treatment group. Immunogenicity analyses will be descriptive and include tabulations by 
treatment group. 
Maternal Subjects:
1) GMEU or GMC, GMFR, proportion of subjects with ≥ 2-fold and ≥ 4-fold increases in 
EU/concentration from baseline (2- and 4-fold seroconversion rates [SCR]); and SRR of 
anti-RSV F IgG and PCA at baseline, post-immunization on Day 14, at delivery, and 
postpartum on Days 35 and 180.

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2) GMT, GMFR, proportion of subjects with ≥ 2-fold and ≥ 4-fold increases in titer from 
baseline (2- and 4-fold seroconversion rates {SCR]); and SRR of RSV/A and B MN titers 
at baseline and delivery.
3) GMFR Transplacental Transfer Proportion, the anti-RSV F IgG GMEU, PCA GMC, and 
RSV/A and B MN GMT of the within-maternal-infant pair ratios for cord blood over 
maternal serum (MS) at delivery (GMFRCord/MS). 
Infant Subjects:
1) GMEU, GMC, or GMT; and SRR of anti-RSV F IgG, PCA, and RSV/A and B MN 
antibodies in cord blood and on D+14, D+35, D+60, D+90, D+120, and D+180.
2) GMFR of anti-RSV F IgG GMEU, PCA GMC, and RSV/A and B MN GMT within-subject 
ratios after delivery (D) on D+14, D+35, D+60, D+90, D+120, and D+180 over cord blood 
value at delivery (GMFRAD/Cord).
3) Exploratory modeling of anti-RSV F antibody decay in infants using first order models and 
infant data.
10.6
Safety Analyses
The primary variable for evaluation of the safety profile will be the number and percentage 
(95% CI) of maternal subjects with solicited and unsolicited AEs recorded post-vaccination and 
the number and percentage (95% CI) of infants with unsolicited AEs occurring since birth. 
Safety analyses will be performed using the Safety Population as defined in Section 10.1. 
Safety will be summarized overall and by treatment group for maternal subjects based on 
Percentages of subjects with:

Solicited seven day reactogenicity events by severity;

Clinical laboratory safety abnormalities by severity;

Caesarean, vaginal, and instrument-assisted vaginal modes of delivery;

Specified third-trimester pregnancy complications (i.e., stillbirth, placental abruption, 
preterm birth, preterm premature rupture of membranes, hypertensive disorders of 
pregnancy, third-trimester hemorrhage, and gestational diabetes) and labor and delivery 
complications (i.e., emergency Caesarean section, postpartum hemorrhage, 
chorioamnionitis, and maternal fever or infection); and 

Unsolicited adverse events through 180 days post-delivery by severity and relatedness 
(possibly, probably, or definitely), including SAEs, MAEs, and SNMCs through 180 
days post-delivery. 
Clinical laboratory data summaries will include (by parameter and treatment group) toxicity 
grade shift summaries; absolute means and standard deviations with minima and maxima 
values, and tabulations of changes from baseline. 
Safety analyses for infant subjects will be summarized overall and by treatment group, and will 
be based on percentages of infants with:

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
Congenital anomalies; respiratory failure other than RSV-associated hospitalization; 
neonatal death; infant death; sudden infant death syndrome; asphyxia; neonatal or 
hypoxic-ischemic encephalopathy; or other adverse events or complications of adverse 
events that necessitate hospitalization during the neonatal period and through the first 
year of life; 

All other unsolicited/unspecified adverse events by severity, relatedness, and 
seriousness, including respiratory events that test negative for RSV by RT-PCR. 
Summary statistics will also be provided for infant length, weight, FOC, and responses to 
environmental and behavioral queries, through one year post-delivery overall, and by treatment 
group. Results of developmental testing will be summarized by treatment group, and 
percentages of infants above normal, normal, at-risk at 6 or 12 months, and at-risk at both 6 and
12 months.
10.7
Exploratory Analyses
Exploratory analysis will be conducted by generating classical two-by-two cross tabulations of 
all RSV respiratory tract infection endpoints detected by active/passive surveillance in infant 
and maternal subjects from immunization through six months after delivery and by treatment 
group. The relative risk (RR) and its 95% CI will be estimated using Poisson regression with 
robust error variance [Zou 2004]. A generalized linear model with unstructured correlation 
matrix (robust error variances) will be used. The explanatory variables in the model will include 
the treatment group. The dependent variable will be the incidence rate. The Robust error 
variances will be estimated using repeated statement and the subject identifier. Poisson 
distribution will be used with a link function logarithm. The vaccine efficacy, and the 
corresponding two-sided 95% CI will be calculated.
Similar analysis will be conducted to assess the incidence of non-RSV LRTI in infant subjects 
as detected by active and passive surveillance from vaccination through six months after 
delivery. Percentages of infants and maternal subjects presenting with respiratory symptoms of 
non-RSV respiratory viruses detected by RT-PCR will be summarized.
All exploratory efficacy analyses will be conducted against the null hypothesis of VE ≤0% 
(i.e., the RR ≤1.00). For each endpoint, in the event that efficacy is shown through the first 90 
days of life, a hierarchical sequence of hypothesis tests will be carried out to examine efficacy 
through 120, 150, and 180 days of life.
10.8
Sample Size and Power
This study is designed to enroll approximately 4,600 total maternal subjects that include a 
minimum of 3,000 RSV F vaccine recipients over 4 global RSV seasons.  
Assuming a medically-significant RSV LRTI incident rate of 4% in the placebo group and a 
vaccine efficacy of 65%, then the power of the design to claim success is 87%. Table 10
summarizes the power for different placebo attack rates and vaccine efficacies. Power 
calculations were performed using the normal approximation (NCSS PASS 14).  An estimated 
PP population size of 4,218 total evaluable infant subjects (2,786 in the RSV F vaccine group 

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and 1,432 in the placebo group to account for 1:1 and 2:1 randomization ratios in Year 1 and 
the subsequent years, respectively) was used for all calculations.  
The target sample size of the safety and efficacy database in third-trimester pregnancy that will 
be required for licensure is at least 3,000 actively-immunized maternal subjects and their 
infants. Therefore, the final analysis for efficacy will commence only after a total of 3,000 
subjects have been enrolled in the active treatment arm. If no events of a given class are 
observed among the 3,000 subjects receiving the RSV F vaccine, an approximation to the one-
sided upper 95% confidence bound on the rate of SAE occurrence would be 0.1%.  
Table 10: Power Calculations for the Primary Efficacy Endpoint (Medically-Significant 
RSV LRTI Through 90 Days)
Placebo Event Rate
True Event Ratio
Efficacy (1-RR)
Power [1]
0.02
0.5
50%
17%
0.4
60%
41%
0.35
65%
57%
0.3
70%
72%
0.2
80%
92%
0.03
0.5
50%
26%
0.4
60%
59%
0.35
65%
76%
0.3
70%
88%
0.2
80%
99%
0.04
0.5
50%
34%
0.4
60%
73%
0.35
65%
87%
0.3
70%
96%
0.2
80%
> 99%
0.05
0.5
50%
42%
0.4
60%
83%
0.35
65%
94%
0.3
70%
99%
0.2
80%
> 99%

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Table 10: Power Calculations for the Primary Efficacy Endpoint (Medically-Significant 
RSV LRTI Through 90 Days)
Placebo Event Rate
True Event Ratio
Efficacy (1-RR)
Power [1]
0.06
0.5
50%
50%
0.4
60%
90%
0.35
65%
97%
0.3
70%
> 99%
0.2
80%
> 99%
[1] Estimated using normal approximation to rule out H0: Vaccine Efficacy < 30% using one-sided Type I error 
rate of 0.0124.
10.9
Interim (Futility and Informational) Analyses and Data and Safety 
Monitoring Board Responsibilities
10.9.1
Blinding and Interim Analyses
The SAP, the study RSV-M-301 DSMB charter, and the Communication Plan will serve to 
establish a written procedure for the careful handling of all interim safety and efficacy data to 
maintain the confidentiality of the interim data and sustained blinding of the study team.
10.9.2
Maintaining Sponsor Study Blind
The Novavax study biostatistician, as well as all Novavax project team members, will remain 
blinded to treatment assignment during the preparation and presentation of all futility analyses 
and the informational analysis prepared in support of the DSMB review. No Novavax project 
team members will have access to unblinded summary tables.
10.9.3
Unblinded Personnel
As described in US 21 CFR 314.126, unblinded interim data and the results of comparative 
interim analyses should not be accessible by anyone other than DSMB members or 
statistician(s) performing these analyses for provision to the DSMB. Two unblinded statisticians 
will be involved in the study:  the DSMB statistician and the IBG statistician. These statisticians 
are external to Novavax and will be responsible for preparation of routine safety data tabulations 
for the DSMB and for conduct of the futility and informational analyses of the primary endpoint. 

Access to study randomization: the DSMB statistician will be unblinded to treatment 
assignment for all subjects enrolled at the end of each season to allow the estimation of 
the number of cases of medically-significant RSV LRTI in the database. Unblinded 
report tables will be sent to the IBG statistician to support the futility and informational 
analyses. In addition, unblinded safety tables may also be prepared by the DSMB 
statistician if requested by the DSMB. The treatment assignments (randomization 
schedule) of the subjects involved will be provided by the IWRS vendor directly to the 
DSMB statistician via secure FTP site or via download through SAS® on-demand.

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
Access to unblinded analyses: Unblinded tables (for medically-significant RSV LRTI 
cases) and listings (safety) prepared by the DSMB statistician will be provided directly 
to the IBG statistician and to the DSMB via secure FTP site. Further dissemination and 
review of the unblinded tables and listings prepared by the DSMB statistician will be 
limited to members of the DSMB (as indicated in the DSMB Charter) and to the IBG 
statistician.

The IBG and the DSMB: Following the analyses for futility, informational, and/or 
efficacy, the IBG will provide the DSMB with a summary of the analyses and 
recommendations. If a protocol-defined stopping decision is reached based on these 
analyses, the IBG will inform the DSMB PM, who will then inform the Sponsor
Contact. 

Sponsor Biostatistician: The Sponsor Biostatistician will be unblinded following 
success or futility, after all data from all enrolled mother-infant pairs through the infant 
D+180 visit and the maternal postpartum Day 180 visit are completed, all queries are 
resolved, and the database is locked. The Sponsor Biostatistician will perform the final 
analysis after all data through the infant D+364 visit are completed, all queries are 
resolved, all immunogenicity testing are completed, and the database is locked. 
10.10 Plan for Analyses and Reporting of Data 
10.10.1
Unblinded Analysis of Efficacy, Immunogenicity, and Safety 
The sequencing of RSV seasons in the Northern and Southern hemispheres lends a natural 
periodicity which will be reflected in the futility analyses.  Futility analyses will be conducted 
based on data available 30 May (for convenience called “Northern hemisphere,” although a 
small number of Southern hemisphere subjects may also meet the criteria for inclusion) and on 
approximately 30 September (for convenience called “Southern hemisphere” or “global 
season”); and subject to the constraint (applied by the DSMB statistician) that at least 10 cases 
will have accrued in the active treatment arm. The DSMB will communicate to the Sponsor 
after each futility analysis its recommendation that the trial is either: a) futile and should be 
discontinued, or b) should continue enrollment. 
When futility (with no requirement for further subject enrollment) has been declared, or when 
all live-born infants of all enrolled pregnant mothers have completed 180 days of follow-up 
after delivery, a final Day 180 Unblinded Analysis of Efficacy, Immunogenicity, and Safety 
will be performed upon completion of the last infant D+180 visit and the last maternal 
postpartum Day 180 visit for all enrolled subjects. This unblinded analysis of efficacy, 
immunogenicity, and safety will include all available efficacy, immunogenicity and safety 
(inclusive of clinical assessments and concomitant medications) data through the infant D+180 
visit and the maternal postpartum Day 180 visit. Treatment codes for this analysis will only be 
unblinded to the Sponsor statistician after all of these data are monitored, all applicable queries 
are resolved, and the database is locked. The data provided in this analysis will be considered 
final for the material contained therein, and will not change. In order to execute this unblinded 
analysis, a select group of study staff will be unblinded at Novavax. No individual unblinded at 
a subject treatment level will be involved in follow-up safety monitoring. Specifically, 
personnel at the clinical study site including, investigators and study staff, research site, and 

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study subjects, will remain blinded to subject treatment assignments until the end of study for 
the last infant on post-delivery study D+364. 
In addition, an informational analysis of efficacy as specified in Section 10.10.2 may be 
performed when approximately 25 primary events, i.e., medically-significant RSV LRTI,
though the first 90 days among the PP-EFF-I population, have accrued. The success criterion is 
defined as the posterior probability that the event ratio is less than or equal to 1.00 (i.e., Vaccine 
Efficacy ≥0%) is greater than or equal to 0.90. This analysis will be performed by the DSMB 
biostatistician and the IBG in a manner entirely analogous to the analyses for efficacy and 
futility. The DSMB will communicate the results of the analysis to the Sponsor only in terms 
of fulfillment or non-fulfillment of the target criterion. Novavax will remain blinded and the 
outcome will not result in any change in the conduct of the study or the primary efficacy 
objectives and endpoints. 
Results of the unblinded analysis of efficacy, immunogenicity, and safety through Day 180 may 
be presented by the Sponsor, and may be submitted to the appropriate regulatory authorities as 
needed.
Modifications or additions to the analyses described above will be included in the SAP. Any 
decisions to deviate from the planned analyses described in the protocol and in the statistical 
analysis plan will be described in detail in the final study report.
10.10.2
Informational Analysis
The Sponsor may trigger the performance of an informational analysis of efficacy as defined in 
the SAP. This analysis will be performed by the DSMB biostatistician and the IBG in a manner 
entirely analogous to the analyses for efficacy and futility, and will address a success criterion 
to be specified in the SAP. The DSMB will communicate the results of the analysis to the 
Sponsor only in terms of fulfillment or non-fulfillment of the target criterion.
10.10.3
Final Clinical Study Report (CSR)
The final CSR will include all efficacy, immunogenicity, and safety data (inclusive of clinical 
assessments and concomitant medications) through the infant subject’s post-delivery study 
D+364 visit, the scheduled end of study. The database will be locked and the final study report 
prepared, when all of the above data have been entered, reviewed and all queries related to the 
data have been addressed.  
10.11 Computer Methods
Statistical analyses will be performed using SAS® version 9.3 or higher under a Windows 
operating system.

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LEGAL AND ETHICAL REQUIREMENTS
11.1
Compliance with Regulatory Requirements
This study will be conducted in accordance with the protocol, the Declaration of Helsinki (1964) 
(amended Fortaleza, Brazil, 2013); International Conference on Harmonization (ICH) GCP 
Guidelines; and all applicable regulatory requirements in the region(s) the study is conducted, 
including the relevant national or local regulatory body having jurisdiction.
11.2
Institutional Review Board/Independent Ethics Committee
This study will be conducted under the auspices of a properly constituted IRB/IEC, as defined 
by US regulatory requirements, and in accordance with the Declaration of Helsinki (1964)
(amended Fortaleza, Brazil, 2013). This committee will review and approve all aspects of the 
study, including the protocol and Informed Consent Forms (ICFs) to be used, any and all 
advertising or informational materials, and any modifications made to the protocol and ICFs, 
prior to, or during the study. Prior to initiation of clinical activity, investigators will provide 
Novavax with a copy of the communication from the IRB/IEC to each investigator indicating 
approval of the protocol and ICF(s). All changes to the protocol or Informed Consent Form 
must be reviewed and approved prior to implementation, except where necessary to eliminate 
apparent immediate hazards to human subjects. 
If applicable, the investigators will be responsible for obtaining annual IRB/IEC renewal 
throughout the duration of the study.  Copies of the investigators’ annual reports to the IRB/IEC 
and copies of the IRB’s/IEC’s continuance of approval must be furnished to Novavax.
11.3
Informed Consent
The investigators or designated site study staff members will be responsible for obtaining 
written Informed Consent (and any applicable local or state regulatory documentation), signed 
and dated by each maternal subject and parent/guardian of each infant, prior to his/her 
participation in the study, including procedures performed at screening. Informed Consent will 
be obtained from each maternal subject and parent/guardian of each infant after a full 
explanation of the purpose of the study, the risks and discomforts involved, potential benefits, 
etc., have been provided by the investigators, both verbally and in writing. The original signed 
copy of the ICF must be maintained in the institution's records, and is subject to inspection by 
a representative of Novavax and/or regulatory agencies. The subject and parent/guardian of 
each infant will also be given a copy of the signed consent form.
11.4
Required Site Documentation
The following documents must be provided to Novavax or its designee prior to the start of the 
study:

Any country-specific administrative form(s) (e.g., Executed Form FDA 1572)

Current Curriculum Vitae and medical licenses (as applicable) for the principal 
investigator and all sub-investigators,

Financial Disclosure Forms from the principal investigator and all sub-investigators,

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
Signed protocol and amendments (if any),

Copy of correspondence from the IRB/IEC indicating approval of the protocol and ICFs, 
signed by the IRB/IEC chairperson or designee, and containing the name and address 
of the IRB/IEC,

Membership roster of the IRB/IEC, listing names and occupations. If an investigator 
participating in this study is an IRB/IEC member, documentation should be provided of 
his/her abstention from voting on this protocol,

ICFs that were reviewed and approved by the IRB/IEC, or a revised document if 
changes were requested by the committee with the IRB/IEC stamp and date, and

Reference ranges for all safety tests required in the protocol and documentation of 
laboratory licensure if the study site’s local clinical laboratory will be used. 
11.5
Subject Confidentiality
Individual subject medical information obtained as a result of this study is considered 
confidential and disclosure to third parties, other than those cited below, is prohibited. 
Confidentiality of maternal and infant subjects will be further ensured by utilizing a subject 
identification code and subject initials. Relevant national and local jurisdictions governing 
privacy rules and protection of human subjects will be followed in this study.
In compliance with regulatory guidelines regarding the monitoring of clinical studies, and in 
fulfillment of the investigator's obligations to Novavax, it is required that data generated as a 
result of the study be available for inspection, on request, by personnel from Novavax, CRO 
monitors representing Novavax, and/or regulatory agencies. These shall include all study 
relevant documentation, including medical histories to verify eligibility, laboratory test results 
to verify transcription accuracy, treatment and diagnostic reports, and admission/discharge 
summaries for hospital admissions occurring while the subject is on-study.
As part of the required content of the Informed Consent, the maternal subject or other 
parent/guardian of the infant subject must be informed that their records will be reviewed by 
Novavax and/or regulatory agencies.  Should access to the medical record require a separate 
waiver or authorization, it is the investigator's responsibility to obtain such permission from the 
maternal subject or other parent/guardian of the infant subject in writing before the subject is 
entered into the study.
11.6
Disclosure of Information
Information concerning the RSV F vaccine, patent application processes, scientific data or other 
pertinent information, is confidential and remains the property of Novavax. The investigator 
may use this information for the purposes of the study only. It is understood by the investigator 
that Novavax will use information developed in this clinical study in connection with the 
development of the investigational vaccine and therefore may disclose it as required to other 
clinical investigators and to regulatory agencies. In order to allow the use of the information 
derived from this clinical study, the investigator understands that he/she has an obligation to 
provide complete test results and all data developed during this study to Novavax.

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Please refer to the clinical trial agreement for contractual terms regarding presentation and 
publication of trial results. 

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Infections. http://apps.who.int/vaccine_research/diseases/ari/en/index2.html

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Zaman K, Roy E, Arifeen SE, et al. Effectiveness of maternal influenza immunization in 
mothers and infants. N Engl J Med. 2008; 359(15):1555-64.
Zou G. A modified poisson regression approach to prospective studies with binary data. Am J 
Epidemiol. 2004; 159(7):702-6.

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Appendix 1 – RSV-M-301 Study Procedures Schedule
Maternal Subject Study Procedures
Study Day:
-28 to 0
0
0-6
7[1]
14[1]
28[1]
Delivery
D+35[1]
D+180[1]
Window (days):
--
--
--
+2
±2
±2
--
±7
±14
Approximate 
Week of Gestation:
24-360/7
28-360/7
28-36
29-37
30-38
32-40
--
--
--
Informed consent
x
Medical history
x
Physical exam
x
Vital signs
x
x[5]
x
x
x[10]
x
x
Physical exam, if indicated
x
x
x
x
x
x
Ultrasound
x[2]
Clinical safety phlebotomy
x[3]
x[3]
x[11]
HIV, syphilis, HBV, and HCV testing 
(if applicable)
x[4]
Pregnancy test
x
Fetal heart tones 
x
x[5]
x
x
Confirm eligibility
x
Injection with recommended licensed 
vaccine dose
x[6]
Injection with RSV F vaccine or 
placebo 
x
Diary card completed
x
Diary card reviewed and collected
x
Distribution of Study Identification 
Card[9]
x
x
x
x
x
x
Memory aid distribution
x
RSV serology phlebotomy
x
x
x[7]
x
x
Cord blood
x[8]
RSV surveillance
Continuous

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Maternal Subject Study Procedures
Study Day:
-28 to 0
0
0-6
7[1]
14[1]
28[1]
Delivery
D+35[1]
D+180[1]
Window (days):
--
--
--
+2
±2
±2
--
±7
±14
Approximate 
Week of Gestation:
24-360/7
28-360/7
28-36
29-37
30-38
32-40
--
--
--
AEs, MAEs, SNMCs, and SAEs query
x
x
x
x
x
x
x
x
Concomitant medications
x
x
x
x
x
x
x
Document perinatal management & 
GBS screening/treatment results
x
x
[1] Performed as a telephone or SMS contact visit (Day 28 only) using an IRB/IEC-approved script, if applicable, or as an in-clinic or home visit (Day 7, 
Day 14, D+35, and D+180) to monitor for safety. Depending on responses, maternal subjects participating via telephone or SMS contact or home visit,
may be asked to return to the clinic or to schedule a home visit for further evaluation.
[2] May be performed if subject does not have a prior second or third-trimester ultrasound that indicates there are no fetal anomalies.
[3] To be performed at least two days prior to the planned Day 0 vaccination and on Day 14 in all subjects enrolled in the first year of study conduct in any 
country for serum chemistry (ALT, AST, total bilirubin, ALP, creatinine, and BUN) and hematology (hemoglobin, platelet count, and WBC count) 
assessments. 
[4] To be performed as required by the central or local laboratory if screening results are not available in prior data collected during the course of the 
current pregnancy. 
[5] To be performed before and 30 minutes after vaccine administration.
[6] Must be administered at least 14 days before or at least 14 days after the Day 0 vaccination, if applicable. 
[7] The blood draw will be performed at any time from admission to the hospital up to 12 hours post-delivery for most deliveries, but may be obtained up 
to 72 hours post-delivery in extenuating circumstances such as a the occurrence of a delivery on a holiday or weekend.
[8] Obstetrical investigator or designee should inform the investigator to the infant (or designee) of the collection status of the cord blood sample.
[9] The Study Identification Card will be distributed at the Day 0 visit; a replacement card will be offered at all follow-up visits.
[10] Limit collection to clinically significant vital sign data at hospital admission.
[11] Performed only for applicable subjects (i.e., those enrolled in the first year of study conduct in any country) who deliver prior to the Day 14 visit.

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Infant Subject Study Procedures
Visits:
1
2
3
4
5
6
7
8
9
Study Day:
Delivery
D+14
D+35
D+60
D+90
D+120
D+180
D+252
D+364
Window:
NA
±3 days
±1 week
±1 week
±1 week
±1 week
±2 weeks
±2 weeks
±2 weeks
Informed consent
x
Physical exam
x
x
x
x
x
x
x
Physical exam, if indicated
x
x
Gestational age,  APGAR scores
x
Weight, length, FOC
x
x
x
x
x
x
x
x
Phlebotomy, Cohort 1
x[1]
x
x
Phlebotomy, Cohort 2
x[1]
x
x
Phlebotomy, Cohort 3
x[1]
x
x
Distribution of Study Identification 
Card[2]
x
x
x
x
x
x
x
x
x
RSV surveillance
Continuous  
Query for smokers and children < 5 
years of age in the household; mode of 
infant feeding; whether infant or 
another child (< 5 years of age)  in the 
household is cared for outside the home 
x
x
x
x
x
x
x
x
x
AEs, MAEs, SNMCs, and SAEs 
x
x
x
x
x
x
x
x
Query for healthcare- provider 
confirmed wheezing
x
x
x
x
x
x
x
x
Performance of all routine baby-
wellness procedures/vaccinations[3]
x
x
x
x
x
x
x
x
x
Concomitant medication
x
x
x
x
x
x
x
x
Developmental testing
x
x[4]

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Infant Subject Study Procedures
Visits:
1
2
3
4
5
6
7
8
9
Study Day:
Delivery
D+14
D+35
D+60
D+90
D+120
D+180
D+252
D+364
Window:
NA
±3 days
±1 week
±1 week
±1 week
±1 week
±2 weeks
±2 weeks
±2 weeks
Note: Study visits after Visit #1 may be performed as in-clinic or home visits to facilitate infant subject follow-up. 
[1] An infant blood draw should be preferentially obtained within 24 hours of birth if cord blood is not collected at delivery, but is permissive up to 72 
hours post-delivery. 
[2] The Study Identification Card will be given to the parent/guardian of the infant subject at the delivery visit; a replacement card will be offered at all 
follow-up visits, as needed.
[3] Performed at the Investigator’s discretion.
[4] Infant subjects with a positive screen detected at both 6 and 12 months of age, or first appearing at 12 months of age, will be offered repeat developmental 
testing at 15 and 18 months of age as a follow-up procedure.

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Appendix 2 – RSV-M-301 Draft Subject Diary (for Maternal Subjects Only)
A subject diary will be provided to all maternal subjects to record solicited and unsolicited adverse events experienced, concomitant medications 
used, and any medical visits/procedures sought, within the first seven days following vaccination. The above is a sample excerpt from such a 
diary. It is provided for informational purposes only and may differ from the actual diary issued to subjects. 

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Appendix 3 – RSV-M-301 Blood Draw Schedule (for Maternal and Infant Subjects) 
 
Maternal Subjects Blood Draw Schedule 
Study Visit Day 
Amount of Blood 
Drawn for Clinical 
Laboratory Safety 
Amount of Blood Drawn for 
Immunogenicity 
Assessments 
Total Drawn 
at Visit 
Day -28 to 0  
10 mL[1] 
20 mL 
30 mL[1] 
Day 14 
(±2 days) 
10 mL 
20 mL 
30 mL 
Delivery - Maternal 
-- 
20 mL 
20 mL 
Delivery – Cord Blood  
-- 
at  least 5 mL 
at  least 5 mL 
Post-delivery Day 35 
(±7 days) 
-- 
20 mL 
20 mL 
Post-delivery Day 180 
(±14 days) 
-- 
20 mL 
20 mL 
Totals 
Venous 
20 mL[1] 
100 mL 
120 mL[1] 
Cord Blood 
-- 
at least 5 mL 
at  least 5 mL 
Note: The blue shaded row indicates the blood volume collected from the umbilical cord at delivery.  
[1] Limited to those subjects participating in the first year of study conduct in any country or subjects that require a 
phlebotomy to document results of HIV, syphilis, HBV, and HCV antigen tests/serologies. 
 
 
 
Infant Subjects Blood Draw Schedule 
Delivery (D) 
Study Visit Day 
Amount of Blood Drawn for Immunogenicity Assessments 
Visit 1: Delivery[1] (+72 hours of birth) 
1mL (heel stick) or 2 mL (venipuncture) 
Visit 2: D+14 (±3 days) 
1mL (heel stick) or 2 mL (venipuncture) 
Visit 3: D+35 (±7 days) 
1mL (heel stick) or 2 mL (venipuncture) 
Visit 4: D+60 (±7 days) 
1mL (heel stick) or 2 mL (venipuncture) 
Visit 5: D+90 (±7 days) 
1mL (heel stick) or 2 mL (venipuncture) 
Visit 6: D+120 (±7 days) 
1mL (heel stick) or 2 mL (venipuncture) 
Visit 7: D+180 (±14 days) 
1mL (heel stick) or 2 mL (venipuncture) 
Cohort 
Totals 
1 
3 to 6 mL[1] 
2 
3 to 6 mL[1] 
3 
3 to 6 mL[1] 
Note: The orange shaded rows indicate the blood volume collected from Cohort 1 infants. The blue shaded rows indicate 
the blood volume collected from Cohort 2 infants.  The green shaded rows indicate the blood volume collected from 
Cohort 3 infants. 
[1] Includes collection of 1 or 2 mL of blood that may be taken within 24 hours of birth if cord blood is not obtained at 
delivery.  

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Appendix 4 – RSV-M-301 Subject Measurement Tool
(Do not use this page in clinic, as it may not be to exact scale)
The Subject Measurement Tool consists of a transparent set of concentric circles with diameters 
that correspond to the ranges in the toxicity grading scale (2.5, 5, and 10 cm in diameter). 
Maternal subjects are instructed to overlay the template over the injection site for any reaction 
that can be visually observed (e.g., redness, swelling, bruising).  An assessment of severity is 
then made by determining the circle that best describes the size of the reaction: reactions that 
are smaller than Circle A (2.5 cm) are considered grade 0; reactions larger than Circle A but 
equal to or smaller than Circle B (5 cm) are considered grade 1; reactions larger than Circle B 
but equal to or smaller than Circle C (10 cm) are considered grade 2; reactions larger than Circle 
C are considered grade 3. The table below summarizes the severity grading for visible injection 
site reactions based on size. 
Definition of Severity Grading for Visible Local Adverse Events
Severity Grade
Injection Site Grading Description
0 - Normal
Reaction size fits inside Circle A
1 - Mild
Reaction size larger than Circle A, but fits inside Circle B
2 - Moderate
Reaction size larger than Circle B, but fits inside Circle C
3 - Severe
Reaction size larger than Circle C
A
B
C

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Appendix 5 – RSV-M-301 Protocol Change History 
Following is a complete tabular summary of changes made to previous versions of the protocol. 
Protocol Version 9.0, 21 July 2017 (revised from 8.0, 23 August 2016)
The following is a summary of the changes made to this version of the protocol.
Location of 
Change
Change/Modification in Version 9.0
Protocol 
Change History 
To enhance section readability, only the protocol change history pertaining to 
Version 9.0 has been retained in this section. Protocol change histories pertaining 
to previous protocol amendments have been provided in Appendix 5 of the 
protocol. 
Section 1.2.1
A brief description of RSV epidemiology among the United States Native 
American pediatric population has been provided. 
Section 1.2.4
The section has been added to provide a brief discussion of RSV in children in 
India, Southeast Asia, and the Philippines.
Section 1.6.2
The summary of clinical experience has been updated to provide safety experience 
from the now-completed phase II trial in 50 pregnant women.
Section 1.8 
Minor updates have been made to the section to reflect discussion of the most
current safety data from relevant clinical trials.  
Synopsis, 
Section 2.1 
The primary efficacy objective in infants has been changed to indicate the 
assessment of efficacy against the updated endpoint of medically-significant RSV 
LRTI. The updated objective is presented below:  
To determine the efficacy of maternal immunization with the RSV F vaccine against 
medically-significant RSV lower respiratory tract infection (LRTI) with EITHER 
hypoxemia (peripheral oxygen saturation [SpO2] < 95% at sea level or < 92% at 
altitudes > 1800 meters) OR tachypnea (≥ 70 bpm for infants 0 to 59 days of age 
or ≥ 60 bpm for infants ≥ 60 days of age) through the first 90 days of life in infants 
of maternal RSV F vaccinees as compared to placebo recipients. In the event that 
efficacy is shown through the first 90 days of life, a hierarchical sequence of 
hypothesis tests will be carried out to examine efficacy at 120, 150, and 180 days 
of life.
Justification: Several recent publications have shown that the presence of 
tachypnea (based on WHO definitions) is an independent predictor of 
hospitalization of infants with RSV acute respiratory disease (Atwell et al. J Infect. 
Dis. [2016]; Modjarrad et al. Vaccine [2016]).  Infants with severe disease may 
maintain their oxygenation through rapid breathing, becoming hypoxemic only 
when they tire and decompensate.  A threshold value for tachypnea 10 breaths per 
minute higher than the WHO definition (which is ≥ 60 bpm for infants 0 to 59 days 
of age and ≥ 50 bpm for infants ≥ 60 days of age) has thus been added to the 
medically-significant RSV LRTI definition.      

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Synopsis, 
Sections 2.3, 
3.3.3 
The 2nd exploratory objective has been updated to include tachypnea. The changed 
objective is as follows: 
To describe the incidence of all-cause LRTI, with and without tachypnea, 
hypoxemia, or severe hypoxemia, in infant subjects as detected by active and 
passive surveillance from vaccination through six months after delivery, and the 
efficacy of maternal immunization with the RSV F vaccine in reducing the incidence 
of these endpoints.
The 2nd corresponding endpoint to the above-stated objective has also been updated 
to include tachypnea. The changed endpoint is as follows: 
Percentages of infant subjects with all-cause LRTI, with or without tachypnea, 
hypoxemia or severe hypoxemia, as detected by active and passive surveillance 
from vaccination through six months after delivery, overall and by pathogen(s).
Synopsis, 
Table 1 
Target subject enrollment has been updated to 2,930 for placebo group and 5,688 
for RSV F Vaccine group to reflect the randomization switch to 2:1 (Active / 
Placebo) after global year 1
Synopsis, 
Section 3.1
The description of the study design has been updated to remove the projected 
number of RSV seasons that the trial could span. The sentence “continuing for up 
to 4 consecutive RSV seasons in each hemisphere” has been removed. 
The word “inclusive” has been removed when specifying the target age range for 
study maternal subjects, ie, 18 to 40 years of age.  
Justification:  The study duration is now specified in terms of enrollment rather 
than time, to allow adjustment of duration if needed based on enrollment rate.  The 
removal of “inclusive” is intended to clarify the intended inclusion of women 18 to 
40 years and zero (0) days, the upper breakpoint co-inciding with identified cut-
offs for higher risk rates in pregnancy.
Synopsis, 
Section 3.2
The description of the group-sequential design strategy has been updated to reflect 
the updated primary objective of efficacy. 
Details of the proposed formal interim analyses for efficacy to evaluate success in 
the primary objective have been added, which will now occur: 
after 1) approximately 4,600 total mother-infant pairs, including at least 3,000 
cumulative actively-immunized mother- infant pairs, have completed at least 6
months of post-partum follow-up; and 2) if necessary, after an additional 2,000 
mother-infant pairs have completed at least 6 months of post-partum follow-up.
Synopsis, 
Section 3.3.1 
The primary efficacy endpoint in infant subjects has been changed to accommodate 
the updated definition of medically-significant RSV LRTI. The changed endpoint 
is as follows:  
o
The presence of RSV infection confirmed by detection of RSV genome by 
RT-PCR on respiratory secretions (obtained within the continuous illness 
episode which fulfills the other criteria listed below); AND 

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o
At least one manifestation of LRTI from among the following: cough, nasal 
flaring, lower chest wall indrawing, subcostal retraction, stridor, rales, 
rhonchi, wheezing, crackles/crepitations, or observed apnea; AND 
o
Evidence of medical significance as defined by the presence of: 
-
EITHER hypoxemia (peripheral  oxygen saturation [SpO2] < 95%  at sea level 
or < 92% at altitudes > 1800 meters) OR 
-
Tachypnea (≥ 70 bpm in infants 0 to 59 days of age and ≥ 60 bpm in infants 
≥60 days of age). 
Section 3.4
It has been specified that the duration of the entire study is estimated to be 
approximately four years, but will be determined by the operation of the group-
sequential design and the actual enrollment rates. 
Synopsis, 
Section 5.1 
Inclusion criterion defining the age at which subjects are eligible to enroll (ie, ≥ 18 
and ≤ 40 years-of-age) has been qualified with the following statement: 
connotes a lower limit of 18 years and 0 days and an upper limit of 40 years and 0 
days 
Synopsis, 
Section 
6.1.2.10
It has been clarified that active surveillance for RSV-suspect illnesses will cease 
after D+180, and that respiratory illnesses passively reported by parents/guardians 
after this time point will be captured as AEs.
Synopsis, 
Section 6.2
RSV surveillance rules have been updated with the  following:
The language describing the window for the study staff to re-evaluate all infant 
subjects with RSV-suspect illnesses has been modified from “24 to 48 hours” to 
“between 2 and 3 days” of any initial RSV surveillance visit.  
The following additional rules have been added: 
Newly-discovered RSV-suspect illnesses as assessed by the presence of “trigger 
symptoms” will precipitate a home or clinic visit for evaluation. 
Study staff will re-evaluate (at home or in the clinic) all infant subjects with RSV-
suspect illnesses between 2 and 3 days after any initial RSV surveillance visit to 
ascertain worsening in the illness. This re-evaluation will include the same 
procedures outlined in Section 6.2.3 of the protocol. 
It has been specified that RSV-suspect illness reported during passive surveillance 
but after D+180 days will be captured as AEs and not on the RSV Surveillance 
page. 
It has been clarified that whenever symptoms of a new respiratory illness emerge, 
or ongoing symptoms worsen, for both infant and maternal subjects, study staff 
should be contacted within 3 days of symptom onset/worsening. 
Justification:  It has been noted over the first two years of the study that a number 
of cases of medically-significant RSV LRTI are being evaluated by study sites 
without fulfilling the primary endpoint definitions, but then are being admitted to 

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hospital 2-3 days later – at which time study assessments are not completed. In 
order to rectify this situation, a follow-up evaluation of subjects who present with 
RSV-suspect illnesses will be added, and parents will further be encouraged to 
report worsening illnesses to the study sites.   
Synopsis, 
Section 6.2.3
Additional procedures have been outlined for the study staff to increase efficiency 
and completeness in capturing study endpoints, including tachypnea, during RSV 
surveillance. The study staff are instructed to perform the following procedures 
during a surveillance visit, specifically for symptomatic infants: 
Measure the respiratory rate on room air (if possible) for all symptomatic infants. 
The measurement should be performed first, on a calm, infant, and should be 
performed by observation only (i.e., without stethoscope auscultation) for a full, 
timed one minute period. 
-
If the result is ≥ 60 bpm in an infant 0 to 59 days age or ≥ 50 bpm in an infant 
≥ 60 days of age, a second timed one minute count should be obtained. 
-
If a second count is obtained, the lower of the two observations should be 
recorded. 
Measure the SpO2 via pulse oximetry (using study-specific pulse oximeter) for all 
symptomatic infants, which is to be performed when the infant is calm and not 
crying, and before administration of oxygen supplementation. The lowest stable 
SpO2 observed during a one minute measure should be recorded. 
The study staff will perform the following additional procedures for all 
symptomatic subjects (including maternal and infant): 
Review and confirm the history of respiratory illness, including the approximate 
date of first symptom onset. 
Perform an examination of the symptomatic infant subject to ascertain, by 
observation or auscultation, the presence of the LRTI manifestations listed in 
Table 3 of the protocol.
Collect vital signs other than respiratory rate (heart rate, blood pressure [if 
available for the infant], and axillary body temperature) for the symptomatic 
subject.
In addition, the section specifies collection of a mid-turbinate swab for RSV 
detection by RT-PCR and completion of vital signs. The section has been 
reorganized to maintain relevance to RSV illness trigger symptoms; and also to 
conform to new instructional materials concerning the evaluation which will be 
distributed to site staff. Guidelines pertaining to follow up of subjects with RSV 
suspect illness have been presented in a new section numbered 6.2.4.
Table 3 
The table has been re-organized to conform more closely to Section 6.2.3, although 
specifying collection of the same observations, save for tachypnea.  Measurement 
of tachypnea has been removed from Table 3, which describes features of LRTI, 
and is now captured within the body text of Section 6.2.3; consistent with the 
revised role of tachypnea in the primary endpoint case definition. 

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Synopsis, 
Section 6.2.4
This section has been added to provide additional direction for the study staff for 
follow-up of RSV-suspect illness among subjects. Specifically, the following have 
been added: 
For symptomatic infant subjects, schedule a follow-up visit in 2 to 3 days to 
ascertain whether the illness is worsening.

The follow-up visit will include the same procedures outlined in
Section 6.2.3.

Parents/guardians will be strongly encouraged to report any worsening 
after the follow-up visit, including hospitalizations, which may trigger any 
number of additional follow-up visits at the investigator’s discretion. 

In the event than an infant is hospitalized, site staff are encouraged to 
perform a follow-up visit in-hospital, if permissible under local 
adiministrative and ethical review procedures. 
For symptomatic maternal subjects, and for symptomatic infant subjects after the 
first follow-up visit described above, a weekly contact by telephone/SMS will be 
performed to ascertain respiratory symptom status through to the D+180 visit, and 
to monitor the status of RSV-suspect illnesses until symptoms have resolved, or 
have returned to baseline if after the D+180 visit. 
In the event new and/or worsening symptoms are reported during active or passive 
follow-up, an in-clinic or home RSV-surveillance visit may be scheduled at the 
investigator’s discretion for an evaluation to occur as soon as possible and a re-
evaluation as per Section 6.2.3, may be performed.
At the investigator’s discretion, collection of ONE more respiratory specimen for 
pathogen detection for infant subjects who have developed qualitatively different 
or quantitatively worse symptoms. Note that no more than 3 respiratory specimens 
should be collected from an infant within the same episode.  
If the new or worsening symptom in the maternal subject is associated with a 
respiratory episode for which a specimen has already been obtained, the 
investigator may exercise his/her judgement as the utility of an additional swab.
Section 7.3 
It has been specified that a respiratory specimen will be collected as soon as 
possible after onset of illness among subjects. 
Section 8.3.1
The following guidance regarding the safety reporting of ASQ abnormalities has 
been added:
As a guidance, and solely for the purposes of consistency within this protocol, it is 
suggested that investigators report ASQ abnormalities which persist at 6 and 12
months in a given infant as an AE that is “moderate” in severity.  If diagnostic 
developmental testing is undertaken, the event should be further classified as a 
medically-attended event (MAE, see 8.4).  If diagnostic evaluation, during the trial 
or afterward, leads to the diagnosis of a persistent developmental disability, the 

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event then also becomes a serious adverse event (SAE, see Section 8.5) as should 
be reported as such. 
It has been specified that assessment for infants born prematurely may use age-
appropriate adjusted scoring.
Section 8.6 
It has been clarified that neonatal and infant deaths should be reported whenever 
possible as the underlying medical condition which resulted in death, with death 
captured as the outcome of the SAE to allow the capture of more granular 
information about the incidence of specific diagnostic entities leading to death, and 
prevent confusion with SIDS in analysis.   
Section 8.7
It has been specified that any pregnancy occurring after the birth of the planned 
child enrolled in the current study AND before the maternal subject has completed 
the Day 180 post-delivery visit will not be captured as an AE.
Section 8.10 
It has been clarified that the DSMB will consist of at least five clinicians to include 
not less than 2 obstetricians (with at least one with expertise in high-risk obstetrics 
or maternal-fetal medicine) and not less than 2 pediatricians (at least one 
neonatologist), and the unblinded DBMB statistician. 
Synopsis, 
Section 10.1
When defining the intent-to-treat efficacy and intent-to-treat immunogenicity study 
populations, the statements “subjects will be analyzed according to treatment as 
actually receive” have been deleted. 
Synopsis, 
Section 10.4.1 
Study definition for RSV LRTI has been changed throughout the protocol by 
omission of “tachypnea at rest” and of the “presence of an acute RSV infection of 
the lower airways and/or lungs manifesting as one or more of cough, nasal flaring, 
or difficulty breathing.” The updated definition of RSV LRTI is presented below: 
Confirmed RSV LRTI will feature a detection of RSV in respiratory secretions by 
RT-PCR and at least one of the following clinical manifestations observed and 
documented by appropriately-trained study staff: cough, nasal flaring, lower chest 
wall indrawing, subcostal retractions, abnormal breath sounds (inclusive of 
stridor, rales, rhonchi, wheezing, and crackles/crepitations); and/or observed 
apnea.
“RSV LRTI with hypoxemia” has been replaced with “medically-significant RSV-
LRTI,” which now is defined by the presence of medically-significant respiratory 
compromise as evidenced by either hypoxemia or tachypnea. The new definition 
of medically-significant RSV-LRTI is presented below: 
An RSV LRTI episode with EITHER a resting peripheral oxygen saturation (SpO2)
< 95% at sea level or < 92% at altitudes > 1800 meters by pulse oximetry on room 
air OR tachypnea defined as ≥ 70 breaths per minute [bpm] in an infant 0 to 59 
days of age, or ≥ 60 bpm in infant ≥ 60 days of age.

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Synopsis, 
Section 10.4.2 
Statistical considerations have been updated to reflect changes in study efficacy 
objective and endpoints and to present the stipulations for stopping the trial for 
success after the conductance of formal interim analyses. Specifically, the 
following statistical criteria have been provided:  
The trial may stop for success after one of two formal interim analyses occurring: 
-
After 3,000 cumulative actively-immunized maternal subjects immunized with 
investigational vaccine (approximately 4,600 total maternal subjects in both 
study arms) and their infants have completed at least 6 months of post-partum 
follow-up, or 
-
After approximately 2,000 additional maternal subjects and their infants 
(approximately 6,600 maternal-infant pairs total) have completed at least 
6 months of post-partum follow-up.  
Alternatively, the trial may achieve success after a final analysis undertaken when 
the projected total of approximately 8,618 maternal subjects and their infants have 
completed at least 6 months of post-partum follow up. 
The interim and final analyses for determination of success in the primary objective 
will utilize data through the first 90 days of life of the infant subjects and will be 
based on the posterior probability of success. Should success be declared, the 
sequential analyses of the co-primary endpoints concerning efficacy through 120, 
150, and 180 days, as well as all secondary and exploratory analyses, will be 
performed on the final dataset.
In view of differing global regulatory requirements, the final analysis (whenever 
this occurs) will be carried out sequentially while maintaining Type I Error rate at 
no more than 1-sided 2.5% level, to address primary hypotheses concerning the 
posterior probability that the event ratio, r = πv / πp, is less than 1.0, and based on 
success in that test, the posterior probability that the event ratio, r= πv / πp, is less 
than or equal to 0.70. 
Text has been updated to indicate that only up to 2 interim analyses are 
contemplated, not three.
Additional specifications for sensitivity analyses have been provided, as described 
below. 
Sensitivity analyses for the primary efficacy endpoint will be performed to 
investigate the impact of missing specimens for suspected-RSV illnesses, including 
RSV-negative specimens collected outside the specified collection window and 
clinical assessments, including clinical signs/symptoms, respiratory rates, and 
pulse oximetry measurements, obtained by non-study healthcare providers (e.g. 
hospitalization record). Further details regarding the sensitivity analyses will be 
described in the statistical analysis plan.
Section 10.6 
Text has been corrected to reflect that all unsolicited AEs for maternal subjects 
through 180 days post-delivery by severity and relatedness, will be captured.  

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Synopsis, 
Section 10.8
The estimated enrollment projections per global season used for the simulation 
scenarios have been updated, as shown below: 
Estimated enrollment projections per global season used for the simulation 
scenarios and operating characteristics were 174 (20 in Northern Hemisphere and 
154 in Southern Hemisphere) in global season 1 and 1,304 (210 in Northern 
Hemisphere and 1094 in Southern Hemisphere); 2,735 (1,220 in Northern 
Hemisphere and 1,515 in Southern Hemisphere); 3,025 (1,510 in Northern 
Hemisphere and 1,515 in Southern Hemisphere); and 3,025 (1,500 in Northern 
Hemisphere and 1,515 in Southern Hemisphere) in subsequent seasons 2, 3, 4, and 
5, respectively. The Southern Hemisphere enrollment estimate for the global 
season 5 was used for the operating characteristics determination for lower than 
projected enrollment rates.
An updated table with simulation scenarios and operating characteristics needed to 
satisfy the study efficacy objective, has been provided.
Section 10.10.1 
It has been specified that the sequence of formal interim analyses for efficacy will 
be conditioned by the US FDA requirement that not less than 3,000 actively-
immunized maternal subjects and their infants (approximately 4,600 mother-infant 
pairs in total) be included in the first formal interim. 
Further specifications have been provided for the conduct of formal interim 
analyses. 
Section 10.10.2
The section has been inserted to indicate that the Sponsor may trigger the 
performance of an informational analysis of efficacy as defined in the SAP. This 
analysis will be performed by the DSMB biostatistician and the IBG in a manner 
entirely analogous to the analyses for efficacy and futility, and will address a 
success criterion to be specified in the SAP. The DSMB will communicate the 
results of the analysis to the Sponsor only in terms of fulfillment or non-fulfillment 
of the target criterion.
General
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Protocol Version 8.0, 23 August 2016 (revised from 7.0, 15 July 2016)
The following is a summary of the changes made to this protocol.
Location of Change
Change/Modification in Version 8.0
Synopsis (Study Design); 
Section 3.1
Further clarified the permissive timing of maternal subject enrollment 
and immunization, and how this will be consistently determined for 
each maternal subject based on their estimated date of delivery and in 
consideration of the historic average onset and end date of increased 
RSV transmission at each study site.  The reader is referred to the 
Study Operations Manual for further details.
Section 3.8
Clarified the procedures for unblinding of subject treatment 
assignment in the event of a medical emergency. The revised text now 
states, “If feasible, the investigator is asked to notify the Medical 
Monitor or designee prior to unblinding; however, the investigator 
may unblind without consulting the Medical Monitor, if it is deemed 
to be in the best interest of the subject.”
Synopsis (Inclusion 
Criteria); Section 5.1
Inclusion criterion #2 now contains the gestational age dating 
composite criteria, which was formerly presented in IC#3 in the prior 
protocol versions.
IC#2 sub-bullets (a) through (d), which already reflected current 
guidelines established by the American College of Obstetricians and 
Gynecologist (ACOG) for gestational age dating [Committee on 
Obstetric Practice 2014], were modified to provide further clarity.  
The requirement to enroll and immunize maternal subjects with an 
estimated date of delivery between approximately six (6) weeks before 
and approximately four (4) weeks after the historic average date of 
onset of increased RSV transmission at the clinical site was removed 
as an inclusion criterion.
Synopsis (Exclusion 
Criteria); Section 5.2
Removed the text, “including known sickle trait or thalassemias” from 
exclusion criterion (EC)#7. 
Modified EC#20 to include anyone with red blood cell allo-
immunization, not just untreated.
Sections 7.2.1 and 7.2.2
The assay descriptions for anti-F IgG and PCA ELISA have been 
reworded for clarity. The Standard Operating Procedure (SOP) 
providing details on the assays has been referenced.
Section 8.7
The safety reporting requirements have been amended to ensure 
compliance with the European Directive 2001/20/EC. Specifically the 
updated text clarifies that Novavax or its designee will report serious 
adverse events (SAEs) to regulatory authorities and investigators, as 
well as to Ethics Committees in jurisdictions where this is a sponsor 
responsibility.

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Sections 10.10.1 and 11.1
Cited the regulatory authorities in Chile and New Zealand where the 
study is also being conducted. 
Protocol Version 7.0, 15 July 2016 (revised from 6.0, 09 May 2016)
The following is a summary of the changes made to this protocol.
Location of Change
Change/Modification in Version 7.0
Synopsis (Maternal Study 
Visit); Section 6.1.1.2 and 
Appendix 1 
Although stated in Exclusion Criterion #4, the administration of any 
licensed vaccine recommended for pregnancy to occur within 14 days 
of the Day 0 vaccination (i.e., at least 14 days before or 14 days after) 
was emphasized in the sections referenced in order to remove 
ambiguity.
Synopsis (Maternal Study 
Visit); Sections 6.1.1.2 
Appendix 1
Changed the screening visit window for subjects from “-28 to -2” to 
“-28 to 0” days relative to the planned Day 0 vaccination to 
accommodate study sites in countries participating beyond their first 
year of study conduct. 
Separately described the testing that will be performed for subjects 
participating in the first year in any country vs those participating in 
all other years in any country as it pertains to clinical safety labs and 
HIV, syphilis, HBV, and HCV antigen tests/serologies.
Synopsis (Maternal and 
Infant Study Visit, RSV 
Surveillance); Sections 6.1, 
6.2, and 7.3
The window for clinician evaluation and respiratory specimen 
collection of maternal and infant subjects with symptoms of RSV-
suspected illness was extended from 5 to 7 days to broaden the 
window for data collection of any respiratory illness.   
Synopsis (Maternal Study 
Visit); Sections 6.1.1.6 
Appendix 1
Telephone contact for the Day 28 safety follow-up will encompass 
short message service (SMS), commonly termed “text messaging.” 
Synopsis (Infant Study 
Visit); Section 6.1.2 ; 
Appendix 1
Specified that all procedures, including routine vaccinations, that are 
considered standard of care for a corresponding baby-wellness visit 
may be performed at any study visit, if applicable.
Synopsis (Infant Study 
Visit); Sections 6.1.2.9 and 
8.3.1; Appendix 1 
Infant subjects with a positive screen detected at both 6 and 12 months 
of age, or first appearing at 12 months of age, will be offered repeat 
developmental testing at 15 and 18 months of age as a follow-up 
procedure. Novavax will collect this information as safety data in the 
main study, rather than in a separate follow-on protocol. 

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Synopsis (RSV 
Surveillance); Section 6.2
As part of passive RSV surveillance, symptomatic maternal subjects 
and parents/guardians of symptomatic infant subjects should contact 
the study site directly within 3 days of the onset of symptoms (rather 
than 5 days) to allow time to schedule and conduct the in-person 
evaluation. 
Synopsis (RSV 
Surveillance); Section 6.2.3
Clarified that the evaluation of maternal and infant subjects with RSV-
suspected illness will occur within 7 days of symptom/s onset. 
Synopsis (RSV 
Surveillance); Section 6.2.2
Added “New or increasing wheezing” and “New or increasing sputum 
production” to the list of trigger symptoms for symptomatic maternal 
subjects with an RSV-suspected illness.  
Section 6.5
Clarified that study completion procedures for maternal subjects who 
discontinue from the study prematurely, will include clinical 
laboratory safety assessments for those subjects with safety labs 
performed as screening only.  
Sections 9.1 and 9.2; 
General
Clarified that template source documents will be used for Global 
Year 1, and the electronic source documentation (eSource System) for 
all subsequent years (i.e., Global Years 2, 3, and 4). 
Clarified that remote monitoring may be performed by independent 
clinical monitors designated by Novavax. 
The term “eSource” or “eSource system” was generally included 
wherever “eCRF” was referenced.
Section 9.4
Briefly updated the study files that will be maintained in the 
centralized filing system. 
Synopsis and Section 10.4.1
Definition provided for a symptomatic RSV infection in maternal 
subjects. 
Synopsis; Appendix 1
The gestational weeks for all visits occurring after Day 0 were updated 
to reflect the broadening of the gestational age for vaccination (28 to 
36 weeks) approved in the prior protocol amendment.
General
Minor edits to correct typographical errors were made to the 
document.

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Protocol Version 6.0, 09 May 2016 (revised from 5.0, 09 February 2016)
The following is a summary of the changes made to this protocol.
Location of Change
Change/Modification in Version 6.0
Synopsis (Study Rationale, 
Inclusion Criteria); Sections 
1.7 and 5.1, and Appendix 1
Results from the first-in-pregnant women study (RSV-M-203) with 
the RSV F vaccine were summarized. 
The gestational age for immunization of pregnant women in the third 
trimester with the RSV F vaccine was widened at the lower end of 
the third trimester, from 31 weeks to 28 weeks; a justification for this 
change was provided. 
Synopsis (Study Objectives, 
Primary and Exploratory); 
Sections 2.1 and 2.3
Clarified that primary efficacy objective will be based on the first 
episode of RSV lower respiratory tract infection (LRTI) with 
hypoxemia experienced for infants with multiple RSV episodes.
Exploratory objectives will all be descriptive in nature. The first 
exploratory objective was clarified to state that vaccine efficacy 
against all symptomatic RSV respiratory tract infections will be 
described in maternal subjects. The second exploratory objective will 
now describe the incidence of, and vaccine efficacy against, all-cause 
LRTI in infant subjects, with and without hypoxemia or severe 
hypoxemia.
Synopsis (Study Endpoints); 
Section 10.5
Any subgroup analysis for an efficacy endpoint will now consider all 
infants of mothers who received test article < 2 weeks prior to 
delivery and all infants of mothers who received any test article
The geometric mean ratio (GMR) will not be derived/calculated for 
any immunological assay. 
The Percentages of infant subjects with all-cause LRTI, with or 
without hypoxemia or severe hypoxemia will now be presented 
based on the updated to the exploratory objective. 
Synopsis (Study Design, 
Group Sequential  Design, 
Inclusion Criteria); Sections 
3.1, 3.2,  and 5.1
The sample size was revised from 8,255 to 8,618 total subjects to 
reflect the minimum requirement of 3,000 actively-treated maternal 
subjects and their infants for the safety database. This change impacts 
how the group sequential design and interim analyses will be handled 
and the study operations that will be triggered based on scenarios 
when futility, or vaccine efficacy, or neither is observed.
The timing for maternal subject enrollment and study inclusion was 
clarified (see inclusion criterion #8) and now considers the projected 
date of delivery and the historical average onset of RSV transmission 
at each clinical study site. RSV onset date will be a best estimate 
based on site, local, state/provincial, or national data as available.
After the first global season of enrollment, the randomization scheme 
will be changed to a 2:1 (active / placebo) ratio to enable more 

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efficient accrual of the safety database. The Data and Safety 
Monitoring Board (DSMB) will continue their supervision and 
monitoring of subject safety in the same manner.
Section 4.1.1
Updated the description for the manufacture (production and 
purification) of the RSV F protein to reflect current processes.
Synopsis (Exclusion 
Criteria); Section 5.2
Added the term “active” to further clarify exclusion criterion #10. 
Synopsis (Eligibility, 
Maternal Study Visit 
Procedures); Sections 5.1, 
6.1.1.2, and 7.1
Screening for hepatitis B (HBV) and C (HCV) viruses, syphilis, and 
HIV can be performed using the central or local laboratory if 
undocumented (based on medical records) in the current pregnancy. 
Synopsis (Maternal Study 
Visit Procedures); Section 
6.1.1.9
Specified that maternal subjects with a positive pregnancy result at 
the D+180 visit will be followed for safety through the time of 
delivery to determine the outcome of this pregnancy.
Synopsis (Maternal and 
Infant Study Visit 
Procedures); Sections 
6.1.1.10 and 6.1.2.10
Clarified that RSV surveillance visits are not considered unscheduled 
visits.
Synopsis (Infant Study Visit 
Procedures); Sections 6.1.2 
and 6.1.2.6, and Appendix 1 
and 3
Added text to allow for procedures and vaccinations associated with 
a baby-wellness visit to be performed at any infant post-partum study 
visit, if applicable.  
The Day 112 visit was changed to Day 120 to accommodate the 4-
month old baby wellness visit that is routine in most countries.  
Synopsis (RSV 
Surveillance); Section 6.2
Clarified that all procedures associated with the RSV surveillance 
visits are performed only on symptomatic subjects. 
As not all regions of the world routinely assess for blood pressure in 
the infant, this procedure can be omitted if not the standard of care. 
Mid-turbinate swabbing will be collected for all symptomatic 
subjects with a report of trigger symptoms evaluated at an RSV 
surveillance visit. Additionally, a throat swab will be collected for 
maternal subjects.
Section 7.3
Clarified that respiratory specimens will be processed and subjected 
to a commercially available multiplex RT-PCR for identification of 
a range of common viral pathogens in addition to RSV.
Section 8.6
Text describing how SAEs are reported was revised to align with 
Novavax standard operating procedures. 

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Section 8.8.1 and Table 7
Clarified that abnormal fetal heart tone measures may be repeated, 
but any consistent abnormality (i.e., < 120 beats/min or > 160 
beats/min and present on more than one observation) should be 
reported as an AE and assessed against the toxicity grading scale.  
Section 9.1
Novavax will provide sites with template source documents for the 
recording and collection of maternal and infant subject data since 
electronic source technology can now be used.
Synopsis (Statistical 
Methods); Section 10.1
The various maternal and infant subject populations to be used in the 
immunogenicity and efficacy analyses were all redefined. 
Synopsis (Statistical 
Methods); Section 10.2
Removed text that indicated symptomatic respiratory tract infections 
not associated with RSV will be summarized as safety data since this 
is no longer valid.
Synopsis (Statistical 
Methods); Sections 10.4.2 
and 10.7
Updated the statistical methods that will be used to analyze the 
primary and secondary efficacy objectives. 
Updated to clarify the prior distribution is defined as Beta(1,1) for 
both treatment arms.
Revised the statistical method and the criterion for the futility 
analyses from the predictive probability of success against the 
relative risk of 0.7 to the posterior probability against the relative risk 
of 0.6.  This change was made to improve the computational property 
and the interpretability and consistency of the rule with failure.
The following sentence was added as clarification for the exploratory 
analyses: “All exploratory efficacy analyses will be conducted using 
the hypothesis based on the posterior probability that the event ratio, 
r= πv / πp, is ≤1.00.”
The following sentence was added as clarification for the data sets to 
be used for the interim analyses: “All interim analyses of efficacy 
data including futility analyses will include infant subjects who are 
at least 90 days old at the time of the data cutoff date.”
The following sentence was added as clarification for the data sets to 
be used for the secondary and exploratory efficacy analyses: “If the 
study is stopped early for efficacy at an interim analysis, all 
secondary and exploratory efficacy analyses will be performed on the 
final data containing all subjects enrolled and their follow-up.”  
Synopsis (Statistical 
Methods); Sections 3.3.3 and 
10.5
The immunogenicity analyses will now include the proportion of 
maternal subjects with 2-fold and 4-fold increases in antibody levels 
from baseline and the seroresponse rate (SRR) based on anti-RSV F 
IgG, palivizumab-competitive antibody (PCA), and RSV/A and B 
microneutralization (MN) levels. The time-points at which the 
analyses will be performed was also specified. 

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Synopsis (Sample Size); 
Section 10.8 and Table 11
Updated the revised sample size and power calculations using new 
simulations that reflect the minimum requirement for a 3,000 
maternal and infant RSV F vaccine exposures in the safety database 
in order to declare efficacy, the change in the number of interim 
analyses and conduct of the group sequential design, new projected 
enrollment estimates, and changes to the simulation scenarios and 
operating characteristics table. 
Section 10.10.1 
The requirement to have at least 3,000 total maternal subjects 
enrollments into the active treatment arm and at least 6 months of 
post-partum follow-up for their infants in order to perform an interim
efficacy analysis was restated.
General 
Clarified that maternal subjects will record their oral temperature 
daily in the diary. For all other assessments of body temperature in 
maternal and infant subjects, the axillary temperature will be 
collected.
Minor edits and revisions for clarity and readability were made to the 
document.
Protocol Version 5.0, 09 February 2016 (revised from 4.0, 08 January 2016)
The following is a summary of the changes made to this protocol.
Location of Change
Change/Modification in Version 5.0
Synopsis 
(Inclusion/Exclusion 
Criteria); Sections 5.1 and 
5.2
Specified that “clinically significant” adverse reactions to prior 
vaccines would be collected on the medical history (Inclusion 
Criterion [IC] #5). 
Clarification regarding what constitutes alcohol and drug abuse was 
provided in Exclusion Criterion [EC] #15.
EC#19 further clarified the use of low-dose aspirin.  
The term “serious” was added to the description of adverse reactions 
to a vaccine that would exclude a subject from participation in this 
study (EC #30).
Synopsis  (Maternal Subject 
Study Procedures); Sections 
6.1.1.4, 6.1.1.5, 6.1.1.9, and 
7.1; Appendix 1
The Day 7 and 14 visits can also be conducted as home visits. 
Pregnancy testing will be administered to all subjects at the D+180 
visit; subjects with a positive result will be followed to determine the 
outcome of this pregnancy in a separate study. 
Section 6.1.1.3
In addition to alcohol swabbing, vaccination procedures now include 
“cleansing of the area of vaccination” to accommodate local 
standards of care.
Synopsis  (Maternal Subject 
Study Procedures); Sections 
For applicable subjects (i.e., those enrolled in the first year of study 
conduct in any country) who deliver prior to the Day 14 visit, the 

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6.1.1.5, 6.1.1.7, and 7.1; 
Appendix 1
clinical safety laboratory assessment will be performed at the 
Delivery visit. 
Synopsis  (Maternal Subject 
Study Procedures); Sections 
6.1.1.6 and 6.2.1; Appendix 1
Institutional Review Board/Independent Ethics Committee approval 
of telephone scripts is now designated “if applicable” as this is not a 
requirement in all countries where the study is being conducted.  
Synopsis  (Infant Subject 
Study Procedures); Section 
6.1.3; Appendix 1
Every infant study visit will query to determine if other children < 5 
years of age reside in the same household as the infant subject.
Synopsis  (RSV 
Surveillance); Section 6.2.3
The collection methods for sampling of upper respiratory secretions 
were expanded to include nasopharyngeal swab, mid-turbinate swab, 
or nasopharyngeal aspirate for maternal and infant subjects. The 
method(s) selected should now be based on accustomed local 
practice and site expertise.
The option to use RT-PCR test results performed by the local 
laboratory on respiratory specimens as an endpoint for this trial is 
still under consideration. Thus, the following sentence was removed: 
“Conversely, local laboratory results, while informative to the 
clinician, will not be included as an endpoint for this trial.”
The following guidance was provided to investigators to address 
when symptomatic maternal and infant subjects should be evaluated 
for an RSV-suspect illness: “…Trigger Symptoms in infant and 
maternal subjects that persist for a period of ≥ 24 hours, either in a 
continuous or intermittent manner, and are assessed as ‘atypical’ (by 
the maternal subject herself, or a parent or other routine caregiver for 
the infant) in nature.”
Protocol Version 4.0, 08 January 2016 (revised from 3.0, 09 July 2015)
The following is a summary of the changes made to this protocol.
Location of Change
Change/Modification in Version 4.0
Title Page
A short protocol title was added.
Synopsis (Group-Sequential 
Design); Section 3.2
The role of the independent biostatistics group (IBG), the data and 
safety monitoring board (DMSB) statistician, and the DSMB project 
manager in the execution of the group-sequential design was 
clarified.
Synopsis (Safety Endpoint); 
Sections 3.3.4.2 and 10.6
Chorioamnionitis was added to the list of labor and delivery 
complications. 
Section 3.7 
All syringes containing the assigned test article will be masked by 
the unblinded vaccine administrator in order to obscure any 
differences in the appearance of the vaccine and placebo to subjects 
and blinded study staff. 
Synopsis (Inclusion Criteria);  
Section 5.1
Clarified that the earliest ultrasound performed will establish the 
gestation age dating of the pregnancy in cases where multiple 
ultrasounds may be available. 

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Synopsis (Exclusion 
Criteria);  Sections 5.2 and 
7.1
“Known syphilis infection” was added to exclusion criterion (EC) 
#13. Clinical testing for syphilis detection will now be performed at 
the screening visit, if results are not available in prior data collected 
during the course of the current pregnancy.
The “Planned receipt of > 1 dose of any licensed vaccine, such as 
tetanus, diphtheria, pertussis (whole cell or acellular) vaccine or 
tetanus toxoid (TT), hepatitis B vaccine, or influenza vaccine, after 
the screening visit” was removed because it was addressed in EC#4.
History of severe post-partum depression was added to EC#27.
Synopsis (Maternal and 
Infant Study Visits and Time 
and Events Tables); Section 
6.1and Appendix 1 
Maternal subjects and parents/guardians of infant subjects will have 
the option of completing postpartum study visits in-clinic or at home 
to enhance compliance and subject safety follow-up.
Synopsis (Screening Visit); 
Section 6.1.1.2
Clarified the study procedures to state maternal subjects will be 
queried for any AE experienced since informed consent was obtained 
beginning at the screening visit (Day -28 to -2). 
Synopsis (Maternal and 
Infant Unscheduled Visits); 
Sections 6.1.2 and 6.1.4
Clarified when maternal and infant subjects may participate in an 
unscheduled visit and the study procedures that may be performed. 
Synopsis (Infant Subject 
Study D+180 Visit and 
Safety Endpoints, Time and 
Events Table); Sections 
3.3.4.1, 6.1.3.7,  6.1.3.9, and 
8.3.1, Appendix 1 
A new section for the “Ages & Stages Questionnaires®, Third 
Edition (ASQ-3™)” was created. Parents/guardians of infant 
subjects with a positive screen detected at both 6 and 12 months of 
age (as this is an AE), or first appearing at 12 months of age, will be 
offered repeat Ages and Stages Questionnaire (ASQ)-3 screening at 
15 and 18 months of age in a follow-on study. In addition, 
appropriate referrals for diagnostic pediatric developmental testing 
(according to local standards of care) will also be advised for these 
infants. 
The ASQ-3 screening will be performed on all infant subjects.  
Synopsis (RSV Surveillance); 
Section 6.2
Content was reorganized and clarified to harmonize with operational 
activities and to be consistent with supplemental study documents 
(e.g., Study Identification Card, electronic case report forms). A 
“Definitions and Rules for RSV Surveillance” section was also 
added. 
Clarified that maternal and infant subjects with ongoing respiratory 
episodes at the D+180 visit will be followed weekly until symptoms 
have resolved or have returned to baseline.
Section 8.2.3 
The toxicity grades used to assess for severity of clinical laboratory 
parameters will be based on third-trimester values published in 
Sheffield et al. [2013]. Normal ranges for these parameters will also 
be based on reference ranges appropriate for women in the third 
trimester of a pregnancy as described in Sheffield et al.
Sections 8.2.4 and 8.8.1
A toxicity grading scale to assess for severity of an abnormal fetal 
heart tone value was developed and provided in Table 7.

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Section 8.4
In addition to being serious adverse events, hospitalizations will now 
be categorized as medically-attended events.
Section 8.6, Table 5
The term “Intrauterine Growth Restriction or Retardation (IUGR)” 
will now be captured as a separate entity, distinct from “Small for 
Gestation Age (SGA)” as a Maternal/Fetal/Neonatal Adverse Event 
of Special Interest.  
Section 8.7
The procedure for SAE reporting was revised to be compliant with 
Novavax internal standard operating procedures. 
Section 8.8.2
Severity for all unsolicited events reported in infant subjects will be 
based on whether medical intervention/therapy is required (as 
applicable) in addition to interference with daily-activities. 
Synopsis (Statistical 
Methods); Section 10.1 and 
10.4.1
Minor improvements to the descriptions of the intent-to-treat (ITT) 
and modified-ITT Populations were made. Definitions for RSV 
season and RSV episode were deleted from the study definitions list 
in the protocol as these terms are more relevant to the statistical 
analysis.  
General
The term “SaO2” was replaced with “SpO2” as the peripheral 
capillary oxygen content or saturation of the blood will be measured 
by pulse oximetry.  
Oral temperature was routinely replaced with body temperature in 
order to accommodate the various modes of temperature collection 
at the different study sites.  
Minor edits and revisions for clarity and readability were made to the 
document.
Protocol Version 3.0, 09 July 2015 (revised from 2.0, 11 June 2015)
The following is a summary of the changes made to this protocol.
Location of Change
Change/Modification in Version 3.0
Synopsis (Inclusion and 
Exclusion Criteria), Section 5 
Text regarding the methodology for gestational age dating was 
further refined in Inclusion Criterion (IC)#3; while IC#4 will now 
only serve to exclude major fetal anomalies. 
The physical exam will no longer include a gynecologic exam 
(IC#5).  
Fetal growth abnormalities identified by ultrasound are now included 
in Exclusion Criterion (EC)#2, as part of a pregnancy complication. 
Subjects who have received any RSV vaccine (EC#6), have an acute 
disease within 72 hours of the day of vaccination (EC #29), or have 
had an adverse reactions to any prior vaccine (EC#31), will now be 
excluded.
Minor updates were made to EC#2, #4, #12, #17, and #20.
Synopsis (Study Endpoints), 
Sections 3.3.4.1, 3.3.4.2, 
3.3.5, 10.4.2, 10.6, 10.7
The term “proportions” was changed to “percentages” throughout the 
document as this more accurately reflects how relevant safety and 
exploratory analyses will be calculated. 

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Location of Change
Change/Modification in Version 3.0
Synopsis (Pre-screening 
Maternal Study Procedures), 
Sections 6.1.1.1
Clarified that depending on the Institutional Review Board (IRB) or 
Independent Ethics Committee (IEC) having authority, informed 
consent to “pre-screen” and identify pregnant women to contact for 
the main study may or may not be required in order for investigators 
to collect medical information on these individuals. 
Synopsis (Study Procedures 
Schedule), Sections 6.1.1.3, 
6.1.2.1, 6.2, Appendix 1 
Study Identification Cards will be issued to the maternal subject on 
study Day 0 and at delivery and to a parent/guardian of the infant at 
delivery. Replacement cards will be available throughout the study, 
if lost or misplaced. The identification cards will indicate the 
maternal and infant subjects are part of an investigational vaccine 
trial, provide the contact number(s) of the obstetrical or pediatric 
investigator’s study staff, and list the clinical signs and symptoms of 
an RSV infection in adults and infants. The Study Identification 
Cards will replace the RSV informational pamphlet.
Synopsis (RSV Suspect 
Illness Surveillance), 
Sections 6.2, 6.2.1 
Active RSV surveillance will consist of weekly phone calls to the 
maternal subject and the parent/guardian of the infant subject during 
RSV season, which is defined by local epidemiological surveillance 
data. 
The relevant subject population to which each Trigger Symptom
should be assessed was assigned. 
Section 1.2.1
The number of hospitalizations and outpatient visits due to RSV 
among children <5 years of age was updated with new information 
from the Centers for Disease Control and Prevention (CDC).
General
The 120µg dose of the RSV F protein adsorbed to a 0.4mg dose of 
aluminum as the phosphate salt was referenced consistently through 
the protocol as the RSV F vaccine.   
General
Minor edits and revisions for clarity and readability were made to the 
document.
Protocol Version 2.0, 11 June 2015 (revised from 1.0, 20 April 2015)
The following is a summary of the changes made to this protocol.
Location of Change
Change/Modification in Version 2.0
Synopsis, Section 3.1 (Study 
Design), Section 10.8 
(Sample Size)
The planned number of third-trimester pregnant maternal subjects to 
be enrolled into the study was increased from 7,805 to 8,255 (4,128 
active vaccinees and 4,127 placebos) to reflect the proposed increase 
in enrollment in the first year (i.e., from 1,250 to 1,700). 
Synopsis, Sections 1.7, 
Appendix 1 (Maternal Study 
Procedures Schedule)  
The upper limit of the gestational age window for maternal 
immunization of third-trimester pregnant subjects was increased by 
1 week to 360/7 weeks gestation. 
Synopsis (Group Sequential 
Design Strategy), Sections 
3.2 and 10.10.1
The calendar dates at which interim analyses will be performed to 
assess for futility and success at the conclusion of RSV seasons in 
the Northern and Southern hemispheres were specified. Justification 
for selection of these dates and the minimum amount of infant subject 

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Version 10.1 – 12 October 2018
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Location of Change
Change/Modification in Version 2.0
data required for each analysis (i.e., at least 3 months of post-natal 
follow-up) was also provided.   
Synopsis and Section 5.1
The sentence “Ultrasound performed at ≤31 weeks estimated 
gestational age is acceptable” was removed. If the last menstrual 
period is unknown or uncertain, and no prior first or second trimester 
ultrasound has been performed, then an ultrasound performed at 
screening within the second trimester, will be used to establish 
gestational age dating.
Synopsis and Section 10.4.1, 
Table 2
The definition of RSV lower respiratory tract infection (LRTI) was 
further refined. Poor feeding/failure to feed, lethargy, and irritability 
were removed from the list of clinical signs/symptoms to be sought 
for RSV-suspect illness.
Synopsis and Section 10.5
The omission of the SCR analysis for anti-F IgG was corrected. The 
geometric mean ratio (GMR) of cord blood over maternal serum 
(GMRCord/MS) and of infant sera over cord blood (GMRAD/Cord) was 
added as an additional means to assess for transplacental transfer of 
maternal antibodies.  
Synopsis and Section 10.8, 
Table 8
Table 8 (Simulation Scenarios and Operating Characteristics) was 
revised to provide placebo RSV event rates of 0.07% and to adjust 
the mean sample size to conclude efficacy and the mean sample size 
to conclude efficacy and safety (based on 3,000 subjects) for each 
true event ratio based on varying placebo event rates.  The 
cumulative probability of stopping for success by global season was 
also revised based on the new simulation scenarios.
Section 6.5
Clarification was provided regarding how subjects with any SNMC 
or SAE that continues beyond the duration of the study are to be 
followed.   
Section 10.10.1
An interim evaluation of immunogenicity and transplacental 
antibody transfer will be performed by the DSMB statistician for the 
first global season analysis. Details of this analysis and the limited 
communication plan to ensure appropriate protection of the study 
blind will be provided in the statistical analysis plan (SAP), the 
DSMB charter, and the written communication plan.
General
Minor edits and revisions for clarity and readability were made to the 
document.

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