A Phase 3, Randomized, Observer-Blind, Multicenter, Noninferiority Study to Evaluate Safety and Immunogenicity of a Cell-Based Quadrivalent Subunit Influenza Virus Vaccine (QIVc) and a United States Licensed Quadrivalent Influenza Virus Vaccine (QIV) in Healthy Subjects 6 Months Through 47 Months
Phase: PHASE3
Conditions: Influenza, Human, Virus Diseases
Sponsor: Seqirus

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CLINICAL STUDY PROTOCOL V130_10
Version 4.0, dated 09 DEC 19
A Phase 3, Randomized, Observer-Blind, Multicenter, Noninferiority Study to 
Evaluate Safety and Immunogenicity of a Cell-Based Quadrivalent Subunit 
Influenza Virus Vaccine (QIVc) and a United States-licensed Quadrivalent 
Influenza Virus Vaccine (QIV) in Healthy Subjects 6 Months Through 47 Months
A Phase 3 Safety and Immunogenicity Study of QIVc in Healthy Pediatric Subjects
IND number 15744
Property of Seqirus*
Confidential
May not be used, divulged, published or otherwise disclosed without written
consent of Seqirus.
* “Seqirus” includes all legal entities under which the company operates

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Table of Contents
TABLE OF CONTENTS ................................................................................................ 2
LIST OF TABLES .......................................................................................................... 7
PROTOCOL SYNOPSIS V130_10................................................................................. 8
LIST OF ABBREVIATIONS........................................................................................ 25
LIST OF DEFINITIONS............................................................................................... 27
1.
BACKGROUND AND RATIONALE ................................................................. 29
1.1
Background ..................................................................................................... 29
1.2
Rationale ......................................................................................................... 30
2.
OBJECTIVES...................................................................................................... 31
2.1
Primary Immunogenicity Objective ................................................................. 31
2.2
Secondary Immunogenicity Objectives ............................................................ 31
2.3
Secondary Safety Objectives............................................................................ 31
2.4
Exploratory Immunogenicity Objectives.......................................................... 31
3.
STUDY DESIGN................................................................................................. 32
3.1
Overview of Study Design............................................................................... 32
3.2
Study Period .................................................................................................... 33
3.3
Blinding Procedures......................................................................................... 33
3.3.1
Blinding Methods ..................................................................................... 33
3.3.2
Planned Unblinding Procedures ................................................................ 34
3.4
Data Collection................................................................................................ 35
3.4.1
Data Collected from Subjects.................................................................... 35
3.4.2
Tools Used for Data Collection................................................................. 35
3.5
Collection of Clinical Specimens ..................................................................... 37
3.6
Stopping/Pausing Guidelines ........................................................................... 37
3.7
Data Monitoring Committee ............................................................................ 38
3.8
Premature Withdrawal From Study.................................................................. 38
3.9
End of Study.................................................................................................... 40
4.
SELECTION OF STUDY POPULATION........................................................... 41

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4.1
Inclusion Criteria ............................................................................................. 41
4.2
Exclusion Criteria ............................................................................................ 41
4.3
Criteria for Delay of Vaccination..................................................................... 42
5.
STUDY PROCEDURES...................................................................................... 44
5.1
Prevaccination Clinic Visits / Day 1 Prevaccination......................................... 44
5.1.1
Informed Consent ..................................................................................... 44
5.1.2
Screening.................................................................................................. 45
5.1.3
Enrollment................................................................................................ 47
5.1.4
Randomization.......................................................................................... 47
5.1.5 Blood draw ............................................................................................... 48
5.2
Vaccination Clinic Visit(s)............................................................................... 48
5.2.1
Day 1 Postvaccination Procedures (All Subjects) ...................................... 48
5.2.2
Day 29 Prevaccination Procedures (“not previously vaccinated” subjects) 50
5.2.3
Day 29 Postvaccination Procedures (“not previously vaccinated” subjects)51
5.2.4
Postvaccination Reminders ....................................................................... 52
5.3
Postvaccination Visits...................................................................................... 52
5.3.1
Postvaccination Clinic Visits..................................................................... 52
5.3.2
Safety assessment calls ............................................................................. 53
5.4 
Unscheduled Visit(s)........................................................................................ 54
5.5
Study Completion Visit.................................................................................... 54
5.5.1
Early Termination Visit............................................................................. 55
6.
TREATMENT OF SUBJECTS ............................................................................ 56
6.1
Study Vaccine(s).............................................................................................. 56
6.2
Non-Study Vaccines ........................................................................................ 58
6.3
Vaccine Preparation and Administration.......................................................... 58
6.4
Vaccine Administration Error or Overdose of Vaccine..................................... 59
6.5
Prior and Concomitant Medications and Vaccines............................................ 59
6.6
Vaccine Supply, Labeling, Storage and Tracking ............................................. 60
7.
ASSESSMENTS.................................................................................................. 63

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7.1
Safety Assessment ........................................................................................... 63
7.1.1
Solicited Adverse Events .......................................................................... 63
7.1.2
Unsolicited Adverse Events ...................................................................... 65
7.1.3
Evaluation of Adverse Events ................................................................... 66
7.1.4
Serious Adverse Events............................................................................. 68
7.1.4.1 Adverse Events of Special Interest ..................................................... 69
7.1.5
Methods for Recording Adverse Events and Serious Adverse Events........ 69
7.1.5.1 Post-Study Events .............................................................................. 70
7.1.6
Pregnancies............................................................................................... 70
7.1.7
Safety Laboratory Measurements.............................................................. 70
7.2
Efficacy Assessment........................................................................................ 70
7.3
Immunogenicity Assessment............................................................................ 70
8.
STATISTICAL CONSIDERATIONS.................................................................. 74
8.1
Endpoints......................................................................................................... 74
8.1.1
Primary Endpoint(s).................................................................................. 74
8.1.1.1 Primary Safety Endpoints................................................................... 74
8.1.1.2 Primary Efficacy Endpoints................................................................ 74
8.1.1.3 Co-Primary Immunogenicity Endpoints ............................................. 74
8.1.2
Secondary Endpoints................................................................................. 75
8.1.2.1 Secondary Safety Endpoints................................................................. 75
8.1.2.2 Secondary Efficacy Endpoints............................................................ 75
8.1.2.3 Secondary Immunogenicity Endpoints ............................................... 75
8.1.3
Exploratory Endpoints .............................................................................. 76
8.1.3.1
Exploratory Safety Endpoints............................................................ 76
8.1.3.2
Exploratory Efficacy Endpoints......................................................... 77
8.1.3.3
Exploratory Immunogenicity Endpoints ............................................ 77
8.2
Success Criteria ............................................................................................... 77
8.2.1
Success Criteria for Primary Objective(s)................................................. 77
8.2.1.1
Success Criteria for Primary Safety Objective(s) ............................... 77

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8.2.1.2
Success Criteria for Primary Efficacy Objective(s)............................ 77
8.2.1.3
Success Criteria for Primary Immunogenicity Objective(s)................ 77
8.2.2
Success Criteria for Secondary Objective(s)............................................. 78
8.2.2.1
Success Criteria for Secondary Safety Objective(s) ........................... 78
8.2.2.2
Success Criteria for Secondary Efficacy Objective(s)........................ 78
8.2.2.3
Success Criteria for Secondary Immunogenicity Objective(s)............ 78
8.3
Analysis Sets ................................................................................................... 78
8.3.1
All Enrolled Set ........................................................................................ 79
8.3.2
Full Analysis Set....................................................................................... 79
8.3.3
Safety Set.................................................................................................. 79
8.3.4
Evaluable Set – Immunogenicity Analysis ................................................ 79
8.3.5
Per Protocol Set ........................................................................................ 79
8.3.6
Subgroups................................................................................................. 80
8.3.7
Protocol Deviations................................................................................... 80
8.4
Statistical Analysis Plan................................................................................... 81
8.4.1
Analysis of Demographic and Baseline Characteristics ............................. 81
8.4.1.1 Concomitant Medications................................................................... 81
8.4.2
Analysis of Primary Objective(s) .............................................................. 81
8.4.2.1 Analysis of Primary Safety Objective(s)............................................. 81
8.4.2.1.1Analysis of Extent of Exposure .......................................................... 81
8.4.2.1.2Analysis of Solicited Local, Systemic and Other Adverse Events....... 81
8.4.2.1.3Analysis of Unsolicited Adverse Events............................................. 81
8.4.2.1.4Analysis of Safety Laboratory Values ................................................ 82
8.4.2.2 Analysis of Primary Efficacy Objective(s).......................................... 82
8.4.2.2.1
Statistical Hypothesis .................................................................. 82
8.4.2.2.2
Analysis Sets............................................................................... 82
8.4.2.2.3
Statistical Methods...................................................................... 82
8.4.2.3 Analysis of Primary Immunogenicity Objective(s) ............................. 82
8.4.2.3.1
Statistical Hypothesis .................................................................. 82

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8.4.2.3.2
Analysis Sets............................................................................... 84
8.4.2.3.3
Statistical Methods...................................................................... 84
Handling of Missing Values for Immunogenicity Data............................... 85
8.4.3
Analysis of Secondary Objective(s)........................................................... 85
8.4.3.1 Analysis of Secondary Safety Objective(s)......................................... 85
8.4.3.1.1
Analysis of Extent of Exposure ................................................... 85
8.4.3.1.2
Analysis of Solicited Local, Systemic and Other Adverse Events 85
8.4.3.1.3
Analysis of Unsolicited Adverse Events ...................................... 86
8.4.3.1.4
Statistical Hypotheses.................................................................. 87
8.4.3.1.5
Analysis Sets............................................................................... 87
8.4.3.1.6
Statistical Methods...................................................................... 87
8.4.3.2 Analysis of Secondary Efficacy Objective(s)...................................... 87
8.4.3.2.1
Statistical Hypothesis .................................................................. 87
8.4.3.2.2
Analysis Sets............................................................................... 87
8.4.3.2.3
Statistical Methods...................................................................... 87
8.4.3.3 Analysis of Secondary Immunogenicity Objective(s) ......................... 87
8.4.3.3.1
Statistical Hypotheses.................................................................. 89
8.4.3.3.2
Statistical Methods...................................................................... 89
8.4.4
Analysis of Exploratory Objectives........................................................... 89
8.4.4.1 Analysis of Exploratory Safety Objectives ......................................... 89
8.4.4.2 Analysis of Exploratory Efficacy Objectives ...................................... 89
8.4.4.3 Analysis of Exploratory Immunogenicity Objectives.......................... 90
8.5
Sample Size and Power Considerations............................................................ 90
8.6
Interim Analysis .............................................................................................. 91
9.
SOURCE DOCUMENTATION, STUDY MONITORING AND AUDITING ..... 93
9.1
Source Documentation..................................................................................... 93
9.2
Study Monitoring, Auditing and Source Data Verification ............................... 94
10.
DATA MANAGEMENT ..................................................................................... 95
10.1 Data Entry and Management............................................................................ 95

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10.2 Data Clarification ............................................................................................ 95
10.3 Data Protection ................................................................................................ 95
11.
RECORD RETENTION....................................................................................... 96
12.
USE OF INFORMATION AND PUBLICATION................................................ 97
13.
ETHICAL CONSIDERATIONS.......................................................................... 98
13.1 Regulatory and Ethical Compliance ................................................................. 98
13.2 Informed Consent Procedures .......................................................................... 98
13.3 Responsibilities of the Investigator and IRB..................................................... 99
13.4 Protocol Amendments.................................................................................... 100
14.
REFERENCE LIST............................................................................................ 101
List of Tables
Table 1-1
Time and Events Table – Previously Vaccinated Subjects...........23
Table 1-2
Time and Events Table – Not Previously Vaccinated Subjects....24
Table 5-1
Study Procedures........................................................................44
Table 6.1-1
QIVc Vaccine Composition ........................................................57
Table 7.3-1
Percentage of Subjects in the Immunogenicity Group Evaluation of 
Cell- and Egg-Derived Target Virus............................................72
Table 7.3-2
Priority Ranking of Serology Testing in Study V130_10.............73
Table 8.5-1
Summary of Assumptions Used for Sample Size Calculations ....91

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PROTOCOL SYNOPSIS V130_10
Name of Sponsor:
Seqirus
Protocol number:
V130_10
Generic name of study vaccine(s):
Cell-Based Quadrivalent Subunit 
Influenza Virus Vaccine (QIVc)
US-licensed Egg-Based 
Quadrivalent Influenza Vaccine 
(QIV)
Title of Study: 
A Phase III, Randomized, Observer-Blind, Multicenter, Noninferiority Study to Evaluate 
Safety and Immunogenicity of a Cell-Based Quadrivalent Subunit Influenza Virus 
Vaccine (QIVc) and a United States-licensed Quadrivalent Influenza Vaccine (QIV) in 
Healthy Subjects  6 Months through 47 Months
Study Period: Approximately 180 days (6 months) 
after last vaccination date 
Clinical Phase:
Phase 3
Background and Rationale: 
Influenza is an infectious disease caused by the influenza virus, an orthomyxovirus with 
two clinically relevant types (Type A and B). Influenza Type A/H1N1, A/H3N2, and 
Type B/Victoria and B/Yamagata strains have circulated and caused disease in humans 
on a global basis since 1977 (Fiore et al. 2010), with a high susceptibility to severe 
influenza in children (Izurieta et al. 2000; Bourgeois et al. 2006). Children <5 years, and 
particularly those <2 years of age, are at high risk of infection and are a priority for 
annual seasonal influenza vaccination throughout the world (World Health 
Organization[WHO] 2012; American Academy of Pediatrics Commitee on Infectious 
Diseases 2016). With vaccination as the recommended method to prevent influenza, both 
childhood influenza disease burden and community viral transmission could be reduced 
(Mertz et al. 2016).
One of the challenges of protecting children against influenza is providing a vaccine 
with an antigenic match against the circulating strains in a given influenza season. Since 
1983, two evolutionarily distinct lineages of influenza B viruses have co-circulated in 
the human population globally (Rota, 1990) and influenza B viruses account for roughly 
20% of total influenza events in all regions of the world (Ciani et al. 2015). As only one 
B lineage is selected for inclusion in current trivalent influenza vaccines (TIVs) and 

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Name of Sponsor:
Seqirus
Protocol number:
V130_10
Generic name of study vaccine(s):
Cell-Based Quadrivalent Subunit 
Influenza Virus Vaccine (QIVc)
US-licensed Egg-Based 
Quadrivalent Influenza Vaccine 
(QIV)
there has been no demonstrated cross protection between the two lineages (Peltola et al.
2003; Hu et al. 2004), there is the risk of a mismatch for the influenza B strain (Couch 
2007; Belshe, 2010; Orsi et al. 2018). Since patients infected with influenza B are 
usually younger than patients infected with influenza A, the effectiveness of vaccination 
in children seems more dependent on adequate matching (Jayasundara et al. 2014; Ciani
et al. 2015; Orsi et al. 2018). To address this problem, quadrivalent influenza vaccines 
(QIV) have been developed containing B strains from both lineages. 
Seqirus’ Flucelvax Quadrivalent (QIVc) is a cell based quadrivalent inactivated subunit 
influenza vaccine prepared from virus propagated in Madin Darby Canine Kidney 
(MDCK) cells, and approved by the Food and Drug Administration (FDA) for use in 
children 4 years and older. QIVc has a formulation with two influenza A strains and two 
influenza B strains updated annually as recommended by the WHO for a specific 
influenza season, and addresses the unmet medical need of better vaccine antigenic 
matching against co-circulating influenza B strains. A shift from egg- to cell-culture based 
manufacturing platforms has several advantages, allowing for the possibility to work 
directly with wild-type viruses, avoiding the generation of egg-adaptive mutations in the 
HA protein, increasing surge capacity in the event of a pandemic, and providing better 
manufacturing control through a closed-system fermentation process (Lambert and Fauci
2010).
The purpose of this study is to demonstrate that vaccination with QIVc elicits an 
immune response that is not inferior to that of a United States (US)-licensed QIV 
containing the recommended strains for the season, in children 6 months through 
47 months of age. 
The data from this study will be used to support the licensure of QIVc for use in children 
6 months through 47 months of age.

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Study Objectives:
Immunogenicity Objectives
The immunogenicity objectives will be evaluated based on antibody responses against 
all strains 4 weeks after last vaccination in subjects 6 months through 47 months of age.
Primary Immunogenicity Objective:
1. To demonstrate that vaccination with QIVc elicits an immune response that is 
not inferior to that of a US-licensed QIV, in subjects 6 months through 
47 months of age, as measured by hemagglutination inhibition (HAI) assay for 
A/H1N1, B/Yamagata and B/Victoria strains and by microneutralization 
(MN) assay for A/H3N2 strain, using cell-derived target viruses
Secondary Immunogenicity Objectives:
1. To describe the immunogenicity of QIVc and US-licensed QIV by HAI assay
for A/H1N1, B/Victoria, and B/Yamagata strains, and by MN assay for 
A/H3N2 strain, using egg-derived target viruses
2. To describe the immunogenicity of QIVc and US-licensed QIV by HAI assay 
for A/H1N1, B/Victoria, and B/Yamagata strains and by MN assay for 
A/H3N2 strain, using cell-derived target viruses
3. To describe the immunogenicity of QIVc and US-licensed QIV by MN assay for 
A/H1N1, B/Victoria, and B/Yamagata strains, in a subset of subjects
Secondary Safety Objective:
1. To evaluate the safety and reactogenicity of QIVc and US-licensed QIV
Exploratory Immunogenicity Objectives:
1. To evaluate the homologous cell-mediated immunity (CMI) response, 
prevaccination and postvaccination, in a small population of subjects
2. To further describe the immune response to vaccination, additional 
immunogenicity analyses may be conducted such as HAI assay for A/H3N2
using cell- and egg-derived target virus

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Name of Sponsor:
Seqirus
Protocol number:
V130_10
Generic name of study vaccine(s):
Cell-Based Quadrivalent Subunit 
Influenza Virus Vaccine (QIVc)
US-licensed Egg-Based 
Quadrivalent Influenza Vaccine 
(QIV)
Study Design: 
This phase 3 clinical study is a randomized, observer-blind, comparator controlled, 
multicenter study of QIVc versus a US-licensed QIV in children 6 months through 
47 months of age. The study features a 2:1 randomization between QIVc and 
US-licensed QIV. Based on influenza vaccination history, subjects will receive either 1
or 2 doses of either QIVc or US-licensed QIV comparator (see Table 1-1 for previously 
vaccinated subjects and Table 1-2 for not previously vaccinated subjects). The study will 
be conducted in approximately 2502 healthy subjects: 2418 subjects for evaluation of 
immunogenicity and 84 subjects for evaluation of CMI response.
The study has a treatment period and a follow-up period. For subjects with a previous 
influenza vaccination history, the treatment period begins at the time of vaccination and 
ends 28 days after vaccination and will consist of 2 clinical visits and 1 reminder call to 
complete the Subject Diary Card. The follow up period begins 28 days after vaccination 
and ends at the time of the study completion visit (180 days after last vaccination). For 
subjects without or unknown previous influenza vaccination history, the treatment 
period begins at the time of first vaccination and ends 28 days after the second 
vaccination and will consist of 3 clinical visits and 2 reminder calls to complete the 
Subject Diary Card, one after each vaccination. The follow up period begins 28 days 
after second vaccination and ends at the time of the study completion visit. All subjects, 
irrespective of previous influenza vaccination history, will receive 1 safety assessment 
call 90 days after last vaccination during the follow up period and the follow-up period 
will conclude with a study completion visit (call). 
The final analysis of the primary and secondary immunogenicity endpoints will be 
conducted on cleaned and locked data once all subjects have completed all 
immunogenicity assessments (end of treatment period, i.e. up to 28 days following the 
last vaccination dose). At this time, the analysis of all solicited adverse events and of 
unsolicited adverse events reported during the treatment period will also be conducted. 
These results will be used to prepare a Clinical Study Report (CSR) with treatment 
period data. No individual unblinded listings will be generated at this stage. 

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Name of Sponsor:
Seqirus
Protocol number:
V130_10
Generic name of study vaccine(s):
Cell-Based Quadrivalent Subunit 
Influenza Virus Vaccine (QIVc)
US-licensed Egg-Based 
Quadrivalent Influenza Vaccine 
(QIV)
A final CSR will present all clinical study data collected up to 180 days following the last 
vaccination dose, including safety data collected during the follow up period.
Number of Subjects planned:
In this study a total of approximately 2502 healthy subjects will be enrolled: 2418 
subjects for evaluation of immunogenicity and 84 subjects for assessment of CMI
response.
For immunogenicity evaluation approximately 2418 subjects will be enrolled, in order to 
have approximately 1450 evaluable subjects in the QIVc group and 725 evaluable 
subjects in the US-licensed QIV group (considering 10% drop-out rate). The subjects 
will be randomized to 1 of 2 vaccine groups in a ratio of 2:1 (Seqirus QIVc:
comparator QIV).
Stratification through Interactive Response Technology (IRT) will be used to ensure a 
balanced distribution among the age groups, at least 30% of subjects should be 6 through 
23 months and at least 30% of subjects should be from 24 through 47 months of age.
For evaluation of cell-mediated immune (CMI) response, approximately 84 subjects 
between 24 through 47 months of age will be enrolled in order to have approximately 50 
evaluable subjects in the QIVc group and approximately 25 evaluable subjects in the 
US-licensed QIV group. The subjects will be randomized to 1 of 2 vaccine groups in a 
ratio of 2:1 (Seqirus QIVc: comparator QIV).
Study Population and Subject Characteristics: 
This study will enroll healthy children 6 months through 47 months of age from the 
United States during one influenza season. The list of inclusion and exclusion criteria is 
included in protocol Section 4, Selection of Study Population.

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Name of Sponsor:
Seqirus
Protocol number:
V130_10
Generic name of study vaccine(s):
Cell-Based Quadrivalent Subunit 
Influenza Virus Vaccine (QIVc)
US-licensed Egg-Based 
Quadrivalent Influenza Vaccine 
(QIV)
Study Procedures:
Written informed consent must be obtained prior to performing any study-related 
procedures. The informed consent process may be conducted up to 10 days before day of 
vaccination (Day 1). 
After signing of the informed consent by the subject’s parent(s)/legally acceptable 
representative (LAR) and undergoing review of the reported medical history, physical 
examination, review of current and prior medications and vaccinations, and confirmation 
of subject eligibility, subjects will be enrolled into the study. 
The study has a treatment period and a follow-up period. The treatment period has 
scheduled visits planned depending on the subject’s influenza vaccination history and 
age of the subject and ends 28 days after last vaccination. The follow-up period will 
conclude with a study completion call. 
Treatment period: 
After vaccination, all subjects will remain under medical supervision and will be 
monitored for any immediate postvaccination reactions for at least 30 minutes. Local 
solicited adverse reactions and systemic solicited adverse events will be collected from 
30 minutes after vaccination on a Subject Diary Card, and collection will continue for a 
total of 7 Days. Three (3) days after vaccination parent(s)/LAR(s) will receive a 
reminder call to complete the Subject Diary Card. Any unsolicited AE and concomitant 
medication will be collected until 28 days after each vaccine dose. 
Blood samples for serology will be collected prior to vaccination (Day 1) and 28 days 
after last vaccination at scheduled clinic visits for immunogenicity evaluation or to
evaluate CMI response. 
The collection of body temperature, solicited local adverse reactions, solicited systemic
adverse events will continue for a total of 7 days on the Diary Card. Training will be 
provided for the individual(s) who will perform the measurements of local reactions and 

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Name of Sponsor:
Seqirus
Protocol number:
V130_10
Generic name of study vaccine(s):
Cell-Based Quadrivalent Subunit 
Influenza Virus Vaccine (QIVc)
US-licensed Egg-Based 
Quadrivalent Influenza Vaccine 
(QIV)
body temperature (often a parent(s)/LAR(s)), and for those who will enter the 
information into the Subject Diary Card. 
Follow-up period: 
During the follow-up period, safety data including adverse events (AEs) leading to 
withdrawal, New Onset of Chronic Diseases (NOCDs), Serious Adverse Events (SAEs), 
and all medications used related to these events will be captured at 90 days and 180 days 
after last vaccination. 
Study completion:
The study will conclude with a study completion call 180 days after last vaccination. 

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Name of Sponsor:
Seqirus
Protocol number:
V130_10
Generic name of study vaccine(s):
Cell-Based Quadrivalent Subunit 
Influenza Virus Vaccine (QIVc)
US-licensed Egg-Based 
Quadrivalent Influenza Vaccine 
(QIV)
Study Vaccines:
Both QIVc and the US-licensed QIV will be administered intramuscularly (IM), in the 
anterolateral aspect of the thigh or into the deltoid muscle. For both QIVc and 
US-licensed QIV, either 1 or 2 doses will be administered depending on each subject’s 
influenza vaccination history. If 2 vaccinations are given, the administration interval will 
be approximately 28 days. 
Study vaccine:
A dose of 0.5 mL of QIVc (Flucelvax Quadrivalent) contains purified 15 µg viral 
envelope-glycoprotein hemagglutinin (HA) of each of the four (4) influenza strains 
recommended by WHO for inclusion in the quadrivalent vaccine formulation for the 
influenza season corresponding to the season of conduct of study. 
Comparator vaccine:
Afluria Quadrivalent will be administered as the US-licensed QIV comparator, 
following dose recommendations described in the US Package Insert (USPI). 
Subjects 6 months through 35 months of age will receive 0.25 mL (1 or 2 doses, 
depending on influenza vaccination history), while subjects 36 months through 47 
months of age will receive 0.5 mL (1 or 2 doses, depending on influenza vaccination 
history). 
Immunogenicity Endpoint
Immunogenicity of study vaccines will be evaluated at Day 1 and Day 29 for “previously 
vaccinated” subjects or Day 1 and Day 57 for “not previously vaccinated” subjects.

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Primary Immunogenicity Endpoints
Serum HAI antibody titer against A/H1N1, B/Victoria and B/Yamagata vaccine strains 
at Day 29/57, using cell-derived target virus:

Geometric Mean Titer (GMT) by HAI assay

Seroconversion rate (SCR) defined as the percentage of subjects with either a 
prevaccination HAI titer <1:10 and a postvaccination HAI titer ≥1:40, or a 
prevaccination HAI titer ≥1:10 and a ≥4-fold increase in postvaccination HAI
titer
Serum neutralizing antibody titer against A/H3N2 vaccine strain at Day 29/57, using 
cell-derived target virus:

GMT by MN assay

SCR defined as the percentage of subjects with either a prevaccination MN titer 
<1:10 (Lower Limit Of Quantification [LLOQ]) and a postvaccination MN titer 
≥1:40 (4*LLOQ), or a prevaccination MN titer ≥1:10 (LLOQ) and a ≥4-fold 
increase in postvaccination MN titer
Derived Variables:

The GMT ratio (QIV/QIVc) for each strain

The inter-group difference in the SCRs (QIV minus QIVc) for each strain
The noninferiority of QIVc compared to US-licensed QIV will be assessed for the eight 
co-primary endpoints of GMT and SCR for each cell-derived target virus strain included 
in QIVc as follows:

The GMT ratio for the A/H1N1 strain (HAI assay)

The GMT ratio for the A/H3N2 strain (MN assay)

The GMT ratio for the B Yamagata strain (HAI assay)

The GMT ratio for the B Victoria strain (HAI assay)

The difference between the SCRs for the A/H1N1 strain (HAI assay)

The difference between the SCRs for the A/H3N2 strain (MN assay)

The difference between the SCRs for the B Yamagata strain (HAI assay)

The difference between the SCRs for the B Victoria strain (HAI assay)
Secondary Immunogenicity Endpoints:
Humoral immune response in terms of HAI antibodies against A/H1N1, B/Victoria and 
B/Yamagata strains, using cell- and egg-derived target virus:

GMT by HAI assay at Days 1 and 29/57

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
Geometric Mean Ratio (GMR), defined as the fold increase in serum HAI GMT
postvaccination (Day 29/57) compared to prevaccination (Day 1)

Seropositivity rates (percentages of subjects with HAI titer ≥1:10) at Days 1 and 
29/57

Percentages of subjects with HAI titer ≥1:40 at Days 1 and 29/57

SCR by HAI assay
Derived variables:

The GMT ratio (QIV/QIVc) for each strain

The inter-group difference in the SCRs (QIV minus QIVc) for each strain
Neutralizing antibody titers against A/H3N2 vaccine strains, using cell- and egg-derived 
target virus:

GMT by MN assay at Days 1 and 29/57

GMR, defined as the fold increase in serum MN GMT postvaccination (Day 
29/57) compared to prevaccination (Day 1)

Seropositivity rates (percentages of subjects with MN titer ≥ 1:10 (LLOQ)) at 
Days 1 and 29/57

SCR by MN assay
Derived variables:

The GMT ratio (QIV/QIVc) for A/H3N2 strain

The inter-group difference in the SCRs (QIV minus QIVc) for A/H3N2 strain
Neutralizing antibody titers against A/H1N1, B/Victoria and B/Yamagata vaccine 
strains, in a subset of subjects:

GMT by MN assay at Days 1 and 29/57

GMR, defined as the fold increase in serum MN GMT postvaccination (Day 
29/57) compared to prevaccination (Day 1)

Seropositivity rates (percentages of subjects with MN titer ≥ 1:10 (LLOQ)) at 
Days 1 and 29/57

SCR by MN assay
Derived variables:

The GMT ratio (QIV/QIVc) for each strain

The inter-group difference in the SCRs (QIV minus QIVc) for each strain

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Name of Sponsor:
Seqirus
Protocol number:
V130_10
Generic name of study vaccine(s):
Cell-Based Quadrivalent Subunit 
Influenza Virus Vaccine (QIVc)
US-licensed Egg-Based 
Quadrivalent Influenza Vaccine 
(QIV)
Secondary Safety Endpoints: 
The measures for assessing safety and reactogenicity are as follows:
1. Percentage of subjects with solicited AEs within 7 days after each study 
vaccination
2. Percentage of subjects with any unsolicited AEs from Day 1 to Day 29 (in
previously vaccinated subjects) and from Day 1 to Day 57 (in not previously 
vaccinated subjects)
3. Percentage of subjects with any SAEs, NOCDs, AEs leading to withdrawal
during the entire study period (ie, from Day 1 to Day 181 for previously 
vaccinated subjects or from Day 1 to Day 209 for not previously vaccinated 
subjects)
Exploratory Immunogenicity Endpoint(s):
For CMI evaluation, CD4+ T-cell responses will be measured by staining and flow 
cytometry at baseline (Day 1), and Day 29 (previously vaccinated subjects) or Day 57 
(not previously vaccinated subjects), as measured by number of cells expressing 
interferon gamma (IFN-γ), interleukin 2 (IL-2), tumor necrosis factor alpha (TNF-α),
and other markers as may be practical within the available volumes of blood/cells.
In case of additional exploratory immunogenicity analyses, the immune response will be 
further characterized similar to the analysis of secondary immunogenicity endpoints.
Statistical Analyses
General Statistical Considerations:
In general, summary descriptive statistics of continuous data will be presented as 
number of observations, mean, standard deviation, median, minimum and maximum. 
For categorical variables, statistical summaries will include counts and percentages 
relative to the appropriate population. 

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Name of Sponsor:
Seqirus
Protocol number:
V130_10
Generic name of study vaccine(s):
Cell-Based Quadrivalent Subunit 
Influenza Virus Vaccine (QIVc)
US-licensed Egg-Based 
Quadrivalent Influenza Vaccine 
(QIV)
Binary data (ie, percentages of subjects with seroconversion [SC]) will be summarized 
for each group using unadjusted estimates and will be reported together with two-sided 
exact 95% CIs (Clopper-Pearson). 
The difference between the proportions of treatment groups will be determined and the 
corresponding two-sided 95% CIs calculated by Miettinen-Nurminen method. 
Safety parameters analysis: descriptive statistic on the number (and percentage) of 
subjects reporting AEs will be calculated.

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Primary Immunogenicity Analysis:
The noninferiority of QIVc compared to the US-licensed QIV will be assessed by HAI 
GMT and HAI Seroconversion rates against cell-derived target viruses for A/H1N1, 
B/Victoria and B/Yamagata strains and by MN GMT and MN seroconversion rates
against cell-derived target virus for H3N2 strain. All eight primary hypotheses need to 
be met in order to demonstrate noninferiority.
Specifically, QIVc will be considered to be noninferior to the US-licensed QIV if, for 
each of the four strains, the following statistical criteria are met: 
A/H1N1 and B strains: 

The upper bound of the two-sided 95% confidence interval (CI) on the ratio of 
the HAI GMTs does not exceed 1.5. The HAI GMT ratio will be calculated as 
HAI GMT US-licensed comparator QIV divided by HAI GMT QIVc.

The upper bound of the two-sided 95% CI on the difference between the HAI 
SCR does not exceed 10%. The HAI SCR difference will be calculated as HAI 
Seroconversion US-licensed comparator QIV minus HAI Seroconversion 
QIVc. The 95% CI will be computed based on the binomial distribution.
A/H3N2 strain only:

The upper bound of the two-sided 95% CI on the ratio of the MN GMT does not 
exceed 1.5. The MN GMT ratio will be calculated as MN GMT US-licensed 
comparator QIV divided by MN GMT QIVc. 

The upper bound of the two-sided 95% CI on the difference between the MN 
SCRs does not exceed 10%. The MN SCR difference will be calculated as MN 
Seroconversion US-licensed comparator QIV minus MN Seroconversion 
QIVc. The 95% CI will be computed based on the binomial distribution.
To determine the GMT ratio, a general linear model (GLM) will be fitted on log-
transformed postvaccination HAI (or MN) titers and terms for covariates (with further 
details specified in the protocol and Statistical Analysis Plan [SAP]). 
From the model an adjusted difference in least-square means (on the log scale) will be 
produced with 95% confidence limits. The estimated difference and the confidence 
limits will be back-transformed to obtain an adjusted GMT ratio with 95% confidence 
limits. Each of the 4 strains will be analysed separately. The adjusted GMT ratio will 
be the result for which the noninferiority assessment will be based on.

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Secondary Immunogenicity Analysis:
Secondary immunogenicity analyses of GMT, GMRs, seropositivity rates, percentages 
of subjects with HAI titer ≥ 1:40, SCRs, GMT ratios, and SCR differences will be 
carried out in a similar fashion as in the primary immunogenicity analyses.
Statistical Considerations for Sample Size Calculations 
QIVc will be tested against comparator, ie, US-licensed comparator QIV. The treatment 
randomization ratio is 2:1 (Seqirus QIVc: Comparator QIV). This study is designed to 
achieve at least 90% power to demonstrate noninferiority for all of the 8 endpoints: 
seroconversion rates for 4 strains and GMT ratios for 4 strains using a one-sided alpha of 
0.025 for each comparison. No alpha adjustment for multiple endpoints needs to be 
made. 
For comparisons of SCRs, a noninferiority margin of 10% (Comparator QIV-Seqirus 
QIVc) will be employed. It is assumed that the SCRs for A/ H1N1, B strains,  and 
A/H3N2 based on TIVc are 81%, 69% and 85%, respectively. These estimates are based 
on the historical data, namely from study V58P16.
It is also assumed that the expected differences between antibody titers (QIVc minus 
QIV) are consistent with the SCR differences reported as per V58P16, namely 7% for 
A/H1N1 and 5% for A/H3N2 (based on the MN assay). It is assumed there is no 
difference between Seqirus QIVc and the comparator QIV for the B strain.
For comparison of GMT ratios, a noninferiority margin of 1.5 (Comparator QIV/ Seqirus 
QIVc, equivalent to a difference on the log scale of 0.405465108) will be employed. It is 
assumed that the GMT ratios for A/ H1N1, A/ H3N2, and B strains for QIVc/QIV are 
1.49 for the A/H1N1, 1.00 for the A/H3N2 (based on the MN Assay), and 0.84 for the B 
strains. These GMT ratio estimates are consistent with those observed in study V58P16. 
It is assumed that the standard deviation of log (titer) is 1.3.
Under these assumptions and with n evaluable = 1450 in the Seqirus QIVc group and 
725 in the Comparator QIV the power for 4 GMT ratio endpoints is 94.90 % and the 
power for 4 SCR endpoints is 99.40%. The overall global power of the 8 endpoints is 
then 94.90%*99.40% = 94.33%. This provides a total N evaluable = 2175. Allowing for 
a 10% drop-out, N=2418 subjects will be recruited for immunogencity evaluation.
Approximately 84 additional subjects between 24 through 47 months of age, in order to 
have approximately 50 evaluable subjects who received QIVc and approximately 25 
evaluable subjects who received US-licensed QIV, will be enrolled to assess CMI 
response. Thus, a total of approximately 2502 subjects will be enrolled in this study.

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Name of Sponsor:
Seqirus
Protocol number:
V130_10
Generic name of study vaccine(s):
Cell-Based Quadrivalent Subunit 
Influenza Virus Vaccine (QIVc)
US-licensed Egg-Based 
Quadrivalent Influenza Vaccine 
(QIV)
Sample size calculations were performed using PASS v12.0.02. 
Success Criteria for the Primary Immunogenicity Objectives:
The study is considered successful if all of the 8 co-primary endpoints are achieved.
Further details regarding the analysis of the secondary and exploratory objectives will be 
fully described in the SAP.
Interim Analysis: 
The final analysis of the primary and secondary immunogenicity endpoints will be 
conducted on cleaned and locked data once all subjects have completed all 
immunogenicity assessments (end of treatment period, i.e. up to 28 days following the last 
vaccination dose). At this time, the analysis of all solicited adverse events and of 
unsolicited adverse events reported during the treatment period will also be conducted. 
These results will be used to prepare a Clinical Study Report (CSR) with treatment period 
data. No individual unblinded listings will be generated at this stage. 
A final CSR will present all clinical study data collected up to 180 days following the 
last vaccination dose, including safety data collected during the follow up period.
Data Monitoring Committee:
A Data Monitoring Committee (DMC) will be not utilized for the study.

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LIST OF ABBREVIATIONS
NOCD
New Onset of Chronic Disease
PFS
Pre-filled Syringes
AE
Adverse Event
BLA 
Biologics License Application
CBER
Center for Biologics Evaluation and Research
CHMP
Committee for Medicinal Products for Human Use
CI
Confidence Interval
CMI
Cell Mediated Immunity
CRF
Case Report Form
CRO
Contract Research Organization
CSR
Clinical Study Report 
DMC
Data Monitoring Committee
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
EMA
European Medicines Agency
ESP
External Service Provider
FAS
Full Analysis Set
FDA
Food and Drug Administration
GLM
General Linear Model
GMR
Geometric Mean Ratio
GMT
Geometric Mean Titer
HA
Hemagglutinin 
HAI
Hemagglutination Inhibition
HIPAA
Health Insurance Portability and Accountability Act 
IB
Investigator’s Brochure
ID
Identification
ICF
Informed Consent Form
ICH
International Conference on Harmonization
IM
Intramuscular
IRB
Institutional Review Board
IRT
Interactive Response Technology
LAR
Legally Acceptable Representative(s)
LLOQ
Lower Limit of Quantification
LSLV
Last Subject Last Visit
MDCK
Madin Darby Canine Kidney 
MedDRA
Medical Dictionary for Regulatory Activities
MN
Microneutralization
NA
Neuraminidase
NI
Noninferiority

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PPS
Per Protocol Set
QIVc
Cell-derived Quadrivalent Influenza Vaccine
QIV
Quadrivalent Influenza Vaccine
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
sBLA
Supplement Biologics License Application
SC 
Seroconversion
SCR
Seroconversion Rate
SDA
Source Document Agreement
SOC
System Organ Class
SOP
Standard Operating Procedure
TIV
Trivalent Influenza Vaccine
USPI
US Package Insert
WHO
World Health Organization

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LIST OF DEFINITIONS
Any Type A and/or B strain: Defined as any strains included in the vaccine, ie, Type A 
(A/H1N1 or A/H3N2) and/or Type B
Follow-up period: The follow-up period starts for subjects 28 days after last vaccination and 
continues up to study completion visit, defined as end of influenza season but at least 180 
days after last vaccination date.
End of Study: End of study is defined as the completion of the Last Subject Last Visit 
(LSLV), i.e, the last subject’s Day 181 or Day 209 safety assessment call, or the completion 
of testing of biological samples to be achieved no later than 8 months after LSLV, whichever 
is longer
Geometric Mean Titer ratio (GMT ratio): Defined as the geometric mean of the post 
vaccination (28 days after last vaccination) HAI titer for the US-licensed QIV over the 
geometric mean of the post vaccination HAI titer for QIVc.
Legally Acceptable Representative (LAR): An individual or other body authorized under 
applicable law to consent, on behalf of a prospective subject, to the subject's participation in 
the clinical trial (see International Conference on Harmonisation-Good Clinical Practice 
[ICH-GCP], ICH E6 (R2)).
Lower limit of quantitation (LLOQ) :  The lowest amount of analyte in a sample which can 
be quantitatively determined with suitable precision and accuracy.
Not previously influenza vaccinated subject: A subject that has not received 2 or more 
doses of influenza vaccine prior to the current influenza season, or who does not know the 
influenza vaccination history.
Previously influenza vaccinated subject: A subject with a known history of at least 
2 influenza doses prior to the current influenza season.
Qualified healthcare professional: Any licensed health care professional who is permitted 
by institutional policy to perform clinical interventions and assessments such as physical 
examinations, is trained on the study procedure(s) and who is identified within the site 
signature and delegation log.
Seroconversion Rate (SCR) based on the HAI assay: Seroconversion rate (SCR) defined 
as the percentage of subjects with either a prevaccination hemagglutinin inhibition (HAI)
titer <1:10 and a postvaccination HAI titer ≥1:40, or a prevaccination HAI titer ≥1:10 and a 
≥4-fold increase in post vaccination HAI titer.

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Seroconversion rates (SCRs) based on the Microneutralization (MN) Assay:  SCR is the 
percentage of subjects with either a prevaccination MN titer <1:10 (LLOQ) and a 
postvaccination MN titer ≥1:40 (4*LLOQ), or a prevaccination MN titer ≥1:10 (LLOQ) and 
a ≥4-fold increase in postvaccination MN titer.
Solicited adverse events:  Either solicited local adverse reactions or solicited systemic 
adverse reactions.
Trained healthcare professional: Any health care professional who is permitted by 
institutional policy, trained to perform delegated tasks, is trained on the study procedure(s) 
and who is identified within the site signature and delegation log.
Treatment period: Per protocol treatment period begins at the time of vaccination and ends 
28 days after last vaccination, which is visit 2 for previously influenza vaccinated subjects 
and at visit 3 for not-previously influenza vaccinated subjects.

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1.
BACKGROUND AND RATIONALE
1.1
Background
Influenza is an infectious disease caused by the influenza virus, an orthomyxovirus with 
two clinically relevant types (Type A and B). The disease is characterized by the abrupt 
onset of respiratory and systemic symptoms, such as fever, cough, sore throat and rhinitis. 
It occurs in epidemics throughout the northern and southern hemisphere winter months in 
temperate climates. Influenza Type A/H1N1, A/H3N2, and Type B/Victoria and 
B/Yamagata strains have circulated and caused disease in humans on a global basis since 
1977 (Fiore et al. 2010), with a high susceptibility to severe influenza in children (Izurieta
et al. 2000; Bourgeois et al. 2006). Children <5 years, and particularly those <2 years of 
age, are at high risk of infection and are a priority for annual seasonal influenza 
vaccination throughout the world (World Health Organization [WHO] 2012; American 
Academy of Pediatrics Committee on Infectious Diseases 2016). With vaccination as the 
recommended method to prevent influenza, both childhood influenza disease burden and 
community viral transmission could be reduced (Mertz et al. 2016).
One of the challenges of protecting children against influenza is providing a vaccine with 
an antigenic match against the circulating strains in a given influenza season. Since 1983, 
two evolutionarily distinct lineages of influenza B viruses have co-circulated in the 
human population globally (Rota 1990) and influenza B viruses account for roughly 20% 
of total influenza events in all regions of the world (Ciani et al. 2015). As only one B 
lineage is selected for inclusion in current trivalent influenza vaccines (TIVs) and there 
has been no demonstrated cross protection between the two lineages (Peltola et al. 2003; 
Hu et al. 2004), there is the risk of a mismatch for the influenza B strain (Couch, 2007; 
Belshe, 2010; Orsi et al. 2018). Since patients infected with influenza B are usually 
younger than patients infected with influenza A, the effectiveness of vaccination in 
children seems more dependent on adequate matching (Jayasundara et al. 2014; Ciani et 
al. 2015; Orsi et al. 2018). To address this, quadrivalent influenza vaccines (QIV) were 
developed containing B strains from both lineages.
Seqirus’ Flucelvax Quadrivalent, is a cell based quadrivalent inactivated subunit influenza 
vaccine (QIVc) prepared from virus propagated in Madin Darby Canine Kidney (MDCK) 
cells, and approved by the Food and Drug Administration (FDA) for use in children
4 years and older. QIVc has a formulation with 2 influenza A strains and 2 influenza B 
strains updated annually as recommended by the WHO for a specific influenza season, 
and addresses the unmet medical need of better vaccine antigenic matching against co-
circulating influenza B strains. A shift from egg- to cell-culture based manufacturing 
platforms has several advantages, allowing for the possibility to work directly with wild-
type viruses, avoiding the generation of egg-adaptive mutations in the HA protein, 
increasing surge capacity in the event of a pandemic, and providing better manufacturing 

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control through a closed-system fermentation process (Lambert and Fauci 2010). In 
addition, cell culture-derived influenza vaccines do not require extensive advanced 
planning and can, in principle, be vital for responding to the threat of an emerging 
pandemic.
A marketing authorization for TIVc (Flucelvax) was received from the FDA in the United 
States (US) in November 2012, for use in subjects of 18 years of age and older. A 
supplemental Biologics License Application (sBLA) to extend the age indication of TIVc 
to 4 years and above was submitted to the FDA in November 2014. This was followed, in 
April 2015, by a Biologics License Application (BLA) submission to obtain marketing 
authorization of QIVc for the prevention of seasonal influenza in both adult and pediatric 
subjects (≥4 years of age). In May 2016, QIVc was approved by the FDA for use in 
people 4 years of age and older. 
The goal of the current observer-blind, comparator controlled study in children 6 months 
through 47 months of age is to demonstrate that vaccination with QIVc elicits an immune 
response that is not inferior to that of a US-licensed QIV containing the recommended 
strains for the season. Immunogenicity will be evaluated at Day 1 and Day 29 (previously 
vaccinated subjects) or Day 1 and Day 57 (not previously vaccinated subjects). For 
noninferiority assessment, the immunogenicity will be evaluated through measurement of 
serum HAI antibody titers for all influenza strains, except for A/H3N2. Recent 
evolutionary changes in A/H3N2 hemagglutinin have resulted in the loss of capacity to 
agglutinate, and therefore the two A/H3N2 endpoints will be assessed using the MN assay.
1.2
Rationale
The purpose of the study is to demonstrate that vaccination with QIVc elicits an immune 
response that is not inferior to that of an US-licensed QIV containing the same virus 
strains, in children 6 months through 47 months of age. This randomized, observer-blind, 
comparator controlled study of Seqirus’ QIVc versus a US-licensed QIV is designed to 
evaluate both safety and immunogenicity of each of the four influenza strains contained in 
QIVc, in subjects 6 months through 47 months of age. The data from this study will be 
used to support the licensure of QIVc for use in children 6 months through 47 months of 
age.

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2.
OBJECTIVES
2.1
Primary Immunogenicity Objective
1. To demonstrate that vaccination with QIVc elicits an immune response that is 
not inferior to that of a US-licensed QIV containing the recommended strains 
for the season, in subjects 6 months through 47 months of age, as measured by 
hemagglutination inhibition (HAI) assay for A/H1N1, B/Yamagata and 
B/Victoria strains and by microneutralization (MN) assay for A/H3N2 strain, 
using cell-derived target viruses.
2.2
Secondary Immunogenicity Objectives
1. To describe the immunogenicity of QIVc and US-licensed QIV by HAI assay for 
A/H1N1, B/Victoria, and B/Yamagata strains, and by MN assay for A/H3N2 
strain, using egg-derived target viruses.
2. To describe the immunogenicity of QIVc and US-licensed QIV by HAI assay for
A/H1N1, B/Victoria, and B/Yamagata strains, and by MN assay for A/H3N2 
strain, using cell-derived target viruses.
3. To describe the immunogenicity of QIVc and US-licensed QIV by MN assay for 
A/H1N1, B/Victoria, and B/Yamagata strains, in a subset of subjects
2.3
Secondary Safety Objectives
1. To evaluate the safety and reactogenicity of QIVc and US-licensed QIV 
2.4
Exploratory Immunogenicity Objectives
1. To evaluate the homologous cell-mediated immunity (CMI) response, 
prevaccination and postvaccination, in a small population of subjects.
2. To further describe the immune response to vaccination, additional 
immunogenicity analyses may be conducted such as HAI assay for A/H3N2 using 
cell- and egg-derived target virus.

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3.
STUDY DESIGN
3.1
Overview of Study Design
This multicenter phase 3 clinical study is a randomized, observer-blind, comparator 
controlled, multicenter study of QIVc versus US-licensed QIV in children 6 months 
through 47 months of age. Study vaccine administration will be a single dose, or 2 doses 
28 days apart, depending on the influenza vaccination history of the subject.
The study will be conducted in approximately 2502 healthy male and female subjects 
6 months through 47 months of age: 2418 subjects for immunogenicity evaluation and 84 
subjects for evaluation of CMI. Stratification through IRT will be used to ensure a 
balanced distribution among the age groups, at least 30% of subjects should be 6 through 
23 months and at least 30% of subjects should be from 24 through 47 months of age.
After signing of the informed consent by the subject’s parent(s)/LAR(s) and undergoing 
review of medical history, physical examination, review of prior and concomitant 
medications/vaccinations, and confirmation of subject eligibility, subjects will be enrolled 
into the study and randomized via an IRT system to receive QIVc or US-licensed QIV in 
a 2:1 ratio. 
The study has a treatment period and a follow-up period. For subjects with a previous 
influenza vaccination history, the treatment period begins at the time of vaccination and 
ends 28 days after vaccination and will consist of 2 clinical visits and 1 reminder call to 
complete the Subject Diary Card. The follow up period begins 28 days after vaccination 
and ends at the time of study completion visit. For subjects without or unknown previous 
influenza vaccination history, the treatment period begins at the time of first vaccination 
and ends 28 days after the second vaccination and will consist of 3 clinical visits and 2
reminder calls to complete the Subject Diary Card, one after each vaccination. The 
follow-up period begins 28 days after second vaccination and ends at the study 
completion visit. All subjects, irrespective of previous influenza vaccination history, will 
receive 1 safety assessment call 90 days after last vaccination during the follow up period 
and the follow-up period will conclude with a study completion visit (call). 
Subjects will provide a serological specimen via a blood draw before vaccination on 
Day 1 and 28 days after last vaccination. Previously vaccinated subjects will provide a 
serological specimen on Day 1 and Day 29 (vaccination on Day 1), while not previously 
vaccinated subjects will provide a serological specimen on Day 1 and Day 57 
(vaccination at Day 1 and Day 29). The serological specimen on the day of vaccination 
will be obtained before vaccination. For the majority of subjects (approximately 2418), 
immunogenicity will be measured by HAI and MN assays from the serological specimen. 
In a small group of approximately 84 subjects, evaluation of CMI response will be 
performed instead of the immunogenicity evaluation.

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Currently available influenza vaccines are not licensed below the age of 6 months. This 
protocol will exclude any subjects who have received influenza vaccine in the past 
6 months. Therefore, all eligible subjects below 12 months of age will be considered as 
not previously vaccinated against influenza for study enrollment.
The final analysis of the primary and secondary immunogenicity endpoints will be 
conducted on cleaned and locked data once all subjects have completed all 
immunogenicity assessments (end of treatment period, i.e. up to 28 days following the 
last vaccination dose). At this time, the analysis of all solicited adverse events and of 
unsolicited adverse events reported during the treatment period will also be conducted. 
These results will be used to prepare a Clinical Study Report (CSR) with treatment period 
data. No individual unblinded listings will be generated at this stage. 
A final CSR will present all clinical study data collected up to 180 days following the last 
vaccination dose, including safety data collected during the follow up period.
Details of the study procedures and assessments are provided in Section 5, Study 
Procedures and Section 7, Assessments, respectively.
3.2
Study Period
Each subject should expect to participate in the study for 180 days after last vaccination
(approximately 6 to 7 months).
3.3
Blinding Procedures
3.3.1
Blinding Methods
The trial is designed as an observer-blind study. During the treatment period of the study
designated unblinded nurse(s), physician(s), or other qualified health care professional 
will be responsible for administering the study vaccine to the subjects. They will be 
instructed not to reveal the identity of the study vaccines either to the subject’s 
parent(s)/LAR(s) or the investigative site personnel (ie, investigator and study nurse) 
involved in the conduct of the trial, except in an emergency. The designated unblinded 
nurse(s) or physician(s) will not take part in evaluating the subject(s) for safety or collect 
study data after the vaccinations. Vaccines will be assigned administered through an IRT
system. Neither the subject’s parent(s)/LAR(s) or any of the investigative staff who are 
involved in the treatments or clinical evaluation of the subject will be aware of the 
vaccine administered. Vaccine administration should be shielded from the subject’s 
parent(s)/legal guardian(s) and blinded study personnel. The unblinded personnel should 
not be involved in data collection such as safety assessments and/or physical assessment 
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Investigator can disclose the subject’s assigned vaccine. The information can be retrieved 
from the IRT system either via web or phone (a 24/7 backup service).
Except in the case of medical necessity, a subject’s treatment should not be unblinded 
without the approval of the Sponsor. In such instance of medical emergency, every effort 
should be made to contact the Sponsor prior to unblinding. If unblinding should occur, by 
either accidental unblinding or emergency unblinding for a serious adverse event (SAE), 
prior to completion of the study, the Investigator must promptly contact the Sponsor and 
document the circumstances on the appropriate forms. In case of an emergency, the 
information can be retrieved by the Investigator from the IRT system either via web or 
phone (a 24/7 backup service). If the subject is unblinded by the Investigator, the subject 
could be removed from an Analyses Set.
Investigators, Seqirus study team members, and all External Service Providers (ESPs)
who are directly involved in the conduct of the trial or in the analysis of the study results, 
or have contact with study centers, will remain blinded to the treatment codes until the 
final database lock at the end of the study. Only biostatisticians conducting the statistical 
analysis for the treatment period, will have access to the individual treatment codes. No 
unblinded individual subject level information will be shared with Seqirus and ESP 
personnel conducting the study until the final database lock. Seqirus study team members 
preparing the draft CSR with treatment period data will remain blinded to the individual 
treatment codes.
3.3.2
Planned Unblinding Procedures
The relevant portions of the clinical database will be cleaned and locked after collection 
of safety and immunogenicity data has been completed for all subjects during the 
treatment period of the study, i.e. up to 28 days following the last vaccination dose (final 
treatment period data). Only personnel of the ESP and Seqirus conducting the statistical 
analysis will have access to the individual treatment codes. This information will not be 
shared with Seqirus and ESP personnel conducting the study until the follow up safety 
data has been locked for final analysis. Seqirus study team members preparing the CSR 
with treatment period data will remain blinded to the individual treatment codes. The 
results will not be shared with investigators and other site staff. 
Safety follow up data will be locked when all subjects have completed all clinical data 
collected up to 180 days following the last vaccination dose (end of study). The Seqirus 
Benefit Risk Physician responsible for Sponsor’s assessment of adverse events during the 
follow up phase will remain blinded at individual and group level through the follow up 
period, until final database lock at study completion. A final clinical study report will 
present all clinical study data collected up to 180 days following the last vaccination dose, 
including safety follow up data.

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3.4
Data Collection
3.4.1
Data Collected from Subjects
The following data will be collected from each subject over the duration of their study 
participation:

Informed Consent

Demographic Information (see Section 5.1.2, Screening).

Physical Examination Information (see Section 5.1.2, Screening).

Adverse Events (see Section 7.1, Safety Assessment).

Relevant Medical History (see Section 5.1.2, Screening).

Influenza Vaccination History

Relevant Concomitant Medications (see Section 5.1.2, Screening and Section 6.5, 
Prior and concomitant Medications and Vaccines).

All Vaccination History (see Section 5.1.2, Screening).
All data collected must only be identified using the Seqirus Subject ID, as described in 
Section 5.1.4, Randomization.
3.4.2
Tools Used for Data Collection
Electronic Data Capture (EDC) system and a paper Subject Diary Card(s) will be used to 
collect data for this study.
Subject Diary Card
Subjects’ parent(s)/LAR will be given a paper diary at their Day 1 clinic visit to complete. 
The paper diary, hereafter referred to as the Subject Diary Card, should be completed by 
the subjects’ parent(s)/LAR. The Subject Diary Card will be the only source document 
allowed for solicited local adverse reactions and systemic adverse events (including body 
temperature measurements), starting after the initial 30-minute postvaccination period, 
and continuing for a total of 7 Days.
At the Day 29 clinic visit (“previously vaccinated” subjects) or at the Day 29 and Day 57 
clinic visit (“not previously vaccinated” subjects) subjects’ parent(s)/LAR are to return 

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the completed Subject Diary Card and the site staff should review the information entered 
with them. The following additional rules apply to documentation of safety information 
collected in the Subject Diary Card:
1. No corrections or additions to the information recorded by the subjects’ 
parent(s)/LAR will be allowed after it is delivered to the site.
2. Any blank or illegible fields on the Subject Diary Card must be described as missing 
in the eCRF.
The following additional rules apply to documentation of Subject Diary Card information
collected in the eCRFs:
1. The site must enter all readable entries in the Subject Diary Card into the eCRF, 
including those values that may be biologically implausible (eg, body temperature: 
1000°F).
2. Any illegible or implausible data should be reviewed with the subject’s parent(s)/ 
legally acceptable representative(s). If an underlying solicited or unsolicited adverse 
event is described on review with the subject’s parent(s)/LAR, this should be 
described in the source document and reported as an unsolicited adverse event in the 
Adverse Event eCRF (eg, if the subject’s parent(s)/LAR(s)above confirms body 
temperature of 100°F on the day in which body temperature 1000°F was written into 
the Subject Diary Card, the temperature of 100°F should be recorded in the Adverse 
Event eCRF and documented in source).
3. Any newly described safety information (including a solicited adverse event) must not 
be written into the Subject Diary Card and must be described in the study file as a 
verbally reported adverse event. Any adverse event reported in this fashion must be 
described as an unsolicited adverse event and therefore entered on the Adverse Event 
eCRF.
Case Report Forms
This study utilizes electronic Case Report Forms (eCRFs) to collect study-related data
from each subject. A trained health care professional is required to enter subject data in 
the eCRFs in English based on the medical information available in each subject’s source
record.
Data should be entered into the eCRF in a timely fashion following each subject’s clinic
visit, study procedure, or phone call. Each subject’s Case Report Form (CRF) casebook 
will be compared with the subject’s source records by a Seqirus-approved study monitor 
(or designee) over the duration of the study in order to ensure data collection accuracy.

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3.5
Collection of Clinical Specimens
The following clinical specimens are required to be collected from each subject in this 
study:

Blood at the Day 1 and the Day 29 clinic visit (previously vaccinated subjects) or at 
the Day 1 and Day 57 clinic visits (not previously vaccinated subjects).
Processing of each specimen should be completed by a trained health care professional
and in accordance with the study-specific Clinical Specimen Laboratory Manual. Testing 
of clinical specimens will be performed by a Seqirus designated laboratory. For additional 
details, see the study-specific Clinical Specimen Laboratory Manual.
Blood Specimen
The total amount of blood collected over the study period per subject will be 
approximately 16 mL. Approximately 8 mL sample of blood will be drawn from all 
subjects at Days 1 and 29 (previously vaccinated subjects), or at Days 1 and 57 (not 
previously vaccinated subjects). In this study, the blood volume will be approximately 8 
mL at each time point. See Section 7, Assessments for additional details.
Blood specimen will be analyzed for immunogenicity evaluation (HAI and MN analyses 
in approximately 2418 subjects) or for assessing CMI response (in approximately 
84 subjects from pre-selected sites based on demonstrated capability to process samples 
for this testing). All 8 mL of the collected blood specimen will be used for HAI and MN 
analyses in the immunogenicity group. For the CMI response group, approximately 5 mL 
of the collected blood sample will be used to measure CMI response. Approximately 
3 mL of the blood specimen provided in the CMI group will be used to measure 
immunogenicity. The intention of assessing immunogenicity in the CMI group is to 
descriptively compare antibody responses between the 2 groups of subjects.
3.6
Stopping/Pausing Guidelines
There are no predetermined stopping rules in this study. Subjects may be withdrawn from 
the study according to investigator discretion as described in Section 3.8, Premature 
Withdrawal from Study.
The Sponsor can halt the study at any time. If the study is halted, the Sponsor will
promptly notify the health authorities and investigators, who will promptly inform the
parent(s)/LAR of study subjects and Institutional Review Board(s) (IRBs) as per local 
regulations. Further enrollment will only occur after written authorization is provided by 
the Sponsor in consultation with the health authorities and IRB(s), as appropriate.

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3.7
Data Monitoring Committee
An independent Data Monitoring Committee (DMC) will not be utilized for the study.
3.8
Premature Withdrawal From Study
A subject may withdraw at any time, or be dropped from the study at the discretion of the 
Investigator should any untoward effects occur and/or for safety reasons. In addition, a 
subject may be withdrawn by the Investigator or the Sponsor if he/she violates the study 
protocol and/or related procedures. The Investigator or study coordinator must notify the 
Sponsor immediately when a subject has been withdrawn due to an adverse event.
The circumstances above are referred to as premature withdrawal from the study, and the 
reason for premature withdrawal should be clearly documented and detailed in the source 
documentation. The Investigator should make every attempt to evaluate the subject’s 
safety, including resolution of ongoing AEs, at the time of premature withdrawal. If a 
subject’s parent(s)/LAR(s) wants to withdraw the subject from the study before all doses 
are administered or prior to the last planned study visit, the subject’s parent(s)/LAR(s)
will be asked to be followed for safety for the duration of the study. When a subject is 
withdrawn from the study, the procedures described in Section 5.5.1, Early Termination 
Visit should be completed whenever possible.
The reasons for premature withdrawal from the study include adverse event, death, 
withdrawal of consent, lost to follow-up, other, and protocol deviation. These reasons are 
described in greater detail below.
Adverse Event
For any subject withdrawn from study participation prior to the planned Study 
Completion Call, it is important to determine if an AE was associated with the reason for 
discontinuing the study. This AE must be identified on the Adverse Event eCRF page by 
indicating “Withdrawn from study due to AE.” Any ongoing AEs at the time of study 
withdrawal must be followed until resolution or stabilization.
Subjects who develop an SAE judged to be possibly or probably related to the study 
vaccine, including hypersensitivity reactions, should not receive subsequent vaccination.
If a medically-attended adverse event occurred, the event should also be reported on the 
Adverse Event eCRF page (see Section 7.1, Safety Assessment).

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Death
For any subject withdrawn from study participation due to death, this should be noted on 
the Study Completion eCRF and the associated SAE that led to the death must be reported 
on the SAE page.
Withdrawal of consent
The subject’s parent(s)/LAR(s) can withdraw consent for participation in the study at any 
time without penalty or loss of benefit to which the subject is otherwise entitled. Reason 
for early termination should be deemed as “withdrawal of consent” if the subject 
withdraws from participation due to a non-medical reason (ie, reason other than AE). If 
the subject’s parent(s)/LAR intends to withdraw consent from the study, the Investigator 
should clarify if the subject will withdraw completely from the study or if the subject will 
continue study participation for safety. If the subject requests complete withdrawal from 
the study, no further study interventions or data collection will be performed with the 
subject.
In the US, if a subject’s parent(s)/LAR withdraws consent but does not revoke the Health 
Insurance Portability and Accountability Act (HIPAA) authorization, the Sponsor will 
have full access to the subject’s medical records, including termination visit information. 
If a subject’s parent(s)/ LAR revokes only the HIPAA authorization, the Sponsor will 
have full access to all of the subject’s medical records prior to the date and time of written 
revocation.
Lost to Follow-Up
For subjects who fail to show up for planned visits (clinic or telephone calls), study staff 
are encouraged to make at least 3 documented attempts to contact the subject’s 
parent(s)/LAR(s) by telephone and at least 1 documented written attempt to contact the 
subject’s parent(s)/LAR(s) to encourage the completion of study completion procedures. 
These efforts to contact the subject should be recorded in the source document. The 
termination date for the subject to be captured on the study completion eCRF page is the 
date of the last successful contact (clinic visit or telephone) with the subject’s 
parent(s)/LARs.
Other
Examples for subjects withdrawn from the study due to other reasons can include: 
Sponsor decision to terminate the study, subject meeting a pre-specified withdrawal 

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criterion, subject discontinuation for insurance issues, moving, no time, etc. This reason 
should be noted in the Study Completion CRF page and any ongoing AE’s at the time of 
study withdrawal must be followed until resolution/stabilization.
Study Terminated by Sponsor
If the clinical study is prematurely terminated by the Sponsor, the Investigator is to 
promptly inform the study subjects and IRB and should assure appropriate therapy and 
follow up for the subjects. All procedures and requirements pertaining to the archiving of 
study documents should be followed. All other study materials (study 
medication/vaccines, etc.) must be returned to the Sponsor.
Protocol Deviation
A protocol deviation is any change, divergence, or departure from the study design or
procedures of a study protocol. In general, subjects associated with protocol deviations
may remain in the study unless continuation in the study jeopardizes the subject’s health,
safety, or rights.
Investigators will apply due diligence to avoid protocol deviations. Under no
circumstances should the Investigator contact Seqirus or its agents, if any, monitoring the
study to request approval of a protocol deviation, as no authorized deviations are
permitted. If the Investigator feels a change to the protocol would improve the conduct of 
the study this must be considered a protocol amendment, and unless such an amendment
is agreed upon by Seqirus and approved by the IRB, it cannot be implemented.
3.9
End of Study
Most clinical trials intended to support the efficacy/immunogenicity and safety of an 
Investigational Product proceed to full completion of planned sample size accrual. 
Evaluation of the primary and secondary immunogenicity objectives requires the testing
of biological samples from the study subjects, which can only be completed after all
samples are collected. The last samples for the analysis of the primary and secondary
immunogenicity objectives will be taken at Day 29 or Day 57. For the purpose of this 
protocol, end of study is defined as the completion of the Last Subject Last Visit (LSLV), 
ie, the last subject’s Day 181 or Day 209 safety assessment call, or the completion of 
testing of biological samples to be achieved no later than 8 months after LSLV, 
whichever is longer.

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4.
SELECTION OF STUDY POPULATION
4.1
Inclusion Criteria
In order to participate in this study, all subjects must meet ALL of the inclusion criteria 
described:
1. Individuals 6 through 47 months of age on the day of informed consent.
2. Individuals whose parent(s)/ LAR(s) have voluntarily given written informed consent 
after the nature of the study has been explained according to local regulatory 
requirements, prior to study entry.
3. Individuals who can comply with study procedures, including follow-up1.
4. Individual who is in generally good health as per the Investigator’s medical 
judgement.
Prior to receipt of second study vaccination, subjects must be re-evaluated to confirm that 
they are eligible for subsequent vaccination. If subjects do not meet criteria 3 and/or 4 of 
the original inclusion criteria listed above, they should not receive additional 
vaccinations.
4.2
Exclusion Criteria
Each subject must not have:
1. Acute (severe) febrile illness (see Section 4.3 Criteria for Delay of Vaccination).
2. History of any anaphylaxis, serious vaccine reactions or hypersensitivity, including 
allergic reactions, to any component of vaccine or medical equipment whose use is 
foreseen in this study.
3. Clinical conditions representing a contraindication to intramuscular vaccination and 
blood draws. These may include known bleeding disorders, or treatment with 
anticoagulants in the 3 weeks preceding vaccination.  
4. A known history of Guillain-Barre Syndrome or other demyelinating diseases such as 
encephalomyelitis and transverse myelitis.
                                               
1 A subject and parent(s)/legally acceptable representative(s) are considered to be compliant if the 
Investigator judges that the subject will complete the Subject Diary Card, return for all the follow-up visits, 
be available for telephone calls, as scheduled in the study.

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5. Abnormal function of the immune system resulting from clinical conditions, which 
include:
a.
Known or suspected congenital or acquired immunodeficiency.
b. Systemic administration of corticosteroids (PO/IV/IM) at any dose for more than 
14 days, within 90 days prior to informed consent. Topical, inhaled and intranasal 
corticosteroids are permitted. Intermittent use (1 dose in 30 days) of intra-articular 
corticosteroids is also permitted.
c.
Administration of antineoplastic and immunomodulating agents or radiotherapy 
within 90 days prior to informed consent.
6. Received immunoglobulins or any blood products within 180 days prior to informed 
consent.
7. Received an investigational or non-registered medicinal product within 30 days prior 
to informed consent, or intend to participate in another clinical trial during the study.
8. Study personnel, family and household members of study personnel should not 
participate.
9. Any other clinical condition that, in the opinion of the investigator, might interfere 
with the results of the study or pose additional risk to the subject due to participation 
in the study.
10. Received influenza vaccination or has had documented influenza disease in the last 
6 months prior to informed consent.
11. Received any other vaccines than influenza vaccine within 14 days (for inactivated 
vaccines) or 28 days (for live vaccines) prior to study vaccination or who are planning 
to receive any vaccine within 28 days after study vaccination.
Prior to receipt of second study vaccination, subjects must be evaluated to confirm that 
they are eligible for subsequent vaccination. If subjects meet any of the original exclusion 
criteria listed above or experienced severe tolerability issues after first study vaccination, 
they should not receive additional vaccinations. However, these subjects should be 
encouraged to continue study participation. This review of eligibility should be 
documented in the source document and the reason for not administrating a scheduled 
study vaccine should be documented in the eCRF.
4.3
Criteria for Delay of Vaccination
There may be instances when individuals meet all eligibility criteria for vaccination yet 
have a transient clinical circumstance which warrant delay of vaccination (ie, body 
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vaccination, or use of antipyretics and/or analgesic medications within 24 hours prior to 
vaccination. Under such circumstances, a subject may be considered eligible for study 
enrollment after the above defined window for delay has passed and inclusion/exclusion 
criteria have been rechecked, and if the subject is confirmed to be eligible. In these 
instances, missing the visit window is not considered a protocol deviation.

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5.
STUDY PROCEDURES
The sections that follow provide an overview of the procedures that are to be followed in 
enrolling, evaluating, and following subjects who participate in this clinical study. Visits can 
be either clinic visits or safety assessment call, as specified in Table 5-1 below and in the 
Time and Events Tables (Table 1-1 and Table 1-2).
Table 5-1
Study Procedures
Visit Category
Procedures
Prevaccination Clinic Visit(s)
Section 5.1, Prevaccination Clinic Visits / Day 1 
Prevaccination describes procedures to be followed 
prior to study vaccination: informed consent, screening, 
enrollment, and randomization
Vaccination Clinic Visit(s)
Section 5.2, Vaccination Clinic Visit(s) describes 
procedures to be followed during each clinic visit 
involving vaccination: vaccination, postvaccination
procedures, and postvaccination reminders 
Postvaccination Visit(s) 
Section 5.3, Postvaccination Visits describes follow-up 
clinic visits and safety assessment calls
Unscheduled Visit(s)
Section 5.4, Unscheduled Visit(s) describes possible 
procedures to be followed at an unscheduled clinic visit
Study completion Visit
Section 5.5, Study Completion Visit describes 
procedures to be followed at the last study visit for a 
subject (may include early termination visit)
5.1
Prevaccination Clinic Visits / Day 1 Prevaccination
This section describes the procedures that must be performed for each potential subject prior 
to vaccination, including obtaining informed consent, screening, enrollment and 
randomization.
5.1.1
Informed Consent
"Informed consent" is the voluntary agreement of an individual or their parent(s)/LAR to 
participate in research. Consent must be given with free will of choice, and without undue 
inducement. The individual’s parent(s)/LAR must have sufficient knowledge and 
understanding of the nature of the proposed research, the anticipated risks and potential 
benefits, and the requirements of the research to be able to make an informed decision. 

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Informed consent of the parent(s)/LAR following IRB guidance must be obtained before 
conducting any study-specific procedures (ie, all of the procedures described in the protocol). 
The process of obtaining informed consent should be documented in the subject source 
document in addition to maintaining a signed and dated version of the informed consent. 
Additional specifics regarding the informed consent processes are located in Section 13.2, 
Informed Consent Procedures. 
If the parent(s)/LAR are unable to read and write, a witness must be present during the 
informed consent discussion and at the time of informed consent signature. An “impartial 
witness” is defined as a person who is independent from study conduct, who cannot be 
unfairly influenced by those involved with the study, who attends the informed consent 
process if the subject or the subject's legally acceptable representative cannot read, and who 
reads the informed consent form (ICF) and any other written information supplied to the 
subject. After the written informed consent form and any other written information to be 
provided to subjects, is read and explained to the subject’s parent(s)/LAR(s) and after the 
subject’s parent(s)/LAR(s) has verbally consented to the subject’s participation in the study 
and, if capable of doing so, has signed and personally dated the informed consent form, the 
witness should sign and personally date the consent form. By signing the consent form, the 
witness attests that the information in the consent form and any other written information was 
accurately explained to, and apparently understood by, the subject’s parent(s)/LAR(s) and 
that informed consent was freely given by the subject’s parent(s)/ LAR. 
The informed consent process may be conducted within 10 days prior to Day 1.
5.1.2
Screening
After an individual’s parent(s)/LAR has consented for the individual to participate in the 
study and informed consent is signed, sites will manually assign subjects a unique Screening 
Number. The subject’s unique Screening Number will be documented in the Screening and 
Enrollment Log. The eligibility of the subject will be determined based on the inclusion and 
exclusion criteria listed in Section 4, Selection of Study Population, and evaluated during this 
screening procedure.
Screening procedures will include the following:
1. Demographic data will be collected from the subject, including: date of birth, sex, 
race, ethnicity, height and weight.
2.
The subject’s prior influenza vaccination history will be obtained and recorded 
(“previously vaccinated” or “not previously vaccinated”). The Investigator will 
request a vaccination card or other documentation of previous vaccination history 
from the subject’s parent(s)/LAR. If available, the card or other documentation will 

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be copied and placed in the subject’s file to serve as source documentation. If 
documentation of vaccination history is not available, subject’s parent(s)/LAR(s) 
verbal recall of prior vaccination will be recognized as sufficient medical history; this 
attempt and information must be captured in the source documentation. If the 
subject’s parent(s)/LAR(s) is unable to recall previous vaccination status, then they 
should be considered “not previously vaccinated.”
3. Relevant medical history will also be collected, including but not limited to any 
medical history that may be relevant to subject eligibility for study participation and 
previous and ongoing illnesses or injuries. Relevant medical history can also include 
any medical history that contributes to the understanding of an adverse event that 
occurs during study participation, if it represents an exacerbation of an underlying 
disease/pre-existing problem.
4. Perform a review of organ systems by interview that queries the subject or subject’s 
parent(s)/LAR(s) as to any complaints the subject has experienced across each organ 
system. This will be performed before enrollment and used to guide physical 
examination.  The general physical examination is to be performed by a qualified 
health care professional. Corresponding information is documented in the subject’s
source documents.
5. If applicable, prior and concomitant medications or vaccinations taken up to 1 month 
prior to start of study should be collected (refer to Section 6.5, Prior and Concomitant 
Medications and Vaccines for further details). 
6. Collection of clinical signs is to be performed: weight, height and 
body temperature. If body temperature is ≥38.0°C / ≥100.4°F at the time of 
screening, vaccination must be postponed until 3 days after the fever has resolved 
(see Section 4.3, Criteria for Delay of Vaccination).
7. The use of antipyretics and/or analgesic medications within 24 hours prior to 
vaccination must be identified and the reason for their use (prophylaxis versus 
treatment) must be described in the source document and Concomitant Medications 
CRF. The use of antipyretics/analgesics within 24 hours prior to vaccine 
administration is a reason to delay study vaccination (see Section 4.3 Criteria for 
Delay of Vaccination, and Section 6.5, Prior and Concomitant Medications and 
Vaccines).
8. Prior to vaccination, blood will be drawn from all subjects (Section 5.1.5, Blood 
Draw).

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Measurement and recording of clinical signs, height, weight, and body temperature may be 
conducted by a trained health care professional (see List of Definitions). 
A general physical examination is to be performed by a qualified health care professional 
(see List of Definitions). 
The data described above will be written in the source document and entered in eCRF (see 
Section 9.1, Source Documentation). Should the physical assessment reveal any abnormal 
values or events, these must be documented as part of medical history.
In the event that the individual is determined ineligible for study participation, he/she is 
considered a screen failure. The reason for screen failure must be documented in the 
Screening and Enrollment Log. If the individual is determined to be eligible for the study, 
he/she will be enrolled into the study.
5.1.3
Enrollment
After signing the informed consent form and review of eligibility criteria, if an individual is 
determined to be eligible for study participation, the investigator or delegate will enroll the 
subject and enter subject information and stratification information into the Interactive 
Response Technology (IRT) system.
5.1.4
Randomization
Enrolled subjects will be randomized in the IRT system by a 2:1 ratio and automatically 
assigned a unique Subject ID. Subjects participating in the CMI group (approximately 84
subjects) will be enrolled in a limited number of sites through sequential allocation (in 
principle, subjects in which CMI will be evaluated will be enrolled first). The Subject ID will 
be the subject’s unique identification (ID) number for all eCRFs and associated study 
documentation that will be used for duration of the study. After randomization, the Screening 
Number ceases to be used and remains in the Screening and Enrollment Log only. The list of 
randomization assignments is produced by the EDC/IRT service provider.
Stratification through IRT will be used to ensure a balanced distribution among the age 
groups, at least 30% of subjects should be 6 through 23 months and at least 30% of subjects 
should be from 24 through 47 months of age.
For A/H1N1, B/Victoria, and B/Yamagata strains, immunogenicity of QIVc and US-licensed 
QIV will be evaluated by MN assay in a 20% subset of subjects. After blood specimens have 
been collected a randomly selected subset (20%) of these samples will be analyzed. Detailed 
information regarding the randomization procedures associated with the selection of the samples 
to be analyzed can be found in the Statistical Analysis Plan (SAP).

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If for any reason, after signing the Informed Consent Form (ICF), the subject who is eligible 
and enrolled fails to be randomized, this is called a randomization failure. The reason for all 
randomization failures should be recorded in the Screening and Enrollment Log and in the 
source document as specified in the Source Document Agreement (SDA). The information 
on subjects who are randomization failures should be kept distinct from subjects who are 
screen failures, as described in Section 5.1.2, Screening. 
If for any reason, after randomization the subject fails to undergo treatment, this is an Early 
Termination and the reason should be recorded in source document as specified in the SDA. 
The information on these Early Termination subjects should be kept distinct in the source 
documentation from randomization failures. 
5.1.5 Blood draw 
After randomization, but prior to vaccination, all subjects will have approximately 8 mL of
blood drawn for immunogenicity evaluation or to assess CMI response. Since there are 2
blood draws per subject, the total blood volume drawn per subject in this study is 
approximately 16 mL. Details regarding the volume of blood and testing to be performed are 
in Section 3.5. (see Section 3.5, Collection of Clinical Specimens). These data will be written 
in the source document (see Section 9.1, Source Documentation) and must be documented in 
the eCRF.
5.2
Vaccination Clinic Visit(s)
Please refer to the Time and Events Tables (Table 1-1 and Table 1-2). Vaccination will be 
performed on Day 1 (all subjects) and Day 29 (“not previously vaccinated” subjects) using 
the vaccine identified by the assigned Pack ID. 
After completing the prevaccination procedures as described in Section 5.1, Vaccination 
Clinic Visit – Day 1 Prevaccination Procedures, the vaccine will be administered to the 
subject according to the procedures described in Section 6.3, Vaccine Preparation and 
Administration, observing the blinding procedures described in Section 3.3, Blinding 
Procedures. 
Prior to administration of the study vaccination, it needs to be confirmed that the subject is 
eligible for vaccination and does not meet any criteria for exclusion or delaying study 
vaccination as described in Section 4, Selection of Study Population. 
5.2.1
Day 1 Postvaccination Procedures (All Subjects)
The following postvaccination procedures will be performed:

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1. Training should be directed at the individual(s) who will perform the measurements of 
local reactions and body temperature, and those who will enter the information into the 
subject diary card. This individual may not be the subject’s parent(s)/LAR(s), but if a 
person other than the subject’s parent(s)/LAR(s) enters information into the subject diary 
card, this person’s identity must be documented in the study file and this person must 
receive training on the diary card. Training of the subject’s parent(s)/LAR(s) on how to 
measure an injection site reaction should be performed while the subject is under 
observation after vaccination. 
Subject Diary Card instruction must include the following:
1. The subject’s parent(s)/LAR(s) must understand that timely completion of the Subject 
Diary Card on a daily basis is a critical component to study participation. The 
subject’s parent(s)/LAR(s) should also be instructed to write clearly and to complete 
the Subject Diary Card in pen. Any corrections to the Subject Diary Card that are 
performed by the person completing the Subject Diary Card should include a single 
strikethrough line with a brief explanation for any change. No changes can be made 
to the Subject Diary Card after it is returned to the clinic.
2. Starting on the day of vaccination, the subject’s parent(s)/LAR(s) will check in the 
evening for specific types of reactions at the injection site (solicited local adverse 
reactions), any specific generalized symptoms (solicited systemic adverse events), 
body temperature  any other symptoms or change in the subject’s health status, and 
any medications/vaccinations taken (excluding vitamins and minerals). These 
solicited adverse events and body temperature will be recorded in the “six hours” 
location on the Subject Diary Card.
3. Body temperature measurement is to be performed using the thermometer provided 
by the site. In children younger than 36 months of age, measurement of temperature 
rectally is preferred.  Oral, axillary or tympanic membrane routes may be used in 
older children.  If the subject appears unusually hot or cold during the day, the 
subject’s parent(s)/LAR(s) should check body temperature. If the subject has fever, 
the highest body temperature observed that day should be recorded on the Subject 
Diary Card. The measurement of solicited local adverse reactions is to be performed 
using the ruler provided by the site. 
4. The collection of body temperature, solicited local adverse reactions, solicited 
systemic adverse events on the Subject Diary Card will continue for a total of 7 days. 
2. After vaccination, the subject will be observed for at least 30 minutes including 
observation for local and systemic adverse events, unsolicited AEs, and body temperature 
measurement. Please take the opportunity to remind the subject’s parent(s)/LAR(s) how
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period. Record all safety data collected in the source documents. The 30-minute 
observation data must be recorded in the source documents only; not in the Subject 
Diary Card.
3. Schedule the next study activities, reminder telephone call, and clinic visit, with the 
subject’s parent(s)/LAR(s).
4. Remind the subject’s parent(s)/LAR(s) to complete the Subject Diary Card daily and to 
contact the site if there are any questions and to contact the site immediately (or as soon 
as the subject is medically stable) if the subject has a medical condition that leads to a 
hospitalization. 
5.2.2
Day 29 Prevaccination Procedures (“not previously vaccinated” subjects)
The following procedures should be carried out at the clinic visit on Day 29 before the 
vaccination is performed: 
1. At the clinic visit, the Subject Diary Card will be reviewed. Please see Section 3.4.2, 
Tools Used for Data Collection for additional guidance on Subject Diary Card review. 
The qualified health care professional will interview the subject’s parent(s)/LAR(s) to 
obtain information relating to unsolicited AEs including SAEs, AEs leading to study or 
vaccine withdrawal, NOCDs, associated concomitant medications and all vaccinations 
(see Section 6.5, Prior and Concomitant Medications and Vaccines). All safety 
information described by the subject’s parent(s)/LAR(s) must be written down in the 
source documents.
2. Perform a review of organ systems by interview that queries the subject’s 
parent(s)/LAR(s) as to any complaints the subject has experienced across each organ 
system. This will be used to guide the physical examination. Corresponding information 
is documented the subject’s source documents.
3. Take body temperature. In children younger than 36 months of age, measurement of 
temperature rectally is preferred.  Oral, axillary or tympanic membrane routes may be 
used in older children. If the body temperature is ≥38.0°C / ≥100.4°F, vaccination must 
be postponed until 3 days after the fever has resolved. Vaccination is also postponed for 
any clinically significant active infection based on investigator’s clinical judgment (see 
Section 4.3, Criteria for Delay of Vaccination).
4. The use of any analgesics (oral, topical, etc.) and/or antipyretics within 24 hours prior to 
vaccination is a reason to delay vaccination (see Section 6.5, Prior and Concomitant 
Medications and Vaccines). Use of these medications can decrease the immune response 
to the vaccination. Verify that the subject has not applied topical analgesic/anesthetic to 
the anticipated injection site within the past 24 hours, as application of 

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analgesic/anesthetic patch/cream may interfere with the ability to interpret local reactions 
after vaccination. If topical analgesic/anesthetic has been applied to the area to be 
injected, the opposite limb that has not been treated with analgesic/anesthetic may be 
injected. If subject took oral antipyretics and/or analgesic medications within 24 hours 
prior to vaccination, document this and the reason for their use (prophylaxis versus 
treatment) in the subject’s source record and eCRF. 
Prior to receipt of second study vaccination (“not previously vaccinated” children), subjects 
must be evaluated to confirm that they are eligible for subsequent vaccination. If subjects 
meet any of the original exclusion criteria (except for those listed under Section 4.2, 
Exclusion Criteria) or meet any of the criteria listed under Section 4.3, Criteria for Delay of 
Vaccination, they should not receive additional vaccinations. This reassessment of eligibility 
should be documented in source documents; if the subjects is found not eligible for the 
second vaccination, the reason for not administering scheduled vaccine should be 
documented in eCRF.
5.2.3
Day 29 Postvaccination Procedures (“not previously vaccinated” subjects)
After confirming subject continues to meet study eligibility criteria by completing procedures 
outlined in Section 5.2.2, Day 29 Prevaccination Procedures (not previously vaccinated 
subjects) above, perform vaccination of the subject according to the assigned study vaccine 
and according to the procedures described in Section 6, Treatment of Subjects.
The following postvaccination procedures should be carried out on Day 29: 
1. Careful re-training, if necessary, of the subject’s parent(s)/LAR(s) on how to measure 
local reactions and body temperature, how to complete and how often to complete the 
Subject Diary Card is crucial. Reference Section 5.2.1, Day 1 Postvaccination Procedures 
(All Subjects) for Subject Diary Card instruction. Any re-training must be recorded in the 
source documents.
2. After vaccination, the subject will be observed for at least 30 minutes including 
observation for local and systemic adverse events, AEs, and body temperature 
measurement. Please take the opportunity to remind the subject’s parent(s)/LAR(s) how 
to measure solicited adverse events and body temperature as part of this observation 
period. Record all safety data collected in the source documents. The 30-minute 
observation data must be recorded in the source documents only; not in the Subject 
Diary Card.
3. Schedule/review the next study activities, reminder telephone calls, and clinic visit, with 
the subject’s parent(s)/LAR. 

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Remind the subject’s parent(s)/LAR(s) to complete the Subject Diary Card daily and to 
contact the site if there are any questions and to contact the site immediately (or as soon as 
the subject is medically stable) if the subject has a medical condition that leads to a 
hospitalization.
5.2.4
Postvaccination Reminders
Reminder calls or alerts are not intended to be an interview for collection of safety data. If 
the subject’s parent(s)/LAR(s) wishes to describe safety information, this information should 
only be collected by a healthcare professional at the site, and the safety data described must 
be written down in the subject’s medical chart. 
Subject Diary Card Reminder Calls 
Subject Diary Card reminder calls will be performed on Day 3 (all subjects) and Day 31 
(“not previously vaccinated” subjects). The purpose of this call is to remind the subject’s 
parent(s)/LAR(s) about completion of the Subject Diary Card. The call follows the Subject 
Diary Card Reminder Telephone Call Script provided to the site. The subject’s 
parent(s)/LAR(s) should be reminded to contact the site to discuss medical questions.
5.3
Postvaccination Visits
Postvaccination visits (clinic visit or safety assessment call) will be performed on Days 29, 
91 and 181. (“previously vaccinated” subjects) or on Days 57, 119 and 209 (“not previously 
vaccinated” subjects). In the event that a scheduled or unscheduled visit or call coincides, 
procedures may be combined.
5.3.1
Postvaccination Clinic Visits
The following procedures will be performed on Day 29 for “previously vaccinated” subjects 
and on Day 57 for “not previously vaccinated” subjects: 
1. At the clinic visit, the Subject Diary Card will be reviewed. Please see Section 3.4.2, 
Tools used for Data Collection for additional guidance on Subject Diary Card review. If 
any other adverse events are reported, this should be discussed with a qualified health 
care professional. 
The subject’s parent(s)/LAR will be interviewed to determine if any unsolicited adverse 
events (including medically attended AEs, SAEs and AEs leading to study or vaccine 
withdrawal) occurred and if any concomitant medications or vaccines were 
taken/received in the time since the last clinic visit. The qualified health care professional 
reviewing these data will discuss the symptoms (if any) reported by the subject and will 
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reported by the subject’s parent(s)/LAR at this follow-up clinic visit must be recorded in 
the subject's source document and on an Adverse Events eCRF, as specified in Section 
7.1, Safety Assessment.
2. Perform a review of organ systems by interview that queries the subject’s 
parent(s)/LAR(s) as to any complaints the subject has experienced across each organ 
system. This will be used to guide the physical examination. Corresponding information 
is documented in the subject’s source documents.
3. Blood will be drawn (approximately 8 mL) from all subjects for serology testing. Details 
regarding the volume of blood and testing to be performed are in Section 3.5, Collection 
of Clinical Specimens.
4. Schedule safety telephone calls on Days 91 and 181 for “previously vaccinated” subjects 
and on Days 119 and 209 for “not previously vaccinated” subjects. 
Remind the subject’s parent(s)/LAR(s) to contact the site if there are any questions and to 
contact the site immediately (or as soon as the subject is medically stable) if the subject has a 
medical condition that leads to a hospitalization or an emergency room visit.  
5.3.2
Safety assessment calls
Safety assessment calls will be performed on Days 91 and 181 (previously vaccinated 
subjects) or Days 119 and 209 (not previously vaccinated subjects). 
Safety assessment calls are calls made to the subject’s parent(s)/ LAR by a qualified 
healthcare professional designated on the site log. These calls will follow a script which will 
facilitate the collection of relevant safety information. The subject’s parent(s)/LAR(s) will be 
interviewed according to the script. Safety assessment calls performed on Days 91 and 181 
(previously vaccinated subjects) or Days 119 and 209 (not previously vaccinated subjects) 
will collect information relating to a subset of unsolicited adverse events including SAEs, 
NOCDs, AEs leading to withdrawal, and concomitant medications or vaccinations associated 
with those events. All safety information described by the subject’s parent(s)/LAR(s) must be 
written down in a designated location within the source document and not written on the 
script used for the telephone call. 
The subject’s parent(s)/LAR(s) will be asked as to whether the subject was hospitalized or 
was evaluated at an emergency room for any illness since the site’s last contact with the 
subject. If an SAE has been identified by the site staff during the interview which has not 
previously been reported by the subject’s parent(s)/LAR, this SAE will be reported by the 
site within 24 hours to Seqirus or delegate. Any additional relevant medical history will be 
reported to Seqirus or delegate and recorded as needed. 

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The subject’s parent(s)/LAR(s) will receive a reminder of the next planned study activity, if 
applicable. The subject’s parent(s)/LAR(s) will be reminded to contact the site immediately 
(or as soon as the subject is medically stable) if the subject has a medical condition that leads 
to a hospitalization or an emergency room visit or to a visit to/by a doctor or is otherwise of 
concern.
5.4 
Unscheduled Visit(s)
An unscheduled study visit may be performed as necessary for further evaluation of safety 
information that is described on the telephone that is to be investigated further at any time 
during the study.
5.5
Study Completion Visit
Study completion will occur 180 days after last vaccination. For all subjects, the termination 
visit is a telephone call performed by a qualified health care professional.
The study completion visit will coincide with the safety call on Day 181 (previously 
vaccinated subjects) or Day 209 (not previously vaccinated subjects). The date of completion
is the date of the last contact (telephone call) in which the subject’s health status was 
assessed or, in cases where the subject’s parent(s)/LAR(s) does not agree to any further 
safety follow-up, it is the date consent is withdrawn. This date should be recorded on the 
Study Completion CRF page. For visit procedures to be performed for a subject whose 
planned study participation ends prematurely, please see Section 5.5.1, Early Termination 
Visit. 
At the Study Completion Visit, the following procedures will be performed:

Interview the subject’s parent(s)/LAR(s) to obtain information regarding potential SAEs,
NOCDs, and AEs leading to withdrawal and the medication to treat these

Ask the subject’s parent(s)/LAR(s) as to whether the subject was hospitalized or was 
evaluated at an emergency room for any illness since the site’s last contact with the 
subject. If an SAE has been identified by the site staff during the interview and has not 
previously been reported by the subject’s parent(s)/LAR(s), this SAE must be reported by 
the site within 24 hours to Seqirus or delegate. Record any additional relevant medical 
history as needed. 
The site will review with the subject’s parent(s)/LAR(s) the plan of when information 
relating to the subject’s participation in the study may be available (eg, study results). It will 
also be discussed how information relating to the subject’s participation in the study will be 
shared with the subject’s healthcare provider, if the subject’s parent(s)/LAR(s) chooses to 
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The site will complete the study completion eCRF page and this will mark the completion of 
the subject’s participation in the study.
5.5.1
Early Termination Visit
When a subject is withdrawn from treatment or withdraws from the study, the Investigator 
will notify the Sponsor and, when possible, will perform the procedures listed below. The 
reason(s) for the early termination will be included in the subject’s source documentation. If 
the Early Termination Visit is a telephone call, collect as much information as possible. Early 
Termination Visits include subjects who were randomized but not treated. 
At the clinic visit or during the telephone call, the same procedures will be performed as 
during the study completion visit, see Section 5.5, Study Completion Visit, if possible. 
In addition, the following procedures will be performed: 

Collect and review Subject Diary Card, if applicable.

Review the subject’s safety data (if collection of these was in progress at the time of 
study completion).
The site will review with the subject’s parent(s)/LAR(s) the plan of when information 
relating to the subject’s participation in the study may be available (eg, study results, 
treatment assignments). It will also be discussed how information relating to the subject’s 
participation in the study will be shared with the subject’s healthcare provider, if the 
subject/subject’s parent(s)/LAR(s) chooses to share this information.
The site will complete the termination eCRF page and this will mark the completion of the 
subject’s participation in the study.

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6.
TREATMENT OF SUBJECTS
All vaccines associated with this study are to be stored separately from other vaccines and 
medications in a secure location under appropriate storage conditions with temperature 
monitoring. All vaccines associated with this study must be checked for expiration 
date prior to use. Expired vaccines must not be administered to subjects.
6.1
Study Vaccine(s)
The term ‘study vaccine’ refers to those vaccines provided by the Sponsor or delegate, 
which will be evaluated as part of the study objectives. The study vaccines specific to this 
study are described below. 
QIVc 
An approximately 0.5 mL dose of QIVc (cell-derived seasonal quadrivalent influenza 
vaccine) contains nominally 15 μg of hemagglutinin (HA) of each of the 2 influenza type 
A strains and each of the 2 influenza type B strains for a total of 60 μg of HA in the 
vaccine. The strain composition will be that recommended by the WHO, Center for 
Biologics Evaluation and Research (CBER), and Committee for Medicinal Products for 
Human Use (CHMP) for quadrivalent influenza vaccines contemporaneous to the timing 
of the study. The full composition of the vaccine is reported in Table 6.1-1.

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For a comprehensive review of Afluria Quadrivalent® please refer to the United States 
Product Information (USPI) supplied by Seqirus or delegate; this document should be 
reviewed by the Investigators prior to initiating the study.
6.2
Non-Study Vaccines
Not applicable.
6.3
Vaccine Preparation and Administration
The investigator or designee will be responsible for oversight of the administration of 
vaccine to subjects enrolled in the study according to the procedures stipulated in this 
study protocol. All vaccines will be administered only by unblinded personnel who are 
qualified to perform that function under applicable local laws and regulations for the 
specific study site. Expired vaccines must not be administered.
QIVc will be provided in pre-filled syringes (PFS), with an injectable volume of 
approximately 0.5 mL. Afluria Quadrivalent is supplied as a 0.25 mL and a 0.5 mL PFS. 
The full volume contained in the PFS is to be administered.
Standard immunization practices are to be observed and care should be taken to 
administer the injection intramuscularly into the anterolateral region of the thigh (for 
subjects 6 through 11 months, in general) or in the deltoid region (for 
subjects ≥12 months, in general).
Detailed vaccine preparation and administration instructions will be provided to 
investigators prior to study start.
It is recommended that 25 gauge, 25 mm (1 inch) of length needle is used for the vaccine
administration.
PRECAUTIONS TO BE OBSERVED IN ADMINISTERING STUDY VACCINE: 
Prior to vaccination, subjects must be determined to be eligible for study vaccination and 
it must be clinically appropriate in the judgment of the investigator to vaccinate. 
Eligibility for vaccination prior to first study vaccine administration is determined by 
evaluating the entry criteria outlined in protocol Sections 4.1, Inclusion Criteria and 4.2, 
Exclusion Criteria.
Eligibility for subsequent study vaccination is determined by following the criteria 
outlined in Section 4.3, Criteria for Delay of Vaccination.

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The study vaccines should not be administered to individuals with known hypersensitivity 
to any component of these vaccines.
Standard immunization practices are to be observed and care should be taken to 
administer the injection: Intramuscularly into the anterolateral region of the thigh (for 
subjects 6 through 11 months, in general) or in the deltoid region (for 
subjects ≥12 months, in general). Before administering a vaccine, the vaccination site is 
to be disinfected with a skin disinfectant (eg, 70% alcohol). Allow the skin to dry. DO 
NOT inject intravascularly or intragluteally.
As with all injectable vaccines, trained medical personnel and appropriate medical 
treatment should be readily available in case of anaphylactic reactions following vaccine 
administration. For example, epinephrine 1:1000, diphenhydramine, and/or other 
medications for treating anaphylaxis must be available.
6.4
Vaccine Administration Error or Overdose of Vaccine
Vaccine administration error is defined as receiving a dose of study vaccine that was not 
reconstituted as instructed or administered by a different route from the intended route of 
administration. An overdose of study vaccine (whether accidental or intentional) is 
defined when a dosage higher than the recommended dosage (as per the QIVc dosing 
regimen referred to in Section 6.1, Study Vaccine(s) or as per the package insert of 
Afluria Quadrivalent®) is administered. 
Any vaccine administration error or overdose of study vaccine detailed in this protocol 
must be reported as an adverse event, and if the vaccine administration error or overdose 
is associated with a SAE, it must be reported as such within 24 hours to the Sponsor.
6.5
Prior and Concomitant Medications and Vaccines
All medications, vaccines and blood products taken or received by the subject within 1 
month prior to the start of the study are to be recorded on the Prior and Concomitant 
Medications eCRF.
In addition, the following are considered prior medications for this protocol: all 
medication/vaccines described in the inclusion and exclusion criteria of this protocol 
including: 
a) Influenza vaccination in the last 12 months.
b) Systemic administration of corticosteroids (PO/IV/IM) within 90 days prior to 
informed consent.
c) Administration of antineoplastic and immunomodulating agents or radiotherapy 
within 90 days prior to informed consent.

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d) Received immunoglobulins or any blood products within 180 days prior to informed 
consent.
The use of antipyretics and/or analgesic medications within 24 hours prior to vaccination 
must be identified and the reason for their use (prophylaxis versus treatment) must be 
described in the source document and Concomitant Medications CRF. The use of 
antipyretics/analgesics within 24 hours prior to vaccine administration is a reason to delay 
study vaccination (see Section 4.3, Criteria for Delay of Vaccination).
Medications taken for prophylaxis are those intended to prevent the onset of symptoms. 
Medications taken for treatment are intended to reduce or eliminate the presence of 
symptoms that are present.
Concomitant medications include all medications (including vaccines with the exception 
of vitamins, minerals and alternative medicines) taken by/administered to the subject at 
and after enrollment continuing up to the end of the treatment period and must be 
documented on the Concomitant Medications eCRF. During the follow-up period, all 
vaccinations should be documented and only those concomitant medications are 
documented on the Concomitant Medications eCRF if associated with an SAE, NOCDs, 
or AE leading to study withdrawal.
When recording concomitant medications/vaccines, they should be checked against the 
study entry and continuation criteria in Section 4, Selection of Study Population to ensure 
that the subject should be enrolled/continue in the study.
A non-study influenza vaccination(s) is considered a protocol deviation if received during 
the study and may result in the subject being excluded from the Per Protocol Set (PPS)
6.6
Vaccine Supply, Labeling, Storage and Tracking
The Sponsor will ensure the following:

Supply the study vaccine(s).

Appropriate labeling of all study vaccines in compliance with the legal requirements 
of each country where the study is to be performed.

Appropriate storage and distribution of study vaccines.

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The Investigator must ensure the following:

Acknowledge receipt of the study vaccines by a designated staff member at the site, 
including:
-
Confirmation that the vaccines were received in good condition and in the right 
amount.
-
Confirmation to the Sponsor that temperature range during shipment from the 
Sponsor to the Investigator’s designated storage location in the correct range (2°C 
to 8°C / 36°F to 46°F).
-
Report any temperature deviation and do not use vaccines until further 
confirmation by the Sponsor or delegate that the vaccines are authorized for use.

Proper storage of the study vaccines, including:
-
Storage in a secure, locked, temperature-controlled location.
-
Proper storage according to the instructions specified on the labels and in the 
Pharmacy Manual.
-
Appropriate record keeping and inventory of the study vaccines, including regular 
documentation of adequate storage temperature.

Appropriate management of the study vaccines, including:
-
Non-use of vaccines in case of temperature deviation, prior to receipt of 
authorization for use from the Sponsor or delegate.
-
Use only in accordance with the approved protocol.
-
Proper handling, including confirmation that the vaccine has not expired prior to 
administration.
-
Appropriate documentation of administration of vaccines to study subjects 
including:
▪
Date, dosage, batch/lot numbers, expiration dates, unique identifying numbers 
assigned to subjects and study vaccines, and time of vaccine administration. 
This information will be maintained in an accountability log that will be 
reviewed by the site monitor.
▪
Reconciliation of all vaccines received from the Sponsor. Reconciliation is 
defined as maintaining records of which and how many vaccines were 
received, which vaccines were administered to subjects, which vaccines were 
destroyed at the site, and which vaccines were returned to the Sponsor, as 
applicable.

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
Proper adherence to the local institutional policy with respect to destruction of study 
vaccines.

Complete record keeping of study vaccine use, wastage, return or destruction, 
including documentation of:
-
Copy of the site’s procedure for destruction of hazardous material.
-
Number of doses destroyed, date of destruction, destruction code (if available), 
method of destruction, and name of individual performing destruction.
Vaccines that have been stored differently from the manufacturer’s indications must not
be used unless the Sponsor provides written authorization for use. In the event that the use 
cannot be authorized, the Sponsor will make every effort to replace the vaccine supply. 
All vaccines used in conjunction with this protocol must be stored separately from normal 
hospital/practice stocks to prevent unintentional use of study vaccines outside of the 
clinical study setting.
Monitoring of vaccine accountability will be performed by the study monitor during site 
visits and at the completion of the study.
At the conclusion of the study, and as appropriate during the course of the study, the 
Investigator must ensure that all unused study vaccines, packaging and supplementary 
labels are destroyed locally (upon approval from Sponsor) or returned to the Sponsor.

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7.
ASSESSMENTS.
7.1
Safety Assessment
The measures of safety used in this study are routine clinical procedures. They include a 
close vigilance for, and stringent reporting of, selected local and systemic adverse events 
routinely monitored in vaccine clinical studies as indicators of reactogenicity. 
An adverse event (AE) is defined as any untoward medical occurrence in a subject or 
clinical investigation subject administered a pharmaceutical product at any dose that does 
not necessarily have to have a causal relationship with this treatment. Therefore, an AE 
can be any unfavorable and unintended sign (including an abnormal laboratory finding, 
for example), symptom, or disease temporally associated with the use of an 
investigational product, whether or not considered related to the investigational product. 
This definition includes intercurrent illnesses or injuries and exacerbation of pre-existing 
conditions. 
The period of observation for AEs extends from the time the subject’s parent(s)/LAR(s) 
signs informed consent until he or she completes the specified safety follow-up period 
Day 181 (for previously vaccinated subjects) or Day 209 (for not previously vaccinated 
subjects). AEs occurring after the informed consent form is signed but prior to receiving 
study vaccine/product will be documented as an AE and recorded within source 
document. However, any AEs occurring prior to receipt of any study vaccine will be 
analyzed separately from “treatment emergent” AEs (AEs occurring after administration 
of the first study vaccine). 
Adverse events are collected as either solicited or unsolicited adverse events. Solicited 
events are derived from organized data collection systems, such as the Subject Diary 
Card(s) or interviews.
7.1.1
Solicited Adverse Events
The term “reactogenicity” refers to solicited signs and symptoms (“solicited adverse 
events”) occurring in the hours and days following a vaccination, to be collected by the 
subject’s parent(s)/LAR(s) for a period of 7 days, using a pre-defined Subject Diary Card.
Each solicited adverse reaction and/or event is to be assessed and entered into the Subject 
Diary Card (see Section 3.4.2, Tools used for Data Collection for more details). Each 
adverse event is to be assessed by the sponsor according a defined severity grading scale 
(further details are provided in the SAP). The following solicited adverse events are 
included in the Subject Diary Card. 

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Solicited local adverse reactions
Injection site:

Induration (hardness), in mm

Erythema (redness), in mm

Ecchymosis (bruising), in mm

Tenderness, grading:
o
0=None
o
1=no interference with daily activity
o
2=interferes with daily activity
o
3=prevents daily activity
Solicited systemic adverse events

Change of eating habits
o
0= None
o
1= Eating less than normal for 1 - 2 feeds / meals
o
2= Missed 1 or 2 feeds / meals
o
3= Missed more than 2 feeds / meals

Sleepiness, grading:
o
0=None
o
1=shows an increased drowsiness
o
2=sleeps through feeds / meals
o
3=sleeps most of the time and it is hard to arouse him/ her

Vomiting (throwing up)
o
0= None
o
1= 1 - 2 times in 24 hours
o
2= 3 - 5 times in 24 hours
o
3= 6 or more times in 24 hours or requires intravenous hydration

Diarrhea (loose stools)
o
0= Fewer than 2 loose stools in 24 hours
o
1= 2-3 loose stools in 24 hours
o
2= 4-5 loose stools in 24 hours
o
3= 6 or more loose stools in 24 hours or requires intravenous hydration

Irritability
o
0= None
o
1= Requires more cuddling and is less playful than usual
o
2= More difficult to settle
o
3= Unable to console

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
Shivering
o
0= None
o
1= Present but does not interfere with daily activity
o
2= Interferes with daily activity
o
3= Prevents daily activity
Other solicited adverse events-related variables

Fever derived from measured body temperature (defined as ≥ 38.0°C/≥ 100.4°F). 
Measurement of temperature with a digital thermometer is preferred. In children 
younger than 36 months of age, measurement of temperature rectally is preferred.  
Oral, axillary or tympanic membrane routes may be used in older children.
The study staff must review the data entered into the Subject Diary Card as described in 
Section 3.4.2, Tools Used for Data Collection and Section 5.3.1, Postvaccination Visits.
All solicited local reactions and solicited systemic adverse events are considered causally 
related to vaccination.
Note: Any solicited adverse event that meets any of the following criteria must be entered 
into subjects’ source document (see Section 9.1, Source Documentation) and also as an 
adverse event on the Adverse Event eCRF:

Solicited local or systemic adverse event leading to the subject withdrawing from the 
study or the subject being withdrawn from the study by the Investigator (adverse 
event leading to withdrawal, see Section 7.1.3, Evaluation of Adverse Events).

Solicited local or systemic adverse event that otherwise meets the definition of a 
serious adverse event (see Section 7.1.4, Serious Adverse Events).

If a solicited local reaction or solicited systemic adverse event continues beyond day 7 
after vaccination, it will also be recorded as an unsolicited AE on the Adverse Event
eCRF.
7.1.2
Unsolicited Adverse Events
All unsolicited adverse events need to be collected during the treatment period, which is 
from informed consent to Day 29 for subjects with a history of previous influenza 
vaccination, or to Day 57 for subjects with an unknown or without an influenza 
vaccination history. During the follow-up period, from Day 29 or Day 57 respectively 
depending on previous influenza vaccination history up to the study completion visit, only 
those unsolicited adverse events that are either NOCD, lead to withdrawal or are Serious 
Adverse Events, need to be reported on the Adverse Events eCRF.

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An unsolicited adverse event is an adverse event that was not solicited using a Subject 
Diary Card and that was spontaneously communicated by a subject’s parent(s)/LAR(s) 
who has signed the informed consent form.
Potential unsolicited AE’s may be medically-attended (defined as symptoms or illnesses 
requiring hospitalization, or emergency room visit, or visit to/by a health care provider), 
or were of concern to the subject’s parent(s)/LAR. In case of such events, subject’s 
parent(s)/LAR(s) will be instructed to contact the site as soon as possible to report the 
event(s). Unsolicited AE may also be reported during postvaccination clinic visits or 
safety assessment phone calls. The detailed information about the reported unsolicited 
AE’s will be collected by a qualified health care professional during the interview and 
will be documented in the subject’s source records.  Depending on the timing and nature 
of the event, the AE should be reported in the AE eCRF (see Section 7.1.3, Evaluation of 
Adverse Events to Section 7.1.5, Methods of Recording Adverse Events and Serious 
Adverse Events).
An unsolicited AE may be considered a worsening of symptoms or illnesses reported in 
the Medical History eCRF (see Section 5.1.2, Screening).
7.1.3
Evaluation of Adverse Events
Every effort should be made by the Investigator to evaluate safety information reported 
by a subject for an underlying diagnosis and to capture this diagnosis as the event in the 
AE page. In other words, the practice of reporting only symptoms (e.g., “cough” or “ear 
pain”) are better reported according to the underlying cause (e.g., “asthma exacerbation” 
or “otitis media”).
The severity of events reported on the Adverse Events eCRF will be determined by the 
investigator as:
Mild:
transient with no limitation in normal daily activity.
Moderate:
some limitation in normal daily activity.
Severe:
unable to perform normal daily activity.
The relationship of the study treatment to an AE will be determined by the Investigator 
based on the following definitions:
1. Not Related
The AE is not related to an investigational vaccine if there is evidence that clearly 
indicates an alternative explanation. If the subject has not received the vaccine, the timing 

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of the exposure to the vaccine and the onset of the AE are not reasonably related in time, 
or other facts, evidence or arguments exist that reasonably suggest an alternative 
explanation, then the AE is not related.
2. Related
a.
Possibly Related
The administration of the investigational vaccine and AE are considered reasonably 
related in time and the AE could be explained by exposure to the investigational vaccine 
or by other causes.
b. Probably Related
Exposure to the investigational vaccine and AE are reasonably related in time and no 
alternative explanation has been identified.
The relationship of the study treatment to an unsolicited AE will be determined by the 
investigator. 
Note: solicited AEs will not be evaluated for relationship to study treatment, as solicited 
events are by default considered as related to study vaccine in this study. Grading for 
severity of solicited local and systemic AEs is described in the SAP.
Adverse events will also be evaluated by the investigator for the co-existence of any of 
the other following conditions:

“Medically-attended adverse event”: an adverse event requiring hospitalization, or 
emergency room visit, or visit to/by a health care provider.  

NOCDs: an adverse event that represents a new diagnosis of a chronic medical 
condition that was not present or suspected in a subject prior to study enrollment.

AEs leading to withdrawal: adverse events leading to study or vaccine withdrawal.
If solicited or unsolicited adverse events have been reported and the subject’s 
parent(s)/LAR(s)indicated that the symptoms required medical attendance or were of 
concern, the subject’s parent(s)/LAR(s) must be contacted for further information.
When the subject’s parent(s)/LAR(s) is contacted for any of these reasons, the contact 
must be documented in the subject’s source documentation.
All AEs, regardless of severity, will be monitored until resolution or until the investigator 
assesses them as chronic or stable. All subjects experiencing AEs - whether considered 
associated with the use of the study vaccine or not - must be monitored until symptoms 

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subside and any abnormal laboratory values have returned to baseline, or until there is a 
satisfactory explanation for the changes observed, or until death, in which case a full 
pathologist’s report should be supplied, if possible. The investigator’s assessment of 
ongoing Adverse Events at the time of each subject’s last visit should be documented in 
the subject’s source document.
7.1.4
Serious Adverse Events
A serious adverse event (SAE) is defined as any untoward medical occurrence that at any 
dose results in one or more of the following:

Death.

Is life-threatening (ie, the subject was, in the opinion of the investigator, at 
immediate risk of death from the event as it occurred); it does not refer to 
an event which hypothetically might have caused death if it were more 
severe.

Required or prolonged hospitalization.

Persistent or significant disability/incapacity (ie, the event causes a 
substantial disruption of a person’s ability to conduct normal life 
functions).

Congenital anomaly/or birth defect.

An important and significant medical event that may not be immediately 
life threatening or resulting in death or hospitalization but, based upon 
appropriate medical judgment, may jeopardize the subject or may require 
intervention to prevent one of the other outcomes listed above.
Adverse events which do not fall into these categories are defined as non-serious.
It should be noted that a severe adverse event need not be serious in nature and that a 
serious adverse event need not, by definition, be severe.
Serious adverse events will be captured on the Adverse Events eCRF. All SAEs will be 
evaluated by the investigator for relationship of the event to study vaccine. SAEs that are 
determined to be possibly or probably related to the study vaccine should be reported to 
the Sponsor as related/suspected events.
The relationship of the study treatment to an SAE will be determined by the investigator 
based on the following definitions:
1. Related/suspected
The SAE is judged by the investigator to be possibly or probably related to the study 
vaccine on the AE CRF page (see Section 7.1.3, Evaluation of Adverse Events).

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2. Not Related
The SAE is not related if exposure to the study vaccine has not occurred, or the 
occurrence of the SAE is not reasonably related in time, or the SAE is considered 
unlikely to be related to use of the study vaccine, i.e. there are no facts (evidence) or 
arguments to suggest a causal relationship.
The relationship of the study vaccine to an SAE will be determined by the investigator.
In addition, SAEs will be evaluated by the Sponsor or designee for “expectedness.” An 
unexpected AE is one that is not listed in the current Summary of Product Characteristics 
or the Investigator’s Brochure (IB) or an event that is by nature more specific or more 
severe than a listed event.
In addition, a pre-existing event or condition that results in hospitalization should be 
recorded on the Medical History CRF. If the onset of an event occurred before the subject 
entered the study (eg, any pre-planned hospitalization for conditions like cosmetic 
treatments or for non-emergency routine visits for a pre-existing condition), the 
hospitalization would not lead to an AE being classified as serious unless, in the view of 
the investigator, hospitalization was prolonged as a result of participation in the clinical 
study or was necessary due to a worsening of the pre-existing condition.
7.1.4.1
Adverse Events of Special Interest
Not applicable.
7.1.5
Methods for Recording Adverse Events and Serious Adverse Events
Findings regarding Adverse Events must be reported on an Adverse Event /SAE CRF, as 
specified in Section 7.1.1, Solicited adverse events. All findings in subjects experiencing 
AEs must be reported also in the subject's source document.
All SAEs which occur during the course of the study, whether considered to be associated 
with the study vaccination or not, must be reported within the EDC system within 24 
hours of the site becoming aware of the event to Seqirus or its designee. Specific 
instructions and contact details for collecting and reporting SAEs to Seqirus will be 
provided to the investigator.
All SAEs are also to be documented on the Adverse Events CRF. Any medication or 
other therapeutic measures used to treat the AE will be recorded on the appropriate 
CRF(s) in addition to the outcome of the AE.

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After receipt of the initial report, representatives of Seqirus or its designee will contact the 
investigator if it is necessary to obtain further information for assessment of the event.
All SAEs must be reported by the investigator to his/her corresponding IRB in accordance 
with institutional policy/regulatory requirements and adequate documentation of this 
notification must be provided to the Sponsor.
Seqirus or its designee must also comply with the applicable regulatory requirement(s) 
related to the reporting of suspected unexpected serious adverse vaccine reactions (also 
known as SUSARs) to the regulatory authority(ies) and the IRB. If a SUSAR or other 
safety signal relating to use of one of the study vaccines is reported to Seqirus or its 
designee, the Sponsor or designee will communicate the information to the investigator 
and the Sponsor or designee will be responsible for submitting this information to the IRB
and other relevant authorities.
7.1.5.1
Post-Study Events
Any SAE that occurs outside of the protocol-specified follow-up period and is considered 
to be caused by the study vaccine must be reported to Seqirus or its designee. These SAEs 
will be processed by Seqirus or its designee as during the course of the study, until 180 
days after study completion. Instructions and contact details for collecting and reporting 
these suspected SAEs will be provided to the investigator.
7.1.6
Pregnancies
Not applicable.
7.1.7
Safety Laboratory Measurements
No scheduled safety laboratory measurements are planned for this study.
7.2
Efficacy Assessment
Not applicable.
7.3
Immunogenicity Assessment
The measure of immunogenicity used in this study are standard, ie, widely accepted and 
generally recognized as reliable, accurate, and relevant (able to describe the quality and 
extent of the immune response).
The immunogenicity analyses will evaluate immunogenicity of QIVc measured by the 
HAI and microneutralization assay by titrating antibodies against the influenza strains 

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homologous to the seasonal vaccine in the immunogenicity group of subjects (see Section 
2.1, Primary Immunogenicity Objective, Section 2.2, Secondary Immunogenicity 
Objectives, and Table 7.3-1). The homologous cell-mediated immunity (CMI) response 
will be evaluated in the CMI group of subjects as an exploratory immunogenicity 
objective. In case of additional exploratory immunogenicity analyses, the immune 
response will be further characterized similar to the analysis of secondary 
immunogenicity endpoints.
The time points for the evaluation of antibody responses after vaccination will help to 
inform how a subject responds to the QIVc vaccine compared to the influenza comparator 
vaccine at Day 1 (baseline) and 29 (previously vaccinated subjects) or at Day 1 (baseline), 
and Day 57 (not previously vaccinated subjects) for peak antibody responses to the strains 
selected for the seasonal vaccine are typically observed after 4 weeks of vaccination.
Blood will be drawn for evaluation of CMI at Day 1 and Day 29 (previously vaccinated 
subjects) or at Day 1 and Day 57 (not previously vaccinated subjects).
HAI antibody responses will be evaluated for A/H1N1 and both B strains, and 
neutralizing antibody responses will be evaluated for the A/H3N2 strain in the 
immunogenicity group of subjects (primary immunogencity evaluation). Recent 
evolutionary changes in A/H3N2 hemagglutinin have resulted in the loss of capacity to 
agglutinate, and therefore the two A/H3N2 endpoints will be assessed using the MN assay. 
Cell-derived target virus data will be used for the primary immunogenicity analysis in 
both assays.
For the secondary immunogenicity evaluation, HAI antibody responses will be evaluated 
in the immunogenicity group of subjects for A/H1N1 and both B strains, and neutralizing 
antibody responses will be evaluated for A/H3N2 strains, using egg- and cell-derived 
target virus in both assays. 

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Table 7.3-1
Percentage of Subjects in the Immunogenicity Group Evaluation of 
Cell- and Egg-Derived Target Virus
Strain
Assay
Cell-derived Target Virus
Egg-derived Target Virus
A/H1N1
HAI assay
100%1
100%2
A/H3N2
MN assay
100%1
100%2
B/Vic
HAI assay
100%1
100%2
B/Yam
HAI assay
100%1
100%2
Abbreviations: HAI = hemagglutination inhibition; MN = microneutralization;
1 covered by primary objective
2 covered by secondary objective 
Neutralizing antibody responses against A/H1N1 and both B strains will be evaluated in a 
subset of subjects (20% of total number of subjects enrolled for immunogenicity). 
Cell-derived target viruses will be used for secondary immunogenicity evaluation of 
neutralizing antibody responses.
Serology tests conducted for the primary immunogenicity evaluation will be prioritized 
over tests conducted for the secondary immunogenicity evaluation, which will be 
prioritized over exploratory immunogenicity testing, as presented in Table 7.3-2. 
Testing will be conducted by Seqirus or designated laboratory in a blinded manner 
towards the treatment arm. 

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Table 7.3-2
Priority Ranking of Serology Testing in Study V130_10
Strain
Assay
Reagents Source
Priority Rank
A/H1N1
HAI
Cell-derived reagents
1
A/H3N2
MN
Cell-derived reagents
B/Yamagata
HAI
Cell-derived reagents
B/Victoria
HAI
Cell-derived reagents
A/H1N1
HAI
Egg-derived reagents
2
A/H3N2
MN
Egg-derived reagents
B/Yamagata
HAI
Egg-derived reagents
B/Victoria
HAI
Egg-derived reagents
A/H1N1 (subset only)
MN
Cell-derived reagents
3
B/Yamagata (subset only)
MN
Cell-derived reagents
B/Victoria (subset only)
MN
Cell-derived reagents
Exploratory testing –
A/H3N2
HAI
Cell-derived reagents
4
Exploratory testing –
A/H3N2
HAI
Egg-derived reagents
Abbreviations: HAI = hemagglutination inhibition; MN = microneutralization 

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8.
STATISTICAL CONSIDERATIONS
A complete description of the statistical analyses and methods will be available in the 
Statistical Analysis Plan, which will be finalized before the database is locked for the 
treatment period data.
8.1
Endpoints
8.1.1
Primary Endpoint(s).
8.1.1.1
Primary Safety Endpoints
Not applicable.
8.1.1.2
Primary Efficacy Endpoints
Not applicable.
8.1.1.3
Co-Primary Immunogenicity Endpoints
Serum HAI antibody titer against A/H1N1, B/Victoria and B/Yamagata vaccine strains at 
Day 29/57, using cell-derived target virus:

Geometric Mean Titer (GMT) by HAI assay

Seroconversion rate (SCR) defined as the percentage of subjects with either a 
prevaccination HAI titer <1:10 and a postvaccination HAI titer ≥1:40, or a 
prevaccination HAI titer ≥1:10 and a ≥4-fold increase in post vaccination HAI
titer
Serum neutralizing antibody titer against A/H3N2 vaccine strain at Day 29/57, using cell-
derived target virus:

GMT by MN assay

SCR defined as the percentage of subjects with either a prevaccination MN titer 
<1:10 and a postvaccination MN titer ≥1:40 or a prevaccination MN titer ≥1:10 
and a ≥4-fold increase in post vaccination MN titer
Derived Variables:

The GMT ratio (QIV/QIVc) for each strain

The inter-group difference in the SCRs (QIV minus QIVc) for each strain

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The noninferiority of QIVc compared to US-licensed QIV will be assessed for the eight 
co-primary endpoints of geometric mean titer (GMT) and seroconversion rate (SCR) for 
each cell-derived target virus strain included in QIVc as follows:

The GMT ratio for the A/H1N1 strain (HAI assay)

The GMT ratio for the A/H3N2 strain (MN assay)

The GMT ratio for the B Yamagata strain (HAI assay)

The GMT ratio for the B Victoria strain (HAI assay)

The difference between the SCRs for the A/H1N1 strain (HAI assay)

The difference between the SCRs for the A/H3N2 strain (MN assay)

The difference between the SCRs for the B Yamagata strain (HAI assay)

The difference between the SCRs for the B Victoria strain (HAI assay)
8.1.2
Secondary Endpoints
8.1.2.1 Secondary Safety Endpoints
The measures for assessing safety and reactogenicity are as follows:
1. Percentage of subjects with solicited AEs within 7 days after each study 
vaccination
2. Percentage of subjects with any unsolicited AEs from Day 1 to Day 29 (in
previously vaccinated subjects) and from Day 1 to Day 57 (in not 
previously vaccinated subjects)
3. Percentage of subjects with any SAEs, NOCDs, AEs leading to withdrawal
during the entire study period (ie, from Day 1 to Day 181 for previously 
vaccinated subjects or from Day 1 to Day 209 for not previously 
vaccinated subjects).
8.1.2.2
Secondary Efficacy Endpoints
Not applicable.
8.1.2.3
Secondary Immunogenicity Endpoints
Humoral immune response in terms of HAI antibodies against A/H1N1, B/Victoria and 
B/Yamagata strains, using cell- and egg-derived target virus:

GMT by HAI assay at Days 1 and 29/57

Geometric Mean Ratio (GMR), defined as the fold increase in serum HAI 
GMT postvaccination (Day 29/57) compared to prevaccination (Day 1)

Seropositivity rates (percentages of subjects with HAI titer ≥1:10) at Days 
1 and 29/57

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
Percentages of subjects with HAI titer ≥1:40 at Days 1 and 29/57

SCR by HAI assay
Derived variables:

The GMT ratio (QIV/QIVc) for each strain

The inter-group difference in the SCRs (QIV minus QIVc) for each strain
Neutralizing antibody titers against A/H3N2 vaccine strains, using cell- and egg-derived 
target virus:

GMT by MN assay at Days 1 and 29/57

GMR, defined as the fold increase in serum MN GMT postvaccination
(Day 29/57) compared to prevaccination (Day 1)

Seropositivity rates (percentages of subjects with MN titer ≥ 1:10 (LLOQ)) 
at Days 1 and 29/57

SCR by MN assay, where SCR for MN is defined as the percentage of 
subjects with either a prevaccination MN titer <1:10 and a postvaccination
MN titer ≥1:40, or a prevaccination MN titer ≥1:10 (LLOQ)) and a ≥4-fold 
increase in post vaccination MN titer
Derived variables:

The GMT ratio (QIV/QIVc) for each strain

The inter-group difference in the SCRs (QIV minus QIVc) for each strain
Neutralizing antibody titers against A/H1N1, B/Victoria and B/Yamagata vaccine strains, 
in a subset of subjects:

GMT by MN assay at Days 1 and 29/57

GMR, defined as the fold increase in serum MN GMT postvaccination
(Day 29/57) compared to prevaccination (Day 1)

Seropositivity rates (percentages of subjects with MN titer ≥1:10 (LLOQ)) 
at Days 1 and 29/57

SCR by MN assay
Derived variables:

The GMT ratio (QIV/QIVc) for each strain

The inter-group difference in the SCRs (QIV minus QIVc) for each strain
8.1.3
Exploratory Endpoints
8.1.3.1
Exploratory Safety Endpoints
Not applicable.

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8.1.3.2
Exploratory Efficacy Endpoints
Not applicable.
8.1.3.3
Exploratory Immunogenicity Endpoints
The CMI responses to vaccination are considered exploratory endpoints in the study. 
CD4+ T-cell responses will be measured by staining and flow cytometry at baseline (Day 
1), and Day 29 (previously vaccinated subjects) or at baseline (Day 1) and Day 57 (not 
previously vaccinated subjects), in approximately 84 subjects (2:1 ratio, 56 subjects in 
QIVc and 28 subjects in licensed QIV group) as measured by numbers of cells 
expressing interferon gamma (IFN-γ), interleukin 2 (IL-2), tumor necrosis factor alpha 
(TNF-α), and other markers as may be practical within the available volumes of
blood/cells (further detailed in the lab manual).
In case of additional exploratory immunogenicity analyses, the immune response will be 
further characterized similar to the analysis of secondary immunogenicity endpoints.
The analysis of the exploratory endpoints will be fully described in the SAP.
8.2
Success Criteria
The study is considered successful if all the 8 co-primary endpoints are achieved. 
8.2.1
Success Criteria for Primary Objective(s)
8.2.1.1
Success Criteria for Primary Safety Objective(s)
Not applicable.
8.2.1.2
Success Criteria for Primary Efficacy Objective(s)
Not applicable.
8.2.1.3
Success Criteria for Primary Immunogenicity Objective(s)
The noninferiority of QIVc compared to the US-licensed QIV will be assessed by the 8 
co-primary endpoints of GMT and SCR for the A/H1N1, A/H3N2 and the B strains. 
Definitions for noninferiority based on endpoints measured by hemagglutination 
inhibition assay (HAI) are derived from the FDA Guidance on seasonal inactivated 
influenza vaccines (Guidance for Industry Clinical Data Needed to Support Licensure of 
Seasonal Inactivated Influenza Vaccines 2007). A modified definition will be applied to 
assessment of the endpoint based on the MN assay. Specifically, Seqirus QIVc will be 

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considered to be non-inferior to the US-licensed QIV if, for each of the four strains, the 
following statistical criteria are met: 
A/H1N1 and B strains: 

The upper bound of the two-sided 95% confidence interval (CI) on the ratio of the 
HAI GMT does not exceed 1.5. The HAI GMT ratio will be calculated as HAI GMT
US-licensed comparator QIV divided by HAI GMT QIVc 

The upper bound of the two-sided 95% CI on the difference between the HAI 
SCRs does not exceed 10%. The difference in HAI SCRs will be calculated as 
HAI Seroconversion US-licensed comparator QIV minus HAI Seroconversion 
QIVc. The 95% CI will be computed based on the binomial distribution
A/H3N2 strain only:

The upper bound of the two-sided 95% confidence interval (CI) on the ratio of the 
MN GMT does not exceed 1.5. The MN GMT ratio will be calculated as MN GMT 
US-licensed comparator QIV divided by MN GMT QIVc.

The upper bound of the two-sided 95% CI on the difference between the SCRs does 
not exceed 10%. The difference in SCRs will be calculated by (Seroconversion US-
licensed comparator QIV–Seroconversion Seqirus QIVc). The 95% CI will be 
computed based on the binomial distribution
No adjustment for type I error for multiplicity will be made. 
8.2.2
Success Criteria for Secondary Objective(s)
8.2.2.1
Success Criteria for Secondary Safety Objective(s)
Not applicable.
8.2.2.2
Success Criteria for Secondary Efficacy Objective(s)
Not applicable.
8.2.2.3
Success Criteria for Secondary Immunogenicity Objective(s)
Not applicable.
8.3
Analysis Sets
There will be 4 analysis populations defined for the study analyses. 

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8.3.1
All Enrolled Set
All screened subjects who provide informed consent, receive subject ID, and provide
demographic and/or baseline screening information, regardless of the subject’s
randomization and treatment status in the study.
8.3.2
Full Analysis Set
All subjects in the All Enrolled Set who are randomized and receive a study vaccination. 
The Full Analysis Set (FAS) will be used to produce summaries and listings of subject 
characteristics.
8.3.3
Safety Set
The Safety Set will comprise all subjects in the FAS who received at least one dose or
partial dose of Study Vaccine and have provided any evaluable follow-up safety data. The
safety set will be used to produce summaries and listings of all safety data.
8.3.4
Evaluable Set – Immunogenicity Analysis
The Evaluable Set for immunogenicity analyses will comprise all subjects in the FAS 
who:

receive vaccine on Day 1

provide serology specimens which yield valid serology assay results from 
both Day 1 and Day 29 (Previously vaccinated subjects) or Day 1 and Day 
57 (Not previously vaccinated subjects)

do not experience a laboratory-confirmed influenza illness between Day 1, 
Day 29, and Day 57

do not receive any prohibited medication during the study that is medically 
assessed to potentially impact immunogenicity results
8.3.5
Per Protocol Set
The Per-Protocol Set (PPS) will comprise all subjects in the Evaluable Set who do not
have any protocol deviations that are medically assessed as potentially impacting on
immunogenicity results.
The Per Protocol Set will be the primary population of interest for the primary/secondary
immunogenicity analysis and a supporting analysis will be performed using the Evaluable
Set. Membership of the PPS will be determined prior to unblinding the study.

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Duplicate tables of primary and secondary immunogenicity analyses may also be
produced based on the Evaluable population if there is >1% difference in the total number
of subjects between the Per-Protocol Population and the Evaluable Population. The
decision to produce tables based on the Evaluable Population will be made by Seqirus
after population sets are finalized and prior to unblinding.
Examples for subjects excluded due to other reasons than protocol deviations are subjects
who withdrew informed consent.
In case of misrandomization with regard to treatment arm, the subject is excluded from
the PPS.
If a subject is unblinded during the study, except for SUSAR, he/she will be excluded
from the PPS.
8.3.6
Subgroups
The immunogenicity analysis will be performed by stratifying for the following
subgroups:

Subjects with a prevaccination HAI titer < 1:10 and prevaccination HAI  
titer ≥1:10

Subjects with a prevaccination MN titer < LLOQ and prevaccination MN 
titer ≥LLOQ

Subjects with and without recent seasonal influenza vaccine (defined as 
influenza vaccine within the past 12 months).

Subjects "previously vaccinated" and "not previously vaccinated.”

Subjects will be additionally analyzed by age, center, gender, race and 
ethnicity.
Safety analyses will also be performed by age groups and time periods as detailed in the 
SAP.
8.3.7
Protocol Deviations
A protocol deviation is any change, divergence, or departure from the study design or 
procedures of a study protocol. A protocol deviation may be a reason to remove data from 
an analysis set at the time of analysis. Clinical study report (CSR)-reportable (major) 
protocol deviations will be defined as exclusionary from the analysis according to 
protocol objectives and endpoints, which will be specified in the Protocol Deviation 
Specifications to this study protocol. In some cases, exclusion of data may be due to a 
reason other than a protocol deviation, e.g. early termination.

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8.4
Statistical Analysis Plan
A complete description of the statistical analyses and methods will be available in the
Statistical Analysis Plan (SAP), which will be finalized prior to unblinding.
8.4.1
Analysis of Demographic and Baseline Characteristics
Descriptive statistics (mean, standard deviation, median, minimum and maximum) for
age, height, weight, BMI, and comorbidity score at enrollment will be calculated overall
and by vaccine groups.
Distributions of subjects by sex, ethnic origin (race, ethnicity), and previous vaccination
status will be summarized overall, and by vaccine group.
8.4.1.1
Concomitant Medications
Use of concomitant medication will be presented by treatment, age cohort, therapeutic
area, and preferred drug name.
Concomitant medications are all medications taken during the study period, including
those started before but ongoing at vaccination.
If a start date for a medication is partially or fully missing, and it is unclear as to whether
the medication is prior or concomitant, it will be assumed that it is concomitant.
Medications will be coded using the WHO Drug dictionary.
8.4.2
Analysis of Primary Objective(s)
8.4.2.1
Analysis of Primary Safety Objective(s)
Not applicable.
8.4.2.1.1
Analysis of Extent of Exposure
Not applicable.
8.4.2.1.2
Analysis of Solicited Local, Systemic and Other Adverse Events
Not applicable.
8.4.2.1.3
Analysis of Unsolicited Adverse Events
Not applicable.

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8.4.2.1.4
Analysis of Safety Laboratory Values
Not applicable.
8.4.2.2
Analysis of Primary Efficacy Objective(s)
8.4.2.2.1
Statistical Hypothesis
Not applicable.
8.4.2.2.2
Analysis Sets
Not applicable.
8.4.2.2.3
Statistical Methods
Not applicable.
8.4.2.3
Analysis of Primary Immunogenicity Objective(s)
The primary immunogenicity objective is:
1. To demonstrate that vaccination with QIVc elicits an immune response that is 
not inferior to that of an US-licensed QIV containing the recommended strains 
for the season, in subjects 6 months through 47 months of age, as measured by 
hemagglutination inhibition (HAI) assay for A/H1N1, B/Yamagata and 
B/Victoria strains and by microneutralization (MN) assay for A/H3N2 strain, 
using cell-derived target viruses.
8.4.2.3.1
Statistical Hypothesis
Noninferiority of QIVc to US-licensed QIV
The noninferiority of QIVc compared to the US-licensed QIV will be assessed by the 8 
co-primary endpoints of GMT and SCR for the A/H1N1, A/H3N2 and the B strains. 
Definitions for noninferiority based on endpoints measured by HAI are derived from the
FDA Guidance on seasonal inactivated influenza vaccines (Guidance for Industry 
Clinical Data Needed to Support Licensure of Seasonal Inactivated Influenza Vaccines 
2007). A modified definition will be applied to assessment of the endpoint based on the 
MN assay. Specifically, Seqirus QIVc will be considered to be noninferior to the 
US-licensed QIV if, for each of the four strains, the following statistical criteria are met: 
A/H1N1 and B strains: 

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
The upper bound of the two-sided 95% confidence interval (CI) on the ratio of the 
HAI GMTs does not exceed 1.5. The HAI GMT ratio will be calculated as HAI 
GMT US-licensed comparator QIV divided by HAI GMT QIVc 

The upper bound of the two-sided 95% CI on the difference between the HAI 
SCRs does not exceed 10%. The difference in HAI SCRs will be calculated as 
HAI Seroconversion US-licensed comparator QIV minus HAI Seroconversion 
QIVc. The 95% CI will be computed based on the binomial distribution
A/H3N2 strain only:

The upper bound of the two-sided 95% confidence interval (CI) on the ratio of the 
MN GMTs does not exceed 1.5. The MN GMT ratio will be calculated as MN GMT 
US-licensed comparator QIV divided by MN GMT QIVc. 

The upper bound of the two-sided 95% CI on the difference between the MN 
SCRs does not exceed 10%. The difference in MN SCRs will be calculated as MN

Seroconversion US-licensed comparator QIV minus MN Seroconversion QIVc. 
The 95% CI will be computed based on the binomial distribution.
In mathematical notation the statistical hypotheses to be tested for the primary 
noninferiority immunogenicity analysis corresponds to:

H0: Ri > 1.5, for any strain

Ha: Ri ≤ 1.5, for any strain, and 

H0: Di > 10, for any strain

Ha: Di ≤ 10, for all strain
where Ri is any of the 4 strain-specific post immunogenicity dose GMT ratios: 

(US-licensed comparator QIV) / (QIVc) for B/Yamagata strain 

(US-licensed comparator QIV) / (QIVc) for B/Victoria strain 

(US-licensed comparator QIV) / (QIVc) for A/H1N1 strain 

(US-licensed comparator QIV) / (QIVc) for A/H3N2 strain 
and Di is the 4 strain-specific post-dose SCR difference, namely

(US-licensed comparator QIV) - (QIVc) for B/Yamagata strain 

(US-licensed comparator QIV) - (QIVc) for B/Victoria strain 

(US-licensed comparator QIV) - (QIVc) for A/H1N1 strain 

(US-licensed comparator QIV) - (QIVc) for A/H3N2 strain 
No adjustment will be made for multiple comparisons.

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8.4.2.3.2
Analysis Sets
The Per Protocol Set will be used for the primary immunogenicity analysis and a
supporting analysis will be performed using the Evaluable Set, as noted in Section 8.3.4.
Evaluable Set – Immunogenicity Analysis. Duplicate tables of primary and secondary
immunogenicity analyses may also be produced based on the Evaluable population if
there is >1% difference in the total number of subjects between the Per-Protocol
Population and the Evaluable Population.
8.4.2.3.3
Statistical Methods
All statistical analyses for HAI (or MN) titers will be performed on the logarithmically
transformed (base 10) values. Individual HAI titers below the detection limit (<10) will 
be set to half of that limit (5). Individual MN titers below the lower limit of quantification 
(LLOQ), will be set to half of that limit (1/2* LLOQ).
Co-primary immunogenicity endpoints of GMT and SCR for each virus strain contained 
in the vaccine will be assessed in subjects 6 Months through 47 Months of Age overall. 
Primary analysis will be performed in subjects 6 Months through 47 Months of Age for 
the Per-Protocol Set. The difference in SCRs will be presented with exact 95% (CIs). 
Each of the four strains will be analyzed separately.
To determine the GMT ratio (adjusted analysis) a general linear model (GLM) will be 
fitted on log transformed (base ten) postvaccination HAI (or MN) titers as the outcome 
variable and terms for covariates: vaccine treatment, prevaccination HAI (or MN) titer, 
age stratum, gender, vaccination history, age-by-vaccine interaction and study site. The 
complete set of covariates that may be used in the model to calculate the adjusted GMT
will be specified in the SAP.
Potential covariate interaction effects will also be examined in the fit of the GLM. From 
the model, an adjusted difference in least square means (on the log scale) will be 
produced with 95% confidence limits. The estimated difference and the confidence limits 
will be back transformed to obtain an adjusted GMT ratio with 95% confidence limits. 
Each of the four strains will be analyzed separately. The adjusted GMT ratio will be the 
result for which the noninferiority assessment of the HAI (or MN) GMT co-primary 
endpoint will be based on. 
The statistical models might be reduced in case they fail to converge. Further details will 
be provided in the Statistical Analysis Plan.
The complete set of covariates that may be used in the model to calculate the adjusted 
GMT ratio will include treatment group (2 treatments), age sub-group, gender (male or 
female), influenza vaccination received prior year (Y or N), prevaccination mean GMT 
titer (value) and investigator site (site identifier)

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The GLM specification is: 
Adjusted Analysis GMT Model: Log-transformed Postvaccination HAI (or MN) Titer = 
Vaccine + Age Strata + Gender + Vaccination History [y/n] + Log-transformed 
Prevaccination HAI (or MN) Titer + Site + Age Strata*Vaccine.
For any strain, the interaction term Age Strata*Vaccine will be removed from the fit of the 
model if it is assessed to be not significant.
The measure of the unadjusted GMT ratio based on postvaccination GMT only will also 
be presented.
Binary data (ie, percentages of subjects with seroconversion and with titer ≥1:40) will be 
summarized for each group using unadjusted estimates and will be reported together with 
two-sided exact 95% CIs. No multiplicity adjustment to the CI levels will be 
implemented.
If all 8 co-primary endpoints fulfilled noninferiority criteria then overall noninferiority 
of  QIV compared to the US-licensed comparator QIV was to be concluded.
Handling of Missing Values for Immunogenicity Data
For immunogenicity data, it may be reasonable to consider missing immunogenicity
values as missing completely at random (MCAR), ie, not informative. Therefore, the 
immunogenicity and key secondary analyses will comprise a complete case analysis only, 
without introducing any bias. Imputation methods will not be used. Further details of the 
statistical methods will be provided in the SAP.
8.4.3
Analysis of Secondary Objective(s)
8.4.3.1
Analysis of Secondary Safety Objective(s)
8.4.3.1.1
Analysis of Extent of Exposure
The number of subjects actually receiving the vaccinations will be summarized by 
vaccine group.
8.4.3.1.2
Analysis of Solicited Local, Systemic and Other Adverse Events
All solicited adverse events will be summarized according to defined severity grading 
scales. 
Frequencies and percentages of subjects experiencing each adverse event will be 
presented for each symptom severity. Summary tables showing the occurrence of any 
local or systemic adverse event overall and at each time point will also be presented.

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Postvaccination solicited adverse events reported for 7 days after each vaccination and 
will be summarized for the intervals day 1 to 3, day 4 to 7, day 1 to 7 by maximal severity 
and by vaccine group, excluding the 30-minute measurement, which will be summarized 
separately. Injection-site erythema, ecchymosis, and induration will be summarized 
according to categories based on linear measurements: Type I: none (0 mm), any (1 to 
<10 mm, 10 to 25 mm, 26 to 50 mm, >50 mm); Type II: Grade 0 (<10 mm), any (10 to 
25 mm, 26 to 50 mm, >50 mm) (see SAP for further details). 
Injection site tenderness and systemic adverse events (except fever) occurring up to 7 
days after each vaccination will be summarized according to “mild”, “moderate” or 
“severe” categorization. For the definition of severity grades see Section 7.1.3, Evaluation 
of Adverse Events of the protocol and SAP.
Each solicited local and systemic adverse event will also be further summarized as “none” 
versus “any.” “Any” will include reactions with a diameter of at least 1 mm. 
Implausible measurements (for further definition see SAP) will be left out of the analysis.
Use of antipyretics and analgesics will be summarized by frequency, by type of use 
(prophylactic versus treatment) and percentage of subjects reporting use.
Body temperature will be summarized by 0.5°C and 1.0°C increments from 36.0°C to 
≥40°C and will be broken down by route of measurement and by age cohort.
8.4.3.1.3
Analysis of Unsolicited Adverse Events
This analysis applies to all adverse events occurring during the study, judged either as 
probably related, possibly related, or not related to vaccination by the investigator, 
recorded in AE CRF, with a start date on or after the date of first vaccination. AE starting 
prior to the first vaccination will only be listed. 
The original verbatim terms used by investigators to identify AEs in the CRFs will be 
mapped to preferred terms using the Medical Dictionary for Regulatory Activities 
(MedDRA) dictionary. The AEs will then be grouped by MedDRA preferred terms into 
frequency tables according to system organ class (SOC). All reported AEs, as well as AEs 
judged by the investigator as at least possibly related to study vaccine, will be 
summarized according to system organ class and preferred term within system organ 
class. These summaries will be presented by vaccination group and by interval of study 
observation (Day 1 to Day 29, Day 29 to Day 181 in “previously vaccinated” subjects and 
Day 1 to Day 57, Day 57 to Day 209 in “not previously vaccinated” subjects). When an 
AE occurs more than once for a subject, the maximal severity and strongest relationship 
to the vaccine group will be counted.

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Separate summaries will be produced for the following categories:

SAE

NOCDs

Adverse events that are possibly or probably related to vaccine

Adverse event leading to withdrawal or early termination

Adverse event resulting in death 

Adverse events leading to a medically-attended visit during the treatment 
period
Data listings of all adverse events will be provided by subject. In addition, adverse events 
in the categories above will be provided as listed data.
8.4.3.1.4
Statistical Hypotheses
Not applicable.
8.4.3.1.5
Analysis Sets
Not applicable.
8.4.3.1.6
Statistical Methods
Not applicable.
8.4.3.2
Analysis of Secondary Efficacy Objective(s)
8.4.3.2.1
Statistical Hypothesis
Not applicable.
8.4.3.2.2
Analysis Sets
Not applicable.
8.4.3.2.3
Statistical Methods
Not applicable.
8.4.3.3
Analysis of Secondary Immunogenicity Objective(s)
Characterization of immunogenicity of QIVc
The measures for immunogenicity will be determined by HAI and MN assay for Day 1 
and Days 29/57 (depending on influenza vaccination history). HAI will be evaluated in all 

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subjects, tested against A/H1N1 and both B strains. MN will also be evaluated in all
subjects, tested against A/H3N2 strain. 
Humoral immune response in terms of HAI antibodies against A/H1N1, B/Victoria and 
B/Yamagata strains, using cell- and egg-derived target virus:

GMT by HAI assay at Days 1 and 29/57

Geometric Mean Ratio (GMR), defined as the fold increase in serum HAI 
GMTs postvaccination (Day 29/57) compared to prevaccination (Day 1)

Seropositivity rates (percentages of subjects with HAI titer ≥1:10) at Days 
1 and 29/57

Percentages of subjects with HAI titer ≥1:40 at Days 1 and 29/57

SCR by HAI assay
Derived variables:

The GMT ratio (QIV/QIVc) for each strain

The inter-group difference in the SCRs (QIV minus QIVc) for each strain
Neutralizing antibody titers against A/H3N2 vaccine strains, using cell- and egg-derived 
target virus:

GMT by MN assay at Days 1 and 29/57

GMR, defined as the fold increase in serum MN GMT postvaccination
(Day 29/57) compared to prevaccination (Day 1)

Seropositivity rates (percentages of subjects with MN titer ≥1:10 (LLOQ)) 
at Days 1 and 29/57

SCR by MN assay
Derived variables:

The GMT ratio (QIV/QIVc) for each strain

The inter-group difference in the SCRs (QIV minus QIVc) for each strain
Neutralizing antibody titers against A/H1N1, B/Victoria and B/Yamagata vaccine strains, 
in a subset of subjects:

GMT by MN assay at Days 1 and 29/57

GMR, defined as the fold increase in serum MN GMT postvaccination
(Day 29/57) compared to prevaccination (Day 1)

Seropositivity rates (percentages of subjects with MN titer ≥1:10 (LLOQ))
at Days 1 and 29/57;

SCR by MN assay
Derived variables:

The GMT ratio (QIV/QIVc) for each strain

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
The inter-group difference in the SCRs (QIV minus QIVc) for each strain
8.4.3.3.1
Statistical Hypotheses
No statistical testing will be performed for the secondary immunogenicity
objectives.
8.4.3.3.2
Statistical Methods
All statistical analyses for HAI (or MN) titers will be performed on the logarithmically
transformed (base 10) values. Individual HAI titers below the detection limit (<10) will 
be set to half of that limit (5). Individual MN titers below the lower limit of quantification 
(LLOQ), will be set to half of that limit (1/2* LLOQ).
Unadjusted for GMT, GMRs and pertaining two-sided 95% CIs will be calculated
assuming log-normal distribution of the titers and will be completed by providing
minimum, maximum and median titers for each vaccine group.
Binary data (i.e. percentages of subjects with seroconversion and with titer ≥ 1:40) will be
summarized for each group using crude estimates and will be reported together with 2-
sided exact 95% CIs. No multiplicity adjustment to the CI levels will be implemented.
For immunogenicity data, it may be reasonable to consider missing immunogenicity
values as missing completely at random (MCAR), i.e. not informative. Therefore, the key
secondary analysis will comprise a complete case analysis only, without introducing any
bias. Imputation methods will not be used.
Further details of the statistical methods will be provided in the SAP.
8.4.4
Analysis of Exploratory Objectives
8.4.4.1
Analysis of Exploratory Safety Objectives
Not applicable.
8.4.4.2
Analysis of Exploratory Efficacy Objectives
Not applicable.

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8.4.4.3
Analysis of Exploratory Immunogenicity Objectives
Exploratory immunogenicity endpoints of homologous CMI responses will be
summarized using descriptive statistics by treatment group.
In case of additional exploratory immunogenicity analyses, the immune response will be 
further characterized similar to the analysis of secondary immunogenicity endpoints.
8.5
Sample Size and Power Considerations
QIVc will be tested against comparator, i.e. US-licensed comparator QIV. The treatment 
randomization ratio is 2:1 (Seqirus QIVc: Comparator QIV). This study is designed to 
achieve at least 90% power to demonstrate noninferiority for all of the 8 endpoints: 
seroconversion rates for 4 strains and GMT for 4 strains using a one-sided alpha of 0.025 
for each comparison. No alpha adjustment for multiple endpoints will be made. 
For comparisons of SCR a noninferiority margin of 10% (Comparator QIV-Seqirus 
QIVc) will be employed. It is assumed that the SCRs for A/H1N1 , B strains and A/H3N2 
based on TIVc are 81%, 69% and 85% respectively. These estimates are based on the 
estimated SCR rates of historical data, namely from study V58P16.
It is also assumed that the expected difference between antibody titers (QIV minus QIVc) 
is consistent with the SCR differences  reported as per V58P16, namely 7% for A/H1N1 
and 5% for A/H3N2 (based on the MN assay). 
It is assumed there is no difference between Seqirus QIVc and the comparator QIV for the 
B/strain.
For comparison of GMT ratio a noninferiority margin of 1.5 (Comparator QIV/ Seqirus 
QIVc, equivalent to a difference on the log scale of 0.405465108) will be employed for 
the assessment of the A/H1N1, A/H3N2 and B strains.  It is assumed that the GMT ratio’s 
for A/H1N1, A/H3N2 and B strains for QIVc are 1.49 for the A/H1N1, 1.00 for the 
A/H3N2 (based on the MN Assay) and 0.84 for the B-strain. These GMT ratio estimates 
are consistent to those observed from protocol V58P16. It is assumed that the standard 
deviation of log (titer) is 1.3 across all strains. 
Under these assumptions and with n evaluable = 1450 in the Seqirus QIVc group and 725 
in the Comparator QIV the power for 4 GMT ratio endpoints is 94.90% and the power for 
4 SCR endpoints is 99.40%. The overall global power of the 8 endpoints is then 
94.90%*99.40% = 94.33%. This provides a total N evaluable = 2175. Allowing for a 10% 
drop-out, 2418 subjects will be recruited for immunogencity assessment. Approximately 
84 additional subjects between 24 through 47 months of age will be enrolled to study 
CMI response, in order to have approximately 50 and 25 evaluable subjects in the QIVc 

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and Comparator QIV groups, respectively. Thus, approximately 2502 subjects will be 
enrolled in this study.
Sample size calculations were performed using PASS v12.0.02.
Table 8.5-1 summarizes the list of all co-primary endpoints with strains, the planned 
noninferiority margin and underlying assumptions used for the sample size computations.
Table 8.5-1
Summary of Assumptions Used for Sample Size Calculations
NI comparison
A/H1N1
A/H3N2
B strains
Test significance level, alpha (1-sided)
2.50%
2.50%
2.50%
Noninferiority Margin for the SCR comparison (%)
10
10
10
Assumed true SCR
81%
85%
69%
Power for SCR comparison tests for each strain (%)
100%
100%
99.7%
Global Power for 4 SCR Endpoints
99.40%
Noninferiority Margin for the GMT ratio
1.5
1.5
1.5
Common Standard Deviation of loge(titer) 
1.3
1.3
1.3
Power for GMT ratio tests for each strain (%)
100%
100%
97.42%
Global Power for 4 GMT ratio Endpoints
94.90%
Global Power for 8 Co-primary Endpoints
94.33%
Abbreviations: GMT = geometric mean titer; NI = noninferiority; SCR = serconversion rate.
Sample size calculations were performed using PASS v12.0.02.
8.6
Interim Analysis
No interim analysis is planned for this study. The final analysis of the primary and 
secondary immunogenicity endpoints will be conducted on cleaned and locked data once 
all subjects have completed all immunogenicity assessments (end of treatment period, i.e. 
up to 28 days following the last vaccination dose). At this time, the analysis of all solicited 
adverse events and of unsolicited adverse events reported during the treatment period will 
also be conducted. These results will be used to prepare a Clinical Study Report (CSR) with 
treatment period data. No individual unblinded listings will be generated at this stage. 

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This analysis constitutes the final analyses of the primary and secondary immunogenicity 
endpoints and therefore preserves the integrity of the clinical study results.

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9.
SOURCE DOCUMENTATION, STUDY MONITORING AND AUDITING
In order to ensure consistency across sites, study monitoring and auditing will be 
standardized and performed in accordance with the Sponsor’s or delegated contract 
research organization’s (CRO) standard operating procedures (SOPs) and applicable 
regulatory requirements (e.g., FDA, EMA, and ICH guidelines).
Prior to enrollment of the first study subject, Seqirus or delegate will train investigators 
and/or their study staff on the study protocol, all applicable study procedures, 
documentation practices and all electronic systems. CRFs supplied by the Sponsor must 
be completed for each enrolled subject (see Section 8.3.1, All Enrolled Set for definition 
of enrolled subject). Documentation of screened but not enrolled subjects must be 
maintained at the site and made available for review by the site monitor. Data and 
documents will be checked by the Sponsor and/or monitor.
9.1
Source Documentation
Prior to the start of the study, the site staff participating in the study conduct will be 
instructed on what documents will be required for review as source documents. The kinds 
of documents that will serve as source documents will be agreed between Sponsor or 
delegate and investigator and designees and specified in the SDA prior to subject 
enrollment.
In addition, source documentation must include all of the following: subject identification 
(on each page), eligibility and participation, proper informed consent procedures, dates of 
visits, adherence to protocol procedures, adequate reporting and follow-up of adverse 
events, documentation of prior/concomitant medication/vaccines, study vaccine 
receipt/dispensing/return records, study vaccine administration information, any data 
collected by a telephone conversation with the subject’s parent(s)/LAR(s) and date of 
completion and reason.
The subject’s parent(s)/LAR(s) must also allow access to the subject’s medical records if 
available. Each subject’s parent(s)/LAR(s) must be informed of this prior to the start of 
the study and consent for access to medical records may be required in accordance with 
local regulations.
All safety data reported by subject’s parent(s)/LAR(s) must be written down in source 
documents prior to entry of the data into eCRFs. If there are multiple sources of 
information (e.g., Subject Diary Card, verbal report of the subject, telephone contact 
details, medical chart) supporting the diagnosis of an adverse event, these sources must be 
identified in the source documents and discrepancies between sources clarified. The 

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ultimate diagnosis must be justified and written in the source documents, and this 
diagnosis must be captured in the Adverse Event eCRF.
The Subject Diary Card source data is hosted by an ESP engaged for this study, on behalf 
of the study investigators. Each investigator will be provided with a certified archive copy 
of all diary data relating to subjects at that site and must confirm it is readable.
9.2
Study Monitoring, Auditing and Source Data Verification
Prior to enrollment of the first study subject, Seqirus or its designee (e.g., a CRO) will 
develop a Clinical Monitoring Plan to specify how centralized and/or on-site monitoring, 
including clinical specimen reconciliation, will be performed for the study. Study 
progress will be monitored by Seqirus or its designee as frequently as necessary to ensure:

that the rights and well-being of human subjects are protected

the reported study data are accurate, complete, and verifiable from the 
source documents and

the conduct of the study is in compliance with the current approved 
protocol/amendment(s), GCP and applicable regulatory requirements
Contact details for the Seqirus team or its designee involved in study monitoring will be 
provided to the investigator. Study data recorded on CRFs will be verified by checking 
the CRF entries against source documents in order to ensure data completeness and 
accuracy as required by study protocol. 
Data verification may also be performed through a centralized review of data (e.g., 
checking for outliers or other anomalies). Additional documents such as the investigator 
site file, pharmacy records, and informed consent documentation must also be available 
for review if requested. Arrangements for monitoring visits will be made in advance in 
accordance with the monitoring plan, except in case of emergency.
The investigator and/or site staff must make source documents of subjects enrolled in this 
study available for inspection by Seqirus or its representative at the time of each 
monitoring visit and Sponsor audits, when applicable. These documents must also be 
available for inspection, verification and copying, as required by regulations, by officials 
of the regulatory health authorities (eg, FDA, EMA and others) and/or IRBs. The 
investigator and study site staff must comply with applicable privacy, data protection and 
medical confidentiality laws for use and disclosure of information related to the study and 
enrolled subjects.

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10.
DATA MANAGEMENT
10.1
Data Entry and Management
In this study, all clinical data (including, but not limited to, AE/SAEs, concomitant 
medications, medical history, and physical assessments), safety data, and immunogenicity 
data will be entered onto electronic case report forms (eCRFs) in a timely fashion by the 
investigator and/or the investigator’s dedicated site staff. Data is entered in eCRF using a 
secure EDC system and stored on a secure server, which is compliant with Title 21 Part 
11 policies of the Code of Federal Regulations (FDA, 1997). The data system includes 
password protection and internal quality checks. The EDC system will be designed and 
validated by the Sponsor or its designated CRO prior to activation for data entry by sites. 
The investigator or designated delegate must review data entered and electronically sign 
the CRFs to verify their accuracy.
Access to the EDC system for data entry or review will require training and distinct 
individual access code assignments to those site staff members who will be entering study 
data and those involved in study oversight who may review study data. Data are collected 
within the EDC system, to which the Sponsor and site monitors have “read only” access.
10.2
Data Clarification
As part of the conduct of the trial, the Sponsor may have questions about the data entered 
by the site, referred to as queries. The monitors and the Sponsor or its designated CRO 
are the only parties that can generate a query. All corrections and clarifications will be 
entered into the EDC system and will be identified by the person entering the information, 
the reason for the change, as well as the time of the changes made. If changes are made to 
a previously and electronically signed CRF, the investigator must confirm and endorse the 
changes.
10.3
Data Protection
Seqirus and its delegate respects the subjects’ rights to privacy and will ensure the 
confidentiality of their medical information in accordance with all applicable laws and 
regulations.
The Sponsor as Data Controller according to the General Data Protection Regulation 
(“GDPR”) on the protection of individuals with regard to the processing of personal data 
and on the free movement of such data confirms herewith compliance to GDPR in all 
stages of Data Management.

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11.
RECORD RETENTION
Investigators must retain all study records required by Seqirus and by the applicable 
regulations in a secure and safe facility. The investigator must consult a Seqirus 
representative before disposal of any study records, and must notify the Sponsor of any 
change in the location, disposition, or custody of the study files. 
The sponsor specific essential documents should be retained until at least 2-years after the 
last approval of a marketing application in an International Conference on Harmonization 
(ICH) region and until there are no pending or contemplated marketing applications in an 
ICH region or at least 2-years have elapsed since the formal discontinuation of clinical 
development of the investigational product. These documents should be retained for a 
longer period however if required by the applicable regulatory requirement(s) or if needed 
by the sponsor (ICH E6 (R2)). 
“Essential documents” are defined as documents that individually and collectively permit 
evaluation of the conduct of a study and the quality of the data produced. These 
documents should be retained for a longer period, however, if required by the applicable 
national regulatory or institutional requirements. (ICH E6 (R2)).
The sponsor should inform the investigator(s)/institution(s) in writing of the need for 
record retention and should notify the investigator(s)/institution(s) in writing when the
trial related records are no longer needed (ICH E6 (R2)).
The principles of record retention will also be applied to the storage of laboratory 
samples, provided that the integrity of the stored sample permits testing. These laboratory 
samples will be securely stored for future testing at a global Seqirus or Seqirus 
controlled/contracted facility for up to 15 years and then destroyed, for purposes to 
conduct additional analyses needed related to the study, or ultimately for future analysis 
to further understand the immune response to the vaccine or to influenza disease. Only 
laboratory staff performing the testing will have access to these samples. By signing the 
ICF, the subject’s parent(s)/LAR(s) agrees that samples will be retained for use limited to 
additional analyses related to this study. If the parent(s)/LAR also agrees to have the 
subject’s samples stored for future testing after the study is completed, this can be 
indicated on the ICF.

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12.
USE OF INFORMATION AND PUBLICATION
Seqirus ensures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov, and in compliance with current regulations. 
Seqirus also ensures that key results of this clinical study will be posted in a publicly 
accessible database within the required time-frame from the end of study as defined in 
Section 3.9, End of Study. 
In accordance with standard editorial, ethical practices and current guidelines of Good 
Publication Practice (Graf, 2009), Seqirus will generally support publication of 
multicenter studies only in their entirety and not as individual center data. In this case, a 
coordinating investigator will be designated by mutual agreement prior to the start of the 
study. The coordinating investigator will also sign the clinical study report on behalf of 
the principal investigators (CPMP/EWP/2747/00). Authorship will be determined by 
mutual agreement and in line with International Committee of Medical Journal Editors 
authorship requirements. Any formal publication of the study in which contribution of 
Seqirus personnel exceeded that of conventional monitoring will be considered as a joint 
publication by the investigator and the appropriate Seqirus personnel. 
Seqirus must be notified of any intent to publish data collected from the study and prior 
approval from Seqirus must be obtained prior to submission for publication.

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13.
ETHICAL CONSIDERATIONS
13.1
Regulatory and Ethical Compliance
The study will be conducted in compliance with the protocol, GCP and applicable 
regulatory requirement(s).
This clinical study was designed and shall be implemented and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with 
applicable local regulations: including European Directive 2001/20/EC, US Code of 
Federal Regulations Title 21, ICH E6 (R2), and Japanese Ministry of Health, Labor, and 
Welfare, Seqirus codes on protection of human rights, and with the ethical principles laid 
down in the Declaration of Helsinki (European Parliament Council 2001, US Code of 
Federal Regulations, ICH 1997).
13.2
Informed Consent Procedures
Eligible subjects may only be included in the study after the subject’s parent(s)/LAR(s)
provide written informed consent, as described in Section 5.1.1, Informed Consent. 
Before the start of the study, the investigator will have the informed consent and any 
other materials that will be provided to the subject’s parent(s)/LAR(s) reviewed and 
approved by the IRB. This review and approval will be documented and stored with other 
study documents. The investigator or designee must fully inform the subject or LAR of all 
pertinent aspects of the study. A copy of the written informed consent will be given to the 
subject’s parent(s)/LAR(s). The subject’s parent(s)/LAR must be allowed ample time to 
ask about the details of the study and to make a decision as to whether or not to 
participate in the study. The subject’s parent(s)/LAR must sign the consent form 
indicating their agreement to participate in the study before any study-related procedures 
are conducted. The informed consent process may be conducted up to 10 days prior to 
vaccination on Day 1. If the subject’s parent(s)/LAR is unable to read and write, a witness 
must be present during the informed consent discussion and at the time of informed 
consent signature.
Prior to the start of the study, Seqirus will provide to investigators a proposed informed 
consent form that complies with the ICH GCP guideline and regulatory requirements and 
is considered appropriate for this study. Any changes to the proposed consent form 
suggested by the investigator must be agreed to by Seqirus before submission to the IRB 
and a copy of the approved version must be provided to the Seqirus monitor after IRB 
approval.

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13.3
Responsibilities of the Investigator and IRB
The protocol and the proposed informed consent form must be reviewed and approved by 
a properly constituted IRB before study start. Properly constituted IRB/EC is defined in 
the integrated addendum to ICH E6: ICH Guideline for Good Clinical Practice E6(R2). A 
signed and dated statement that the protocol and informed consent have been approved by 
the IRB/EC must be given to Seqirus before study initiation. Prior to study start and at 
any time the protocol is amended during study conduct, the investigator is required to sign 
a protocol signature page confirming his/her agreement to conduct the study in 
accordance with these documents and all of the instructions and procedures found in this 
protocol and to give access to all relevant data and records to Seqirus monitors, auditors, 
Seqirus Clinical Quality Assurance representatives, designated agents of Seqirus, IRBs, 
and regulatory authorities as required. If an inspection of the clinical site is requested by a 
regulatory authority, the investigator must inform Seqirus immediately that this request 
has been made.
The investigator also responsible for the following:

Maintaining a list of appropriately qualified persons to whom the 
investigator has delegated significant study-related duties.

Demonstrating the capability of recruiting the required number of suitable 
subjects within the recruitment period.

Demonstrating sufficient time and staffing to properly conduct and 
complete the study within the agreed study period.

Ensuring that all persons assisting with the study are adequately informed 
about the protocol, the investigational product(s), and their study-related 
duties and functions

Ensuring that qualified healthcare professionals are responsible for all 
study-related medical decisions and for ensuring appropriate medical care 
of subjects experiencing any adverse event related to the study.

If permission to do so is given by the subject’s parent(s)/LAR, ensuring 
that the subject’s primary healthcare provider is informed of the subject’s 
participation in the study.
The investigator should not implement any deviation from, or changes of the protocol 
without agreement by the Sponsor and prior review and documented approval/favorable 
opinion from the IRB of an amendment, except where necessary to eliminate an 
immediate hazard(s) to study subjects, or when the change(s) involves only logistical or 
administrative aspects of the study (eg, change in monitor(s), change of telephone 
number(s)). In addition, the investigator, or person designated by the investigator, should 
document and explain any deviation from the approved protocol.

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The investigator may implement a deviation from, or a change of, the protocol to 
eliminate an immediate hazard(s) to study subjects without prior IRB approval/favorable 
opinion. As soon as possible, the implemented deviation or change, the reasons for it, and, 
if appropriate, the proposed protocol amendment(s) should be submitted:
(a) to the IRB for review and approval/favorable opinion,
(b) to the Sponsor for agreement and, if required,
(c) to the regulatory authority(ies).
13.4
Protocol Amendments
An amendment is a written description of change(s) to or formal clarification of a study 
protocol which may impact on the conduct of the clinical study, potential benefit of the 
clinical study, or may affect subject safety, including changes of study objectives, study 
design, subject population, sample sizes, study procedures, or significant administrative 
aspects. An administrative change of a study protocol is a minor correction or 
clarification that has no significant impact on the way the clinical study is to be conducted 
and no effect on subject safety (eg, change of telephone number(s), logistical changes). 
Protocol amendments must be approved by Seqirus, health authorities where required, 
and the IRB. In cases when the amendment is required in order to protect the subject 
safety, the amendment can be implemented prior to IRB approval. Notwithstanding, the 
need for formal approval of a protocol amendment, the investigator is expected to take 
any immediate action required for the safety of any subject included in this study, even if 
this action represents a deviation from the protocol. In such cases, Seqirus should be 
notified of this action, the IRB at the study site, and, if required by local regulations, the 
relevant health authority) should be informed within 10 working days.

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14.
REFERENCE LIST
American Academy of Pediatrics Committee on Infectious Diseases. (2016) 
Recommendations for Prevention and Control of Influenza in Children, 2016–2017. 
Pediatrics; 138: e20162527.
Belshe RB. (2010) The need for quadrivalent vaccine against seasonal influenza. 
Vaccine; 28: D45-53.
Bourgeois FT, Valim C, Wei JC, et al. (2006) Influenza and other respiratory virus-
related emergency department visits among young children. Pediatrics; 118(1): e1-8.
Ciani S, Huang QS, Ciblak MA, et al. (2015) Epidemiological and virological 
characteristics of influenza B: results of the Global Influenza B Study. Influenza and 
Other Respiratory Viruses; 9(Suppl. 1): 3–12.
Code of Federal Regulations (1997): Food and Drug Administration, U.S. Department of 
Health and Human Services: Title 21, Part 11: Electronic Records Electronic Signatures. 
Federal Register 62: 13464
Committee for Medicinal Products for Human Use (CHMP). Note for Guidance on 
Coordinating Investigator Signature of Clinical Study Reports CPMP/EWP/2747/00 
[internet]. London: EMA; 2001. Available from: 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/
WC500003656.pdf
Couch RB. (2007) Background and presentation of possible vaccine options. Presented at: 
Food and Drug Administration, Center for Biologics Evaluation and Research, Vaccines 
and Related Biological Products Advisory Committee Meeting; February 27-28, 2007; 
Washington, DC.
European Parliament Council (2001): Directive 2001/20/EC of the European Parliament 
and of the Council of 4 April 2001. Official Journal of the European Communities. L 
121/34-44
Fiore AE, Uyeki TM, Broder K, et al. (2010) Prevention and control of influenza with 
vaccines: recommendations of the Advisory Committee on Immunization Practices 
(ACIP), 2010. MMWR Recomm Rep; 59: 1-62.
Graf C, Battisti WP, Bridges D (2009). Good publication practice for communicating 
company Sponsored medical research: the GPP2 guidelines. BMJ; 339: b4330

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Hu JJ, Kao CL, Lee PI, et al. (2004) Clinical features of influenza A and B in children 
and association with myositis. J Microbiol Immunol Infect; 37: 95–8.
International Conference on Harmonisation (ICH) (1997) ICH Harmonised Tripartite ICH 
Guideline for Good Clinical Practices E6 (R2). Federal Register, 62 (90): 25691-25709
Izurieta HS, Thompson WW, Kramarz P, et al. (2000) Influenza and the rates of 
hospitalization for respiratory disease among infants and young children. N Engl J Med; 
342: 232-9. 
Jayasundara K, Soobiah C, Thommes E, et al. (2014) Natural attack rate of influenza in 
unvaccinated children and adults: a meta-regression analysis. BMC Infectious Diseases; 
14: 670.
Lambert LC, Fauci AS. (2010) Influenza Vaccines for the Future. N Engl J Med; 363: 
2036-44.
Mertz D, Fadel SA, Lam P, et al. (2016) Herd effect from influenza vaccination in non-
healthcare settings: a systematic review of randomised controlled trials and observational 
studies. Euro Surveill; 21: pii=30378. 
Orsi A, Colomba GME, Pojero F, et al. (2018) Trends of influenza B during the 2010-
2016 seasons in two regions of north and south Italy: the impact of the vaccine mismatch 
on influenza immunisation strategy. Hum Vaccin Immunother; 14: 523-31.
Peltola V, Ziegler T, Ruuskanen O, et al. (2003) Influenza A and B virus infections in 
children. Clin Infect Dis; 36: 299–305.
Rota PA. Co-circulation of two distinct evolutionary lineages of influenza type B virus
since 1983. Virology 1990; 175: 59-68.
U.S. Department of Health and Human Services, Food and Drug Administration, Center 
for Biologics Evaluation and Research (CBER) (2009): Guidance for Industry. Patient-
Reported Outcome Measures: Use in Medical Product Development to Support Labeling 
Claims.
U.S. Department of Health and Human Services, Food and Drug Administration, Center 
for Biologics Evaluation and Research (CBER) (2007): Guidance for Industry. Clinical 
Data Needed to Support the Licensure of Seasonal Inactivated Influenza Vaccines.
World Health Organization (WHO). (2012) Weekly Epidemiologic Record; 87: 461-76.

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59th World Medical Association General Assembly (October 2008) Declaration of 
Helsinki - Ethical Principles for Medical Research Involving Human Subjects. Seoul, 
Korea.

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CLINICAL STUDY PROTOCOL AMENDMENT
Study Number: V130_10
Protocol Title: A Phase 3, Randomized, Observer-Blind, Multicenter, Noninferiority 
Study to Evaluate Safety and Immunogenicity of a Cell-Based Quadrivalent Subunit 
Influenza Virus Vaccine (QIVc) and a United States-licensed Quadrivalent Subunit 
Influenza Virus Vaccine (QIV) in Healthy Subjects 6 Months Through 47 Months
Amendment Number 3
Revised Protocol version 4.0 issued on 09 DEC 19  
The present amendment reflects changes to Protocol version 3 issued on 17 MAY 19
Property of Seqirus UK Ltd. (hereafter referred to as Seqirus)
Confidential
May not be used, divulged, published or otherwise disclosed without written
consent of Seqirus

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DESCRIPTION OF CHANGE(S) AND RATIONALE:
Study V130_10 has been designed to demonstrate that vaccination with QIVc elicits an 
immune response that is not inferior to that of an US-licensed QIV in children 6 months 
through 47 months of age. QIVc is currently approved by the Food and Drug
Administration (FDA) for use in children 4 years and older. The data from this study will 
be used to support the licensure of QIVc for use in children 6 months through 47 months 
of age. In order to allow for timely submission of this sBLA it was decided to accelerate 
the V130_10 Clinical Study Report. The final analysis of the primary and secondary 
immunogenicity endpoints will be conducted once all subjects have completed all 
immunogenicity assessments (end of treatment period, i.e. up to 28 days following the 
last vaccination dose). At this time, the analysis of all solicited adverse events and of 
unsolicited adverse events reported during the treatment period will also be conducted.
This document describes the changes to the V130_10 Study Protocol Version 3.0 that are 
associated with the above described analysis of data collected during the treatment period. 
CHANGE
LOCATION(S) OF 
CHANGE
RATIONALE FOR 
CHANGE
The synopsis and study protocol 
text contain wording explaining 
that the final analysis of the 
primary and secondary 
immunogenicity endpoints will be 
conducted once all subjects have 
completed all immunogenicity 
assessments (end of treatment 
period). At this time, the analysis 
of all solicited adverse events and 
of unsolicited adverse events 
reported during the treatment 
period will also be conducted.
Synopsis, Protocol 
Section 3.1 (Overview 
of Study Design), 
Section 8.6 (Interim 
Analysis)
Acceleration of Clinical 
Study Report is required 
for timely sBLA 
submission to extend 
the approved age range 
in the USA from the 
current 4 years and 
above to 6 months and 
above.

Seqirus
Clinical Study Protocol V130_10 Amendment 3
09 DEC 19
Confidential
Page 3 of 3
PRO-01 TEMP 08 / Atlas No. 293623
Version No. 2 / Version Date: May 5, 2014
CHANGE
LOCATION(S) OF 
CHANGE
RATIONALE FOR 
CHANGE
Procedures describing Database 
Lock and Unblinding of 
Randomization Code for the 
Analysis were added to the 
protocol text.
Protocol Section 3.3.1 
(Blinding Methods), 
3.3.2 (Planned 
Unblinding Procedures) 
of the Study Protocol
Procedures for Database 
Lock and Unblinding at 
the end of the treatment 
period were described 
because of final analysis 
of the safety and 
immunogenicity data 
collected during the 
treatment period.
Screening procedures include 
collection of prior and 
concomitant medications or 
vaccinations taken up to 1 month
prior to start of study
Section 5.1.2 
(Screening)
Correction of 
typographical error. In 
version 3.0 of the 
protocol a 2 months 
period was erroneously 
mentioned.
ESP term (External Service 
Providers) was added to Protocol 
and List of abbreviations. End of 
Study definition was added to the 
List of Definitions
Protocol List of 
Abbreviations, List of 
Definitions, Section 9.1
(Source 
Documentation), 
Section 3.3.1 (Blinding 
Methods), Section 3.3.2 
(Planned Unblinding 
Procedures)
The term vendor was 
replaced by ESP 
(External Service 
Provider) consistent 
with standard list of 
abbreviations. End of 
Study was defined in 
Section 3.9 of version 
3.0 of the protocol but 
was not mentioned in 
the List of Definitions.