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Clinical Trial Results:
A Phase III, Stratified, Randomized, Observer Blind, Controlled, Multicenter Clinical Study to Evaluate the Safety, Immunogenicity and Efficacy of an Adjuvanted Quadrivalent Subunit Influenza Virus Vaccine Compared to Non-Adjuvanted Comparator Influenza Vaccine in Children ≥6 to < 72 Months of Age

Summary
EudraCT number	2012-000218-12
Trial protocol	FI IT ES
Global end of trial date	09 Sep 2016

Results information
Results version number	v1(current)
This version publication date	26 Sep 2017
First version publication date	26 Sep 2017
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

V118_05

ISRCTN number

US NCT number

NCT01964989

WHO universal trial number (UTN)

Sponsor organisation name

Seqirus UK Limited

Sponsor organisation address

The Point, 29 Market Street, Maidenhead, United Kingdom, SL6 8AA

Public contact

Clinical Trial Disclosure Manager, Seqirus, Seqirus.Clinicaltrials@seqirus.com

Scientific contact

Clinical Trial Disclosure Manager, Seqirus, Seqirus.Clinicaltrials@seqirus.com

Is trial part of an agreed paediatric investigation plan (PIP)

Yes

EMA paediatric investigation plan number(s)

EMEA-001715-PIP01-14

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

16 Nov 2016

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

09 Sep 2016

Was the trial ended prematurely?

Main objective of the trial

The relative efficacy of aQIV compared to comparator vaccine as determined by RT-PCR-confirmed influenza

Protection of trial subjects

This clinical study was designed and was to be implemented and reported in accordance with the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Harmonized Tripartite Guidelines for Good Clinical Practice (GCP), with applicable local regulations including European Directive 2001/20/EC, US Code of Federal Regulations (CFR) Title 21, 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 Council 2001, US CFR, ICH 1997).

Background therapy

Evidence for comparator

Actual start date of recruitment

03 Nov 2013

Long term follow-up planned

Yes

Long term follow-up rationale

Safety

Long term follow-up duration

12 Months

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Poland: 444

Country: Number of subjects enrolled

Spain: 52

Country: Number of subjects enrolled

Finland: 648

Country: Number of subjects enrolled

Italy: 215

Country: Number of subjects enrolled

Canada: 182

Country: Number of subjects enrolled

Philippines: 2273

Country: Number of subjects enrolled

Taiwan: 282

Country: Number of subjects enrolled

Thailand: 2040

Country: Number of subjects enrolled

United States: 4508

Worldwide total number of subjects

10644

EEA total number of subjects

1359

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

2686

Children (2-11 years)

7958

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Subjects were enrolled from 146 sites in 9 countries

Screening details

All enrolled subjects were included in the trial

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst, Carer, Assessor

Are arms mutually exclusive

Yes

aQIV (≥6 to <72 months)

Arm description

Vaccine non-naïve and naïve subjects ≥6 to <72 months of age who received aQIV

Arm type

Experimental

Investigational medicinal product name

Adjuvanted Quadrivalent Influenza Vaccine (aQIV) -surface antigen, inactivated, adjuvanted with MF59

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

IM/0.5ml (0.25 mL for subjects <36 months)

TIV/QIV (≥6 to <72 months)

Arm description

Vaccine non-naïve and naïve subjects ≥6 to <72 months of age who received TIV/QIV

Arm type

Experimental

Investigational medicinal product name

Inactivated Trivalent/Quadrivalent Influenza Virus Vaccine

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

IM/0.5ml (0.25 mL for subjects <36 months)

Number of subjects in period 1	aQIV (≥6 to <72 months)	TIV/QIV (≥6 to <72 months)
Started	5352	5292
Completed	4568	4545
Not completed	784	747
Adverse event, serious fatal	1	3
Consent withdrawn by subject	156	160
Adverse event, non-fatal	-	1
Other	267	252
Lost to follow-up	254	232
Administrative reason	103	95
Protocol deviation	3	4

Baseline characteristics

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Reporting group title

aQIV (≥6 to <72 months)

Reporting group description

Vaccine non-naïve and naïve subjects ≥6 to <72 months of age who received aQIV

Reporting group title

TIV/QIV (≥6 to <72 months)

Reporting group description

Vaccine non-naïve and naïve subjects ≥6 to <72 months of age who received TIV/QIV

Reporting group values	aQIV (≥6 to <72 months)	TIV/QIV (≥6 to <72 months)	Total
Number of subjects	5352	5292	10644
Age categorical
Units: Subjects
In utero	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0
Newborns (0-27 days)	0	0	0
Infants and toddlers (28 days-23 months)	1322	1364	2686
Children (2-11 years)	4030	3928	7958
Adolescents (12-17 years)	0	0	0
Adults (18-64 years)	0	0	0
From 65-84 years	0	0	0
85 years and over	0	0	0
Age continuous
Units: months
arithmetic mean (standard deviation)	38.4 ( 18.43 )	38 ( 18.4 )	-
Gender categorical
Units: Subjects
Female	2643	2590	5233
Male	2709	2702	5411

End points

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Reporting group title

aQIV (≥6 to <72 months)

Reporting group description

Vaccine non-naïve and naïve subjects ≥6 to <72 months of age who received aQIV

Reporting group title

TIV/QIV (≥6 to <72 months)

Reporting group description

Vaccine non-naïve and naïve subjects ≥6 to <72 months of age who received TIV/QIV

Subject analysis set title

All Enrolled Set

Subject analysis set type

Intention-to-treat

Subject analysis set description

All screened subjects who provided informed consent and provided demographic and/or other baseline screening measurements, were randomized and received a subject ID.

Subject analysis set title

Full Analysis Set (FAS) - Efficacy

Subject analysis set type

Full analysis

Subject analysis set description

All subjects in the Enrolled Set who actually received a study vaccination and were evaluated for efficacy at least 21 days after the last vaccination.

Subject analysis set title

FAS - Immunogenicity

Subject analysis set type

Full analysis

Subject analysis set description

FAS Immunogenicity (or FAS Immunogenicity Homologous): All subjects in the Enrolled Set selected for Immunogenicity Subset during randomization, who received a study vaccination AND provided evaluable serum samples for both before (baseline) and after vaccination to test against vaccine strains

Subject analysis set title

FAS Immunogenicity Heterologous

Subject analysis set type

Full analysis

Subject analysis set description

All subjects in the Enrolled Set selected for Immunogenicity Subset during randomization, who received a study vaccination AND provided evaluable serum samples for both before (baseline) and after vaccination to test against heterologous strains.

Subject analysis set title

aQIV (≥6 to <24 months) - FAS Efficacy

Subject analysis set type

Full analysis

Subject analysis set description

Subjects ≥6 to <24 months in the Enrolled Set who actually received aQIV and were evaluated for efficacy at least 21 days after the last vaccination

Subject analysis set title

TIV/QIV (≥6 to <24 months) - FAS Efficacy

Subject analysis set type

Full analysis

Subject analysis set description

Subjects ≥6 to <24 months in the Enrolled Set who actually received TIV/QIV and were evaluated for efficacy at least 21 days after the last vaccination

Subject analysis set title

aQIV (≥6 to <36 months) - FAS Efficacy

Subject analysis set type

Full analysis

Subject analysis set description

Subjects ≥6 to <36 months in the Enrolled Set who actually received aQIV and were evaluated for efficacy at least 21 days after the last vaccination

Subject analysis set title

TIV/QIV (≥6 to <36 months) - FAS Efficacy

Subject analysis set type

Full analysis

Subject analysis set description

Subjects ≥6 to <36 months in the Enrolled Set who actually received TIV/QIV and were evaluated for efficacy at least 21 days after the last vaccination

Subject analysis set title

aQIV (≥36 to <72 months) - FAS Efficacy

Subject analysis set type

Full analysis

Subject analysis set description

Subjects ≥36 to <72 months in the Enrolled Set who actually received aQIV and were evaluated for efficacy at least 21 days after the last vaccination

Subject analysis set title

TIV/QIV (≥36 to <72 months) - FAS Efficacy

Subject analysis set type

Full analysis

Subject analysis set description

Subjects ≥36 to <72 months in the Enrolled Set who actually received TIV/QIV and were evaluated for efficacy at least 21 days after the last vaccination

Primary: Efficacy Endpoint: First-Occurrence RT-PCR confirmed influenza A and/or B of any influenza strain in subjects ≥6 to <72 months of age

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End point title

Efficacy Endpoint: First-Occurrence RT-PCR confirmed influenza A and/or B of any influenza strain in subjects ≥6 to <72 months of age

End point description

Relative efficacy of aQIV compared to non-adjuvanted comparator (TIV/QIV) was determined by the number of subjects ≥6 to <72 months of age with RT-PCR confirmed occurrence of influenza A and/or B of any influenza strain that occurred at ≥21 days and ≤ 180 days after the last vaccination. Relative vaccine efficacy was calculated as relative vaccine efficacy=1-Hazard Ratio Efficacy was determined on influenza cases caused by any of the influenza strains related to the two A subtypes and the B lineage(s) common to aQIV and TIV (i.e. A/H1N1, A/H3N2 and B/Yamagata during first influenza season), and common to aQIV and QIV (i.e. A/H1N1, A/H3N2 and both B lineages during second season and through the end of the trial)

End point type

Primary

End point timeframe

≥21 days and ≤ 180 days after last vaccination

End point values	aQIV (≥6 to <72 months)	TIV/QIV (≥6 to <72 months)
Number of subjects analysed	5278	5193
Units: Subjects	256	252

Relative vaccine efficacy (≥6 to <72 months)

Statistical analysis description

rVE = (1-HR) is the relative vaccine efficacy of aQIV and HR is defined as hazard ratio between aQIV and non adjuvanted comparator.

Comparison groups

aQIV (≥6 to <72 months) v TIV/QIV (≥6 to <72 months)

Number of subjects included in analysis

10471

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Cox Proportional Hazard regression

Point estimate

-0.67

Confidence interval

level

95%

sides

2-sided

lower limit

-19.81

upper limit

15.41

Secondary: Efficacy Endpoint: First-Occurrence RT-PCR confirmed influenza A and/or B of any influenza strain in subjects ≥6 to <72 months, ≥6 to <24 months, ≥6 to <36 months and ≥36 to <72 months of age

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End point title

Efficacy Endpoint: First-Occurrence RT-PCR confirmed influenza A and/or B of any influenza strain in subjects ≥6 to <72 months, ≥6 to <24 months, ≥6 to <36 months and ≥36 to <72 months of age

End point description

Relative efficacy of aQIV compared to non-adjuvanted comparator (TIV/QIV) was determined by the number of subjects with RT-PCR confirmed occurrence of influenza A and/or B of any influenza strain that occurred at ≥21 days and ≤ 180 days after the last vaccination or until the end of the influenza season, whichever was longer. Efficacy was determined on influenza cases caused by any of the influenza strains related to the two A subtypes and the B lineage(s) common to aQIV and TIV (i.e. A/H1N1, A/H3N2 and B/Yamagata during first influenza season), and common to aQIV and QIV (i.e. A/H1N1, A/H3N2 and both B lineages during second season and through the end of the trial)

End point type

Secondary

End point timeframe

≥21 days and ≤ 180 days after last vaccination

End point values	aQIV (≥6 to <72 months)	TIV/QIV (≥6 to <72 months)	aQIV (≥6 to <24 months) - FAS Efficacy	TIV/QIV (≥6 to <24 months) - FAS Efficacy	aQIV (≥6 to <36 months) - FAS Efficacy	TIV/QIV (≥6 to <36 months) - FAS Efficacy	aQIV (≥36 to <72 months) - FAS Efficacy	TIV/QIV (≥36 to <72 months) - FAS Efficacy
Number of subjects analysed	5278	5193	1299	1339	2484	2471	2794	2722
Units: Subjects
A/H1N1	7	17	2	5	5	8	2	9
A/H3N2	200	196	44	66	92	99	108	97
B/Yamagata	36	36	5	9	13	12	23	24
B/Victoria	14	9	4	0	5	1	9	8

No statistical analyses for this end point

Secondary: Efficacy Endpoint: First-Occurrence culture confirmed influenza A and/or B of any influenza strain in subjects ≥6 to <72 months, ≥6 to <24 months, ≥6 to <36 months and ≥36 to <72 months of age

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End point title

Efficacy Endpoint: First-Occurrence culture confirmed influenza A and/or B of any influenza strain in subjects ≥6 to <72 months, ≥6 to <24 months, ≥6 to <36 months and ≥36 to <72 months of age

End point description

Relative efficacy of aQIV compared to non-adjuvanted comparator (TIV/QIV) was determined by the number of subjects with culture confirmed occurrence of influenza A and/or B of any influenza strain that occurred at ≥21 days and ≤ 180 days after the last vaccination or until the end of the influenza season, whichever was longer. Efficacy was determined on influenza cases caused by any of the influenza strains related to the two A subtypes and the B lineage(s) common to aQIV and TIV (i.e. A/H1N1, A/H3N2 and B/Yamagata during first influenza season), and common to aQIV and QIV (i.e. A/H1N1, A/H3N2 and both B lineages during second season and through the end of the trial).

End point type

Secondary

End point timeframe

≥21 days and ≤ 180 days after last vaccination

End point values	aQIV (≥6 to <72 months)	TIV/QIV (≥6 to <72 months)	aQIV (≥6 to <24 months) - FAS Efficacy	TIV/QIV (≥6 to <24 months) - FAS Efficacy	aQIV (≥6 to <36 months) - FAS Efficacy	TIV/QIV (≥6 to <36 months) - FAS Efficacy	aQIV (≥36 to <72 months) - FAS Efficacy	TIV/QIV (≥36 to <72 months) - FAS Efficacy
Number of subjects analysed	5278	5193	1299	1339	2484	2471	2794	2722
Units: subjects	140	146	31	48	64	68	76	78

No statistical analyses for this end point

Secondary: Efficacy Endpoint: First-occurrence RT-PCR-confirmed influenza A and/or B of any influenza strain in subjects ≥6 to <72 months of age at ≥7 days and at ≥14 days after first vaccination up to the day of second vaccination in vaccine naïve subjects only

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End point title

Efficacy Endpoint: First-occurrence RT-PCR-confirmed influenza A and/or B of any influenza strain in subjects ≥6 to <72 months of age at ≥7 days and at ≥14 days after first vaccination up to the day of second vaccination in vaccine naïve subjects only

End point description

Relative efficacy of aQIV compared to non-adjuvanted comparator (TIV/QIV) was determined by the number of vaccine naive subjects ≥6 to <72 months of age with RT-PCR confirmed occurrence of influenza A and/or B of any influenza strain that occurred at ≥ 7 days and ≥ 14 days after the first vaccination up to the day of the second vaccination. Efficacy was determined on influenza cases caused by any of the influenza strains related to the two A subtypes and the B lineage(s) common to aQIV and TIV (i.e. A/H1N1, A/H3N2 and B/Yamagata during first influenza season), and common to aQIV and QIV (i.e. A/H1N1, A/H3N2 and both B lineages during second season and through the end of the trial)

End point type

Secondary

End point timeframe

≥7 days and at ≥14 days after first vaccination up to day of second vaccination

End point values	aQIV (≥6 to <72 months)	TIV/QIV (≥6 to <72 months)
Number of subjects analysed	3559	3535
Units: Subjects
≥7 days after first and up to second vaccination	16	35
≥14 days after first and up to second vaccination	8	27

No statistical analyses for this end point

Secondary: Efficacy Endpoint: First-occurrence RT-PCR-confirmed influenza A and/or B of any influenza strain in subjects ≥6 to <72 months of age occurring at ≥7 days and ≤21 days after last vaccination, in all subjects.

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End point title

Efficacy Endpoint: First-occurrence RT-PCR-confirmed influenza A and/or B of any influenza strain in subjects ≥6 to <72 months of age occurring at ≥7 days and ≤21 days after last vaccination, in all subjects.

End point description

Relative efficacy of aQIV compared to non-adjuvanted comparator (TIV/QIV) was determined by the number of vaccine naive subjects ≥6 to <72 months of age with RT-PCR confirmed occurrence of influenza A and/or B of any influenza strain that occurred at ≥ 7 days and ≤ 21 after the last vaccination. Efficacy was determined on influenza cases caused by any of the influenza strains related to the two A subtypes and the B lineage(s) common to aQIV and TIV (i.e. A/H1N1, A/H3N2 and B/Yamagata during first influenza season), and common to aQIV and QIV (i.e. A/H1N1, A/H3N2 and both B lineages during second season and through the end of the trial).

End point type

Secondary

End point timeframe

≥7 days and ≤21 days after the last vaccination

End point values	aQIV (≥6 to <72 months)	TIV/QIV (≥6 to <72 months)
Number of subjects analysed	5286	5208
Units: Subjects
≥7 days and ≤21 days after last vaccination	4	15

No statistical analyses for this end point

Secondary: Immunogenicity Endpoint: Antibody response 21 days after last vaccination of aQIV and TIV/QIV against vaccine strains according to Center for Biologics Evaluation and Research hemagglutination inhibition (HI) criteria in subjects ≥6 to <72 months of age

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End point title

Immunogenicity Endpoint: Antibody response 21 days after last vaccination of aQIV and TIV/QIV against vaccine strains according to Center for Biologics Evaluation and Research hemagglutination inhibition (HI) criteria in subjects ≥6 to <72 months of age

End point description

The CBER criteria were met if the lower bound of the 2-sided 95% CI for the percent of subjects achieving SC for HI antibody met or exceeded 40% AND the lower bound of the 2-sided 95% CI for the percent of subjects achieving an HI titer ≥1:40 met or exceeded 70%. Seroconversion is defined as HI ≥1:40 for subjects negative at baseline (ie, HI titer <1:10); or a minimum 4-fold increase in HI titer for subjects positive at baseline (ie, HI titer HI ≥1:10). Homologous Strains: H1N1=A/California/7/2009-like; H3N2=A/Texas/50/2012; B Yamagata=B/Massachusetts/2/2012; B Victoria=B/Brisbane/60/2008 For B/Victoria results from Season 2 only are presented for both vaccine groups.

End point type

Secondary

End point timeframe

21 days after last vaccination

End point values	aQIV (≥6 to <72 months)	TIV/QIV (≥6 to <72 months)
Number of subjects analysed	1481	1405
Units: Percentage of subjects
number (confidence interval 95%)
A/H1N1, Seroconversion	81.9 (79.7 to 83.9)	73.7 (71.2 to 76.1)
A/H1N1, HI ≥1:40	99.3 (98.7 to 99.7)	96.3 (95.2 to 97.3)
A/H3N2, Seroconversion	78.4 (76.1 to 80.6)	73.2 (70.7 to 75.6)
A/H3N2, HI ≥1:40	99.6 (99.1 to 99.9)	98.2 (97.3 to 98.8)
B/Yamagata, Seroconversion	86 (84.1 to 87.8)	64.7 (62.1 to 67.3)
B/Yamagata, HI ≥1:40	93.5 (92 to 94.7)	76.7 (74.3 to 78.9)
B/Victoria, Seroconversion	91 (88.7 to 93)	77.4 (74.2 to 80.3)
B/Victoria, HI ≥1:40	96.1 (94.5 to 97.4)	84.8 (82 to 87.3)

No statistical analyses for this end point

Secondary: Immunogenicity Endpoint: HI antibody responses to aQIV vs TIV/QIV against each of the vaccine strains in terms of ratio of GMT 21 days after the last vaccination in subjects ≥6 to <72 months of age (superiority analysis)

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End point title

Immunogenicity Endpoint: HI antibody responses to aQIV vs TIV/QIV against each of the vaccine strains in terms of ratio of GMT 21 days after the last vaccination in subjects ≥6 to <72 months of age (superiority analysis)

End point description

GMT Ratio: aQIV (GMT) over TIV/QIV (GMT) Superiority criterion for the GMT ratio: The lower bound of the two-sided 95% CI on the adjusted ratio of GMTs for HI antibody titer should exceed 1. Homologous Strains: H1N1=A/California/7/2009-like; H3N2=A/Texas/50/2012; B Yamagata=B/Massachusetts/2/2012; B Victoria=B/Brisbane/60/2008 For B/Victoria results from Season 2 only are presented for both vaccine groups.

End point type

Secondary

End point timeframe

21 days after the last vaccination

End point values	FAS - Immunogenicity
Number of subjects analysed	2886 ^[1]
Units: titer ratios
geometric mean (confidence interval 95%)
A/H1N1	1.91 (1.8 to 2)
A/H3N2	1.71 (1.6 to 1.8)
B/Yamagata	2.19 (2 to 2.4)
B/Victoria	2.27 (2 to 2.6)

Notes
[1] - aQIV=1481, TIV/QIV=1405

No statistical analyses for this end point

Secondary: Immunogenicity Endpoint: HI antibody responses to aQIV vs TIV/QIV against each of the vaccine strains in terms of differences in the percentage of subjects with SC 21 days after last vaccination in subjects ≥6 to <72 months of age (superiority analysis)

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End point title

Immunogenicity Endpoint: HI antibody responses to aQIV vs TIV/QIV against each of the vaccine strains in terms of differences in the percentage of subjects with SC 21 days after last vaccination in subjects ≥6 to <72 months of age (superiority analysis)

End point description

SC Differences= aQIV (%Subjects with SC) - TIV/QIV (%Subjects with SC) Seroconversion is defined as HI ≥ 1:40 for subjects negative at baseline (ie, HI titer<1:10); or a minimum 4-fold increase in HI titer for subjects positive at baseline (ie, HI tier ≥ 1:10). Superiority criterion for seroconversion: The lower bound of the two-sided 95% CI on the unadjusted difference of percentages of subjects seroconverted for HI antibody should exceed 0%. Homologous Strains: H1N1=A/California/7/2009-like; H3N2=A/Texas/50/2012; B Yamagata=B/Massachusetts/2/2012; B Victoria=B/Brisbane/60/2008 For B/Victoria results from Season 2 only are presented for both vaccine groups

End point type

Secondary

End point timeframe

21 days after the last vaccination

End point values	FAS - Immunogenicity
Number of subjects analysed	2886 ^[2]
Units: percentage of subjects
number (confidence interval 95%)
A/H1N1	8.2 (5 to 11.3)
A/H3N2	5.2 (1.9 to 8.4)
B/Yamagata	21.3 (18.1 to 24.5)
B/Victoria	13.6 (10 to 17.3)

Notes
[2] - aQIV=1481, TIV/QIV=1405

No statistical analyses for this end point

Secondary: Immunogenicity Endpoint: HI antibody responses to aQIV vs TIV/QIV against heterologous strains in terms of ratio of GMT 21 days after last vaccination in subjects ≥6 to <72 months of age

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End point title

Immunogenicity Endpoint: HI antibody responses to aQIV vs TIV/QIV against heterologous strains in terms of ratio of GMT 21 days after last vaccination in subjects ≥6 to <72 months of age

End point description

GMT Ratio: aQIV (GMT) over TIV/QIV (GMT) Heterologous Strains: H1N1=A/Brisbane/59/2007-like; H3N2=A/Hong Kong/4801/2014; B Yamagata=B/Phuket/3073/2013-like; B Victoria=B/Malaysia/2506/2004 For B/Victoria results from Season 2 only are presented for both vaccine groups and used in the vaccine comparison analysis.

End point type

Secondary

End point timeframe

21 days after last vaccination

End point values	FAS Immunogenicity Heterologous
Number of subjects analysed	592 ^[3]
Units: titer ratios
geometric mean (confidence interval 95%)
A/H1N1	1.14 (1.1 to 1.2)
A/H3N2	1.94 (1.6 to 2.3)
B/Yamagata	2.17 (1.8 to 2.6)
B/Victoria	2.12 (1.6 to 2.7)

Notes
[3] - aQIV=297, TIV/QIV=295

No statistical analyses for this end point

Secondary: Immunogenicity Endpoint: HI antibody responses to aQIV vs TIV/QIV against heterologous strains in terms of differences in percentages of subjects with SC 21 days after last vaccination in subjects ≥6 to <72 months of age

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End point title

Immunogenicity Endpoint: HI antibody responses to aQIV vs TIV/QIV against heterologous strains in terms of differences in percentages of subjects with SC 21 days after last vaccination in subjects ≥6 to <72 months of age

End point description

SC Differences= aQIV (%Subjects with SC) - TIV/QIV (%Subjects with SC) Seroconversion was defined as: HI titer ≥40 for subjects negative at baseline (ie, HI titer <10); or a minimum 4-fold increase in HI titer for subjects positive at baseline (HI titer ≥10) Heterologous Strains: H1N1=A/Brisbane/59/2007-like; H3N2=A/Hong Kong/4801/2014; B Yamagata=B/Phuket/3073/2013-like; B Victoria=B/Malaysia/2506/2004

End point type

Secondary

End point timeframe

21 days after last vaccination

End point values	FAS Immunogenicity Heterologous
Number of subjects analysed	592 ^[4]
Units: percentage of subjects
number (confidence interval 95%)
A/H1N1	1.3 (-1.1 to 4.1)
A/H3N2	12.5 (6 to 19)
B/Yamagata	22.8 (15.6 to 29.8)
B/Victoria	14.9 (6.6 to 23.3)

Notes
[4] - aQIV=297, TIV/QIV=295

No statistical analyses for this end point

Secondary: Safety Endpoint: Number of subjects with solicited local and systemic AEs

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End point title

Safety Endpoint: Number of subjects with solicited local and systemic AEs

End point description

Safety was assessed in terms of number of subjects ≥6 to <72 months of age reporting solicited local and systemic reactions, day 1 to day 7 after vaccination with either aQIV or TIV/QIV

End point type

Secondary

End point timeframe

7 days following each vaccination

End point values	aQIV (≥6 to <72 months)	TIV/QIV (≥6 to <72 months)
Number of subjects analysed	5138	5056
Units: Number of subjects
Any	3748	3242
Local	2651	2188
Systemic	2714	2174
Others	1536	907

No statistical analyses for this end point

Secondary: Safety Endpoint: Number of subjects with unsolicited AEs

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End point title

Safety Endpoint: Number of subjects with unsolicited AEs

End point description

Safety was assessed in terms of number of subjects ≥6 to <72 months of age reporting unsolicited reactions up to 12 months after last vaccination, Serious Adverse Events (SAEs), AEs leading to New Oncet of Chronic Diseases (NOCD), Adverse Events of Special Interests (AESI), AEs leading to withdrawal from the study or study vaccination after vaccination with either aQIV or TIV/QIV.

End point type

Secondary

End point timeframe

Up to 12 months after last vaccination

End point values	aQIV (≥6 to <72 months)	TIV/QIV (≥6 to <72 months)
Number of subjects analysed	5243	5161
Units: Number of subjects
Any unsolicited AEs	3576	3543
Possibly or probably related unsolicited AEs	686	533
SAEs	234	230
Possibly or probably related SAEs	6	1
AEs with an outcome of death	1	3
AEs leading to premature withdrawal	10	9
AEs leading to NOCD	87	96
AESI	5	4

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Solicited AEs: day 1 to day 7 after each vaccination, unsolicited AEs: day 1 today 22 for vaccine non-naive and day 1 to day 50 for vaccine naive subjects, SAEs: day 1 to day 366 for vaccine non-naïve and day 1 to day 390 for vaccine naïve subjects

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

19.1

Reporting group title

aQIV (≥6 to <72 months)

Reporting group description

Vaccine non-naive and naive subjects (≥6 to <72 months old) received one or two doses of adjuvanted quadrivalent influenza virus vaccine

Reporting group title

TIV/QIV (≥6 to <72 months)

Reporting group description

Vaccine non-naive and naive subjects (≥6 to <72 months old) received one or two doses of non-adjuvanted comparator influenza virus vaccine

Serious adverse events	aQIV (≥6 to <72 months)	TIV/QIV (≥6 to <72 months)
Total subjects affected by serious adverse events
subjects affected / exposed	234 / 5339 (4.38%)	230 / 5273 (4.36%)
number of deaths (all causes)	1	3
number of deaths resulting from adverse events	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute lymphocytic leukaemia
subjects affected / exposed	0 / 5339 (0.00%)	1 / 5273 (0.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ependymoma
subjects affected / exposed	1 / 5339 (0.02%)	0 / 5273 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular disorders
Kawasaki's disease
subjects affected / exposed	1 / 5339 (0.02%)	0 / 5273 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Influenza like illness
subjects affected / exposed	7 / 5339 (0.13%)	8 / 5273 (0.15%)
occurrences causally related to treatment / all	0 / 7	0 / 8
deaths causally related to treatment / all	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	1 / 5339 (0.02%)	6 / 5273 (0.11%)
occurrences causally related to treatment / all	0 / 1	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
Systemic inflammatory response syndrome
subjects affected / exposed	0 / 5339 (0.00%)	1 / 5273 (0.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Injection site inflammation
subjects affected / exposed	1 / 5339 (0.02%)	0 / 5273 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Immune system disorders
Allergy to arthropod bite
subjects affected / exposed	1 / 5339 (0.02%)	0 / 5273 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Allergy to arthopod sting
subjects affected / exposed	0 / 5339 (0.00%)	1 / 5273 (0.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Anaphylactic reaction
subjects affected / exposed	1 / 5339 (0.02%)	1 / 5273 (0.02%)
occurrences causally related to treatment / all	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypersensitivity
subjects affected / exposed	1 / 5339 (0.02%)	0 / 5273 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Type I hypersensitivity
subjects affected / exposed	1 / 5339 (0.02%)	0 / 5273 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Reproductive system and breast disorders
Atelectasis
subjects affected / exposed	0 / 5339 (0.00%)	1 / 5273 (0.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Adenoidal hypertrophy
subjects affected / exposed	1 / 5339 (0.02%)	1 / 5273 (0.02%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Asthma
subjects affected / exposed	9 / 5339 (0.17%)	11 / 5273 (0.21%)
occurrences causally related to treatment / all	0 / 9	0 / 11
deaths causally related to treatment / all	0 / 0	0 / 0
Asthmatic crisis
subjects affected / exposed	0 / 5339 (0.00%)	1 / 5273 (0.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bronchial hyperreactivity
subjects affected / exposed	4 / 5339 (0.07%)	3 / 5273 (0.06%)
occurrences causally related to treatment / all	0 / 4	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Bronchospasm
subjects affected / exposed	1 / 5339 (0.02%)	3 / 5273 (0.06%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Hypoxia
subjects affected / exposed	0 / 5339 (0.00%)	1 / 5273 (0.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary hypertension
subjects affected / exposed	0 / 5339 (0.00%)	1 / 5273 (0.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Respiratory distress
subjects affected / exposed	1 / 5339 (0.02%)	2 / 5273 (0.04%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	1 / 5339 (0.02%)	1 / 5273 (0.02%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Status asthmaticus
subjects affected / exposed	1 / 5339 (0.02%)	2 / 5273 (0.04%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Tonsillar hypertrophy
subjects affected / exposed	1 / 5339 (0.02%)	0 / 5273 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Wheezing
subjects affected / exposed	1 / 5339 (0.02%)	0 / 5273 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Psychiatric disorders
Irritability
subjects affected / exposed	0 / 5339 (0.00%)	1 / 5273 (0.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Mental status changes
subjects affected / exposed	1 / 5339 (0.02%)	0 / 5273 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Product issues
Device malfunction
subjects affected / exposed	1 / 5339 (0.02%)	0 / 5273 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Accidental exposure to product
subjects affected / exposed	2 / 5339 (0.04%)	1 / 5273 (0.02%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Animal bite
subjects affected / exposed	24 / 5339 (0.45%)	19 / 5273 (0.36%)
occurrences causally related to treatment / all	0 / 24	0 / 19
deaths causally related to treatment / all	0 / 0	0 / 0
Animal scratch
subjects affected / exposed	2 / 5339 (0.04%)	3 / 5273 (0.06%)
occurrences causally related to treatment / all	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Burns second degree
subjects affected / exposed	0 / 5339 (0.00%)	1 / 5273 (0.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Chemical burn of gastrointestinal tract
subjects affected / exposed	0 / 5339 (0.00%)	1 / 5273 (0.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Concussion
subjects affected / exposed	1 / 5339 (0.02%)	0 / 5273 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Craniocerebral injury
subjects affected / exposed	1 / 5339 (0.02%)	0 / 5273 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Exposure to toxic agent
subjects affected / exposed	1 / 5339 (0.02%)	0 / 5273 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Femur fracture
subjects affected / exposed	1 / 5339 (0.02%)	0 / 5273 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Forearm fracture
subjects affected / exposed	1 / 5339 (0.02%)	1 / 5273 (0.02%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Foreign body
subjects affected / exposed	1 / 5339 (0.02%)	1 / 5273 (0.02%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gun shot wound
subjects affected / exposed	1 / 5339 (0.02%)	0 / 5273 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hand fracture
subjects affected / exposed	0 / 5339 (0.00%)	1 / 5273 (0.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Head injury
subjects affected / exposed	1 / 5339 (0.02%)	0 / 5273 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Humerus fracture
subjects affected / exposed	2 / 5339 (0.04%)	1 / 5273 (0.02%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Injury
subjects affected / exposed	0 / 5339 (0.00%)	1 / 5273 (0.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Joint dislocation
subjects affected / exposed	0 / 5339 (0.00%)	1 / 5273 (0.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Laceration
subjects affected / exposed	0 / 5339 (0.00%)	2 / 5273 (0.04%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Lower limb fracture
subjects affected / exposed	1 / 5339 (0.02%)	0 / 5273 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Muscle strain
subjects affected / exposed	0 / 5339 (0.00%)	1 / 5273 (0.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Post procedural haemorrhage
subjects affected / exposed	2 / 5339 (0.04%)	0 / 5273 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Thermal burn
subjects affected / exposed	0 / 5339 (0.00%)	2 / 5273 (0.04%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Tongue injury
subjects affected / exposed	0 / 5339 (0.00%)	1 / 5273 (0.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Traumatic liver injury
subjects affected / exposed	1 / 5339 (0.02%)	0 / 5273 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vulvovaginal injury
subjects affected / exposed	1 / 5339 (0.02%)	0 / 5273 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Congenital, familial and genetic disorders
Ankyloglossia congenital
subjects affected / exposed	0 / 5339 (0.00%)	1 / 5273 (0.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Dacryostenosis congenital
subjects affected / exposed	0 / 5339 (0.00%)	1 / 5273 (0.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Heart disease congenital
subjects affected / exposed	0 / 5339 (0.00%)	1 / 5273 (0.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Cardiogenic shock
subjects affected / exposed	0 / 5339 (0.00%)	1 / 5273 (0.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Nervous system disorders
Autism
subjects affected / exposed	1 / 5339 (0.02%)	0 / 5273 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cerebral haemorrhage
subjects affected / exposed	1 / 5339 (0.02%)	0 / 5273 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Encephalitis autoimmune
subjects affected / exposed	1 / 5339 (0.02%)	0 / 5273 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Febrile convulsion
subjects affected / exposed	13 / 5339 (0.24%)	7 / 5273 (0.13%)
occurrences causally related to treatment / all	1 / 13	0 / 7
deaths causally related to treatment / all	0 / 0	0 / 0
Generalised tonic-clonic seizure
subjects affected / exposed	1 / 5339 (0.02%)	0 / 5273 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Headache
subjects affected / exposed	1 / 5339 (0.02%)	0 / 5273 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Loss of consciousness
subjects affected / exposed	1 / 5339 (0.02%)	0 / 5273 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Partial seizures
subjects affected / exposed	1 / 5339 (0.02%)	0 / 5273 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Seizure
subjects affected / exposed	3 / 5339 (0.06%)	1 / 5273 (0.02%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0
Status epilepticus
subjects affected / exposed	2 / 5339 (0.04%)	0 / 5273 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Immune thrombocytopenic purpura
subjects affected / exposed	0 / 5339 (0.00%)	1 / 5273 (0.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Leukocytosis
subjects affected / exposed	1 / 5339 (0.02%)	0 / 5273 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lymphadenitis
subjects affected / exposed	1 / 5339 (0.02%)	0 / 5273 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	1 / 5339 (0.02%)	0 / 5273 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Coeliac disease
subjects affected / exposed	0 / 5339 (0.00%)	1 / 5273 (0.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Constipation
subjects affected / exposed	1 / 5339 (0.02%)	1 / 5273 (0.02%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Crohn's disease
subjects affected / exposed	1 / 5339 (0.02%)	0 / 5273 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	1 / 5339 (0.02%)	5 / 5273 (0.09%)
occurrences causally related to treatment / all	0 / 1	1 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Dysphagia
subjects affected / exposed	1 / 5339 (0.02%)	0 / 5273 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Enteritis
subjects affected / exposed	1 / 5339 (0.02%)	0 / 5273 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastritis
subjects affected / exposed	5 / 5339 (0.09%)	5 / 5273 (0.09%)
occurrences causally related to treatment / all	0 / 5	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal inflammation
subjects affected / exposed	1 / 5339 (0.02%)	0 / 5273 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Incarcerated inguinal hernia
subjects affected / exposed	0 / 5339 (0.00%)	1 / 5273 (0.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Inguinal hernia
subjects affected / exposed	1 / 5339 (0.02%)	1 / 5273 (0.02%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Intussusception
subjects affected / exposed	0 / 5339 (0.00%)	1 / 5273 (0.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 5339 (0.00%)	1 / 5273 (0.02%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Angioedema
subjects affected / exposed	0 / 5339 (0.00%)	1 / 5273 (0.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Henoch-Schonlein purpura
subjects affected / exposed	1 / 5339 (0.02%)	1 / 5273 (0.02%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lichen sclerosus
subjects affected / exposed	0 / 5339 (0.00%)	1 / 5273 (0.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Papule
subjects affected / exposed	1 / 5339 (0.02%)	0 / 5273 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Swelling face
subjects affected / exposed	1 / 5339 (0.02%)	0 / 5273 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Urticaria
subjects affected / exposed	3 / 5339 (0.06%)	2 / 5273 (0.04%)
occurrences causally related to treatment / all	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Hydronephrosis
subjects affected / exposed	0 / 5339 (0.00%)	1 / 5273 (0.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Post streptococcal glomerulonephritis
subjects affected / exposed	2 / 5339 (0.04%)	0 / 5273 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Endocrine disorders
Hyperaldosteronism
subjects affected / exposed	0 / 5339 (0.00%)	1 / 5273 (0.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Fasciitis
subjects affected / exposed	0 / 5339 (0.00%)	1 / 5273 (0.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Osteochondrosis
subjects affected / exposed	0 / 5339 (0.00%)	1 / 5273 (0.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Polyarthritis
subjects affected / exposed	0 / 5339 (0.00%)	1 / 5273 (0.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Abdominal wall abscess
subjects affected / exposed	0 / 5339 (0.00%)	1 / 5273 (0.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Abscess jaw
subjects affected / exposed	1 / 5339 (0.02%)	0 / 5273 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Acute sinusitis
subjects affected / exposed	1 / 5339 (0.02%)	0 / 5273 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Adenovirus infection
subjects affected / exposed	0 / 5339 (0.00%)	2 / 5273 (0.04%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Amoebiasis
subjects affected / exposed	1 / 5339 (0.02%)	0 / 5273 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Amoebic dysentery
subjects affected / exposed	0 / 5339 (0.00%)	1 / 5273 (0.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Atypical pneumonia
subjects affected / exposed	0 / 5339 (0.00%)	1 / 5273 (0.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bacteraemia
subjects affected / exposed	2 / 5339 (0.04%)	0 / 5273 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bacterial sepsis
subjects affected / exposed	1 / 5339 (0.02%)	0 / 5273 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Brain abscess
subjects affected / exposed	0 / 5339 (0.00%)	1 / 5273 (0.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Breast abscess
subjects affected / exposed	1 / 5339 (0.02%)	0 / 5273 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bronchiolitis
subjects affected / exposed	7 / 5339 (0.13%)	1 / 5273 (0.02%)
occurrences causally related to treatment / all	0 / 7	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	12 / 5339 (0.22%)	13 / 5273 (0.25%)
occurrences causally related to treatment / all	0 / 12	0 / 13
deaths causally related to treatment / all	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	5 / 5339 (0.09%)	1 / 5273 (0.02%)
occurrences causally related to treatment / all	0 / 5	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cellulitis staphylococcal
subjects affected / exposed	1 / 5339 (0.02%)	0 / 5273 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cholera
subjects affected / exposed	1 / 5339 (0.02%)	0 / 5273 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Corona virus infection
subjects affected / exposed	0 / 5339 (0.00%)	1 / 5273 (0.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Croup infectious
subjects affected / exposed	3 / 5339 (0.06%)	2 / 5273 (0.04%)
occurrences causally related to treatment / all	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Dengue fever
subjects affected / exposed	9 / 5339 (0.17%)	9 / 5273 (0.17%)
occurrences causally related to treatment / all	0 / 9	0 / 9
deaths causally related to treatment / all	0 / 0	0 / 0
Diarrhoea infectious
subjects affected / exposed	0 / 5339 (0.00%)	2 / 5273 (0.04%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Exanthema subitum
subjects affected / exposed	0 / 5339 (0.00%)	1 / 5273 (0.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Folliculitis
subjects affected / exposed	0 / 5339 (0.00%)	1 / 5273 (0.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastritis viral
subjects affected / exposed	2 / 5339 (0.04%)	1 / 5273 (0.02%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	23 / 5339 (0.43%)	23 / 5273 (0.44%)
occurrences causally related to treatment / all	0 / 23	0 / 23
deaths causally related to treatment / all	0 / 0	0 / 0
Gastroenteritis rotavirus
subjects affected / exposed	0 / 5339 (0.00%)	5 / 5273 (0.09%)
occurrences causally related to treatment / all	0 / 0	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Gastroenteritis salmonella
subjects affected / exposed	0 / 5339 (0.00%)	2 / 5273 (0.04%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Gastroenteritis viral
subjects affected / exposed	3 / 5339 (0.06%)	4 / 5273 (0.08%)
occurrences causally related to treatment / all	0 / 3	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Groin abscess
subjects affected / exposed	0 / 5339 (0.00%)	1 / 5273 (0.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hand-foot-and-mouth disease
subjects affected / exposed	2 / 5339 (0.04%)	4 / 5273 (0.08%)
occurrences causally related to treatment / all	0 / 2	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Herpangina
subjects affected / exposed	5 / 5339 (0.09%)	1 / 5273 (0.02%)
occurrences causally related to treatment / all	0 / 5	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infectious mononucleosis
subjects affected / exposed	0 / 5339 (0.00%)	1 / 5273 (0.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Laryngitis viral
subjects affected / exposed	0 / 5339 (0.00%)	1 / 5273 (0.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Mastoiditis
subjects affected / exposed	1 / 5339 (0.02%)	0 / 5273 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Meningitis aseptic
subjects affected / exposed	1 / 5339 (0.02%)	0 / 5273 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Meningitis bacterial
subjects affected / exposed	0 / 5339 (0.00%)	1 / 5273 (0.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Mycoplasma infection
subjects affected / exposed	1 / 5339 (0.02%)	1 / 5273 (0.02%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nasopharyngitis
subjects affected / exposed	1 / 5339 (0.02%)	1 / 5273 (0.02%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Oral herpes
subjects affected / exposed	0 / 5339 (0.00%)	1 / 5273 (0.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Otitis media
subjects affected / exposed	1 / 5339 (0.02%)	1 / 5273 (0.02%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Otitis media acute
subjects affected / exposed	2 / 5339 (0.04%)	0 / 5273 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Periorbital cellulitis
subjects affected / exposed	2 / 5339 (0.04%)	1 / 5273 (0.02%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pharyngitis
subjects affected / exposed	4 / 5339 (0.07%)	7 / 5273 (0.13%)
occurrences causally related to treatment / all	0 / 4	0 / 7
deaths causally related to treatment / all	0 / 0	0 / 0
Pharyngotonsillitis
subjects affected / exposed	3 / 5339 (0.06%)	3 / 5273 (0.06%)
occurrences causally related to treatment / all	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	38 / 5339 (0.71%)	28 / 5273 (0.53%)
occurrences causally related to treatment / all	0 / 38	0 / 28
deaths causally related to treatment / all	0 / 1	0 / 1
Pneumonia adenoviral
subjects affected / exposed	1 / 5339 (0.02%)	0 / 5273 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia bacterial
subjects affected / exposed	0 / 5339 (0.00%)	1 / 5273 (0.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia chlamydial
subjects affected / exposed	1 / 5339 (0.02%)	0 / 5273 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia mycoplasmal
subjects affected / exposed	1 / 5339 (0.02%)	1 / 5273 (0.02%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia respiratory syncytial viral
subjects affected / exposed	3 / 5339 (0.06%)	2 / 5273 (0.04%)
occurrences causally related to treatment / all	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia viral
subjects affected / exposed	4 / 5339 (0.07%)	2 / 5273 (0.04%)
occurrences causally related to treatment / all	0 / 4	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Pyelonephritis acute
subjects affected / exposed	1 / 5339 (0.02%)	0 / 5273 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory syncytial virus bronchiolitis
subjects affected / exposed	1 / 5339 (0.02%)	0 / 5273 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory syncytial virus infection
subjects affected / exposed	3 / 5339 (0.06%)	3 / 5273 (0.06%)
occurrences causally related to treatment / all	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory tract infection
subjects affected / exposed	1 / 5339 (0.02%)	2 / 5273 (0.04%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Rhinitis
subjects affected / exposed	1 / 5339 (0.02%)	0 / 5273 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Rhinovirus infection
subjects affected / exposed	1 / 5339 (0.02%)	0 / 5273 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Sepsis
subjects affected / exposed	1 / 5339 (0.02%)	3 / 5273 (0.06%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 1
Staphylococcal infection
subjects affected / exposed	1 / 5339 (0.02%)	0 / 5273 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Staphylococcal scalded skin syndrome
subjects affected / exposed	0 / 5339 (0.00%)	1 / 5273 (0.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Staphylococcal sepsis
subjects affected / exposed	0 / 5339 (0.00%)	1 / 5273 (0.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Subcutaneous abscess
subjects affected / exposed	3 / 5339 (0.06%)	1 / 5273 (0.02%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Tonsillitis
subjects affected / exposed	5 / 5339 (0.09%)	3 / 5273 (0.06%)
occurrences causally related to treatment / all	0 / 5	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Tooth abscess
subjects affected / exposed	0 / 5339 (0.00%)	1 / 5273 (0.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Typhoid fever
subjects affected / exposed	0 / 5339 (0.00%)	2 / 5273 (0.04%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	1 / 5339 (0.02%)	4 / 5273 (0.08%)
occurrences causally related to treatment / all	0 / 1	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	3 / 5339 (0.06%)	7 / 5273 (0.13%)
occurrences causally related to treatment / all	0 / 3	0 / 7
deaths causally related to treatment / all	0 / 0	0 / 0
Viral diarrhoea
subjects affected / exposed	0 / 5339 (0.00%)	1 / 5273 (0.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Viral infection
subjects affected / exposed	4 / 5339 (0.07%)	3 / 5273 (0.06%)
occurrences causally related to treatment / all	0 / 4	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Viral pharyngitis
subjects affected / exposed	1 / 5339 (0.02%)	0 / 5273 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Viral rash
subjects affected / exposed	1 / 5339 (0.02%)	1 / 5273 (0.02%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Viral sinusitis
subjects affected / exposed	0 / 5339 (0.00%)	1 / 5273 (0.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Wound infection
subjects affected / exposed	1 / 5339 (0.02%)	0 / 5273 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	15 / 5339 (0.28%)	11 / 5273 (0.21%)
occurrences causally related to treatment / all	0 / 15	0 / 11
deaths causally related to treatment / all	0 / 0	0 / 0
Diabetic ketoacidosis
subjects affected / exposed	1 / 5339 (0.02%)	0 / 5273 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypokalaemia
subjects affected / exposed	2 / 5339 (0.04%)	1 / 5273 (0.02%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	0 / 5339 (0.00%)	2 / 5273 (0.04%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Hypovolaemia
subjects affected / exposed	2 / 5339 (0.04%)	1 / 5273 (0.02%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolic acidosis
subjects affected / exposed	3 / 5339 (0.06%)	1 / 5273 (0.02%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Obesity
subjects affected / exposed	0 / 5339 (0.00%)	1 / 5273 (0.02%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Type 1 diabetes mellitus
subjects affected / exposed	1 / 5339 (0.02%)	1 / 5273 (0.02%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 2%

Non-serious adverse events	aQIV (≥6 to <72 months)	TIV/QIV (≥6 to <72 months)
Total subjects affected by non serious adverse events
subjects affected / exposed	4627 / 5339 (86.66%)	4330 / 5273 (82.12%)
Nervous system disorders
Somnolence
subjects affected / exposed	1366 / 5339 (25.59%)	1107 / 5273 (20.99%)
occurrences all number	1366	1107
General disorders and administration site conditions
Influenza like illness
subjects affected / exposed	2690 / 5339 (50.38%)	2664 / 5273 (50.52%)
occurrences all number	2690	2664
Injection site pain
subjects affected / exposed	2360 / 5339 (44.20%)	1861 / 5273 (35.29%)
occurrences all number	2360	1861
Injection site erythema
subjects affected / exposed	1226 / 5339 (22.96%)	1031 / 5273 (19.55%)
occurrences all number	1226	1031
Pyrexia
subjects affected / exposed	1178 / 5339 (22.06%)	778 / 5273 (14.75%)
occurrences all number	1178	778
Injection site induration
subjects affected / exposed	804 / 5339 (15.06%)	576 / 5273 (10.92%)
occurrences all number	804	576
Injection site haemorrhage
subjects affected / exposed	407 / 5339 (7.62%)	374 / 5273 (7.09%)
occurrences all number	407	374
Chills
subjects affected / exposed	356 / 5339 (6.67%)	210 / 5273 (3.98%)
occurrences all number	356	210
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	701 / 5339 (13.13%)	677 / 5273 (12.84%)
occurrences all number	701	677
Vomiting
subjects affected / exposed	634 / 5339 (11.87%)	516 / 5273 (9.79%)
occurrences all number	634	516
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	305 / 5339 (5.71%)	312 / 5273 (5.92%)
occurrences all number	305	312
Rhinorrhoea
subjects affected / exposed	206 / 5339 (3.86%)	225 / 5273 (4.27%)
occurrences all number	206	225
Psychiatric disorders
Irritability
subjects affected / exposed	1441 / 5339 (26.99%)	1204 / 5273 (22.83%)
occurrences all number	1441	1204
Eating disorder
subjects affected / exposed	1163 / 5339 (21.78%)	898 / 5273 (17.03%)
occurrences all number	1163	898
Infections and infestations
Upper respiratory tract infection
subjects affected / exposed	722 / 5339 (13.52%)	724 / 5273 (13.73%)
occurrences all number	722	724
Nasopharyngitis
subjects affected / exposed	387 / 5339 (7.25%)	365 / 5273 (6.92%)
occurrences all number	387	365
Otitis media
subjects affected / exposed	375 / 5339 (7.02%)	352 / 5273 (6.68%)
occurrences all number	375	352
Pneumonia
subjects affected / exposed	218 / 5339 (4.08%)	241 / 5273 (4.57%)
occurrences all number	218	241
Rhinitis
subjects affected / exposed	215 / 5339 (4.03%)	221 / 5273 (4.19%)
occurrences all number	215	221
Bronchitis
subjects affected / exposed	186 / 5339 (3.48%)	201 / 5273 (3.81%)
occurrences all number	186	201
Gastroenteritis
subjects affected / exposed	156 / 5339 (2.92%)	139 / 5273 (2.64%)
occurrences all number	156	139

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Were there any global substantial amendments to the protocol? Yes

03 Apr 2014

- A secondary efficacy objective was added to evaluate the relative efficacy of aQIV compared to non-adjuvanted QIV comparator as determined by the proportion of subjects with first-occurrence confirmed influenza A and/or B of any influenza strain (second season and subsequent season(s) if applicable). - Two secondary immunogenicity objectives were added, to compare immunogenicity of the adjuvanted and non-adjuvanted vaccines in healthy and high risk subjects. - The number of subjects enrolled overall and in the immunogenicity subset was revised and randomization was restricted to the first approximately 4000 enrolled subjects in Season 2. - The wording of the statistical analysis of the primary objective was revised. - End of influenza season was defined as the end of June for NH influenza season and end of December for Southern Hemisphere influenza season. - Subgroups were added and revised for efficacy, immunogenicity and safety analyses.

30 Apr 2015

- Objectives were added to include RT-PCR-confirmed cases starting from: ≥7 days up to 21 days after the last vaccination in all subjects and ≥7 days up to 180 days after the last vaccination, or end of influenza season, whichever was longer in all subjects. - A Healthcare Utilization and HEO objective was added to evaluate the relative efficacy of aQIV to comparator for prevention of moderate-to-severe influenza cases. - An exploratory objective was added to include confirmed cases reported ≥21 days after last vaccination until study termination.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Efficacy Endpoint: First-Occurrence RT-PCR confirmed influenza A and/or B of any influenza strain in subjects ≥6 to <72 months of age

Primary: Efficacy Endpoint: First-Occurrence RT-PCR confirmed influenza A and/or B of any influenza strain in subjects ≥6 to <72 months of age

Secondary: Efficacy Endpoint: First-Occurrence RT-PCR confirmed influenza A and/or B of any influenza strain in subjects ≥6 to <72 months, ≥6 to <24 months, ≥6 to <36 months and ≥36 to <72 months of age

Secondary: Efficacy Endpoint: First-Occurrence RT-PCR confirmed influenza A and/or B of any influenza strain in subjects ≥6 to <72 months, ≥6 to <24 months, ≥6 to <36 months and ≥36 to <72 months of age

Secondary: Efficacy Endpoint: First-Occurrence culture confirmed influenza A and/or B of any influenza strain in subjects ≥6 to <72 months, ≥6 to <24 months, ≥6 to <36 months and ≥36 to <72 months of age

Secondary: Efficacy Endpoint: First-Occurrence culture confirmed influenza A and/or B of any influenza strain in subjects ≥6 to <72 months, ≥6 to <24 months, ≥6 to <36 months and ≥36 to <72 months of age

Secondary: Efficacy Endpoint: First-occurrence RT-PCR-confirmed influenza A and/or B of any influenza strain in subjects ≥6 to <72 months of age at ≥7 days and at ≥14 days after first vaccination up to the day of second vaccination in vaccine naïve subjects only

Secondary: Efficacy Endpoint: First-occurrence RT-PCR-confirmed influenza A and/or B of any influenza strain in subjects ≥6 to <72 months of age at ≥7 days and at ≥14 days after first vaccination up to the day of second vaccination in vaccine naïve subjects only

Secondary: Efficacy Endpoint: First-occurrence RT-PCR-confirmed influenza A and/or B of any influenza strain in subjects ≥6 to <72 months of age occurring at ≥7 days and ≤21 days after last vaccination, in all subjects.

Secondary: Efficacy Endpoint: First-occurrence RT-PCR-confirmed influenza A and/or B of any influenza strain in subjects ≥6 to <72 months of age occurring at ≥7 days and ≤21 days after last vaccination, in all subjects.

Secondary: Immunogenicity Endpoint: Antibody response 21 days after last vaccination of aQIV and TIV/QIV against vaccine strains according to Center for Biologics Evaluation and Research hemagglutination inhibition (HI) criteria in subjects ≥6 to <72 months of age

Secondary: Immunogenicity Endpoint: Antibody response 21 days after last vaccination of aQIV and TIV/QIV against vaccine strains according to Center for Biologics Evaluation and Research hemagglutination inhibition (HI) criteria in subjects ≥6 to <72 months of age

Secondary: Immunogenicity Endpoint: HI antibody responses to aQIV vs TIV/QIV against each of the vaccine strains in terms of ratio of GMT 21 days after the last vaccination in subjects ≥6 to <72 months of age (superiority analysis)

Secondary: Immunogenicity Endpoint: HI antibody responses to aQIV vs TIV/QIV against each of the vaccine strains in terms of ratio of GMT 21 days after the last vaccination in subjects ≥6 to <72 months of age (superiority analysis)

Secondary: Immunogenicity Endpoint: HI antibody responses to aQIV vs TIV/QIV against each of the vaccine strains in terms of differences in the percentage of subjects with SC 21 days after last vaccination in subjects ≥6 to <72 months of age (superiority analysis)

Secondary: Immunogenicity Endpoint: HI antibody responses to aQIV vs TIV/QIV against each of the vaccine strains in terms of differences in the percentage of subjects with SC 21 days after last vaccination in subjects ≥6 to <72 months of age (superiority analysis)

Secondary: Immunogenicity Endpoint: HI antibody responses to aQIV vs TIV/QIV against heterologous strains in terms of ratio of GMT 21 days after last vaccination in subjects ≥6 to <72 months of age

Secondary: Immunogenicity Endpoint: HI antibody responses to aQIV vs TIV/QIV against heterologous strains in terms of ratio of GMT 21 days after last vaccination in subjects ≥6 to <72 months of age

Secondary: Immunogenicity Endpoint: HI antibody responses to aQIV vs TIV/QIV against heterologous strains in terms of differences in percentages of subjects with SC 21 days after last vaccination in subjects ≥6 to <72 months of age

Secondary: Immunogenicity Endpoint: HI antibody responses to aQIV vs TIV/QIV against heterologous strains in terms of differences in percentages of subjects with SC 21 days after last vaccination in subjects ≥6 to <72 months of age

Secondary: Safety Endpoint: Number of subjects with solicited local and systemic AEs

Secondary: Safety Endpoint: Number of subjects with solicited local and systemic AEs

Secondary: Safety Endpoint: Number of subjects with unsolicited AEs

Secondary: Safety Endpoint: Number of subjects with unsolicited AEs

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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