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Clinical Trial Results:
A Phase III, Randomized, Observer Blind, Multicenter Study to Evaluate the Safety and Immunogenicity of Repeated Exposure to Either the Same or Alternate Type of Vaccine, Adjuvanted or Non-adjuvanted Quadrivalent Subunit Influenza Virus Vaccine (aQIV or QIV), Administered to Subjects Previously Vaccinated in Trial V118_05

Summary
EudraCT number	2015-002973-39
Trial protocol	FI
Global end of trial date	09 May 2017

Results information
Results version number	v1(current)
This version publication date	13 Mar 2019
First version publication date	13 Mar 2019
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_05E3

ISRCTN number

US NCT number

NCT02583256

WHO universal trial number (UTN)

Sponsor organisation name

Seqirus UK Limited

Sponsor organisation address

100 New Bridge Street, London, United Kingdom, EC4V 6JA

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

24 Aug 2018

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

09 May 2017

Was the trial ended prematurely?

Main objective of the trial

Primary Immunogenicity Objective(s) - To demonstrate non-inferiority of Haemagglutination Inhibition (HI) antibody responses to aQIV vs QIV vaccine against each of the 4 homologous strains in terms of Geometric Mean Titer ratio (GMT-ratio) 21 days after vaccination in children who have previously received vaccination with aQIV in parent trial V118_05 (A vs. B). Once the above primary objective is successfully tested the following primary objective will be tested. - To demonstrate superiority of HI antibody responses to aQIV vs QIV vaccine for at least two out of four homologous strains in terms of GMT-ratio 21 days after vaccination in children who have previously received vaccination with aQIV in parent trial V118_05 (treatment arms A vs B).

Protection of trial subjects

This clinical study was designed and was implemented and reported in accordance with the International Council for Harmonisation Guideline for Good Clinical Practice (GCP), with applicable local regulations including European Directive 2001/20/EC2, US Code of Federal Regulations Title 213, and Japanese Ministry of Health, Labor, and Welfare, Sponsor codes on protection of human rights, and with the ethical principles laid down in the Declaration of Helsinki4 (European Council 2001, US Code of Federal Regulations, International Council for Harmonisation 2016).

Background therapy

Evidence for comparator

Actual start date of recruitment

26 Jan 2016

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?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Finland: 155

Country: Number of subjects enrolled

Philippines: 846

Country: Number of subjects enrolled

Thailand: 600

Worldwide total number of subjects

1601

EEA total number of subjects

155

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)

Children (2-11 years)

1547

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

This study was conducted at 17 sites in total; 9 sites in Finland, 4 sites in the Philippines and 4 sites in Thailand.

Screening details

All enrolled subjects were included in the study.

Period 1 title

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

Blinding implementation details

The study was observer blind. Dedicated unblinded staff was involved in the vaccine administration which allowed the subject (and parent) and the responsible investigator to remain blinded to the treatment.

Are arms mutually exclusive

Yes

aQIV/aQIV

Arm description

Subjects previously vaccinated with aQIV followed one year later with aQIV. aQIV = adjuvanted Quadrivalent Influenza Vaccine

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)

aQIV/QIV

Arm description

Subjects previously vaccinated with aQIV followed one year later with QIV QIV = Nonadjuvanted Quadrivalent Influenza Vaccine

Arm type

Experimental

Investigational medicinal product name

Quadrivalent Influenza Vaccine (nonadjuvanted)

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)

QIV/aQIV

Arm description

Subjects previously vaccinated with QIV followed one year later with aQIV aQIV = adjuvanted Quadrivalent Influenza Vaccine

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)

QIV/QIV

Arm description

Subjects previously vaccinated with QIV followed one year later with QIV QIV: Quadrivalent Influenza Vaccine

Arm type

Active comparator

Investigational medicinal product name

Quadrivalent Influenza Vaccine (nonadjuvanted)

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/aQIV	aQIV/QIV	QIV/aQIV	QIV/QIV
Started	403	403	402	393
Completed	400	401	400	390
Not completed	3	2	2	3
Consent withdrawn by subject	-	1	1	-
Administrative	2	-	1	2
Lost to follow-up	1	1	-	1

Baseline characteristics

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Reporting group title

aQIV/aQIV

Reporting group description

Subjects previously vaccinated with aQIV followed one year later with aQIV. aQIV = adjuvanted Quadrivalent Influenza Vaccine

Reporting group title

aQIV/QIV

Reporting group description

Subjects previously vaccinated with aQIV followed one year later with QIV QIV = Nonadjuvanted Quadrivalent Influenza Vaccine

Reporting group title

QIV/aQIV

Reporting group description

Subjects previously vaccinated with QIV followed one year later with aQIV aQIV = adjuvanted Quadrivalent Influenza Vaccine

Reporting group title

QIV/QIV

Reporting group description

Subjects previously vaccinated with QIV followed one year later with QIV QIV: Quadrivalent Influenza Vaccine

Reporting group values	aQIV/aQIV	aQIV/QIV	QIV/aQIV	QIV/QIV	Total
Number of subjects	403	403	402	393	1601
Age categorical
Units: Subjects
In utero	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0
Infants and toddlers (28 days-23 months)	12	10	17	15	54
Children (2-11 years)	391	393	385	378	1547
Adolescents (12-17 years)	0	0	0	0	0
Adults (18-64 years)	0	0	0	0	0
From 65-84 years	0	0	0	0	0
85 years and over	0	0	0	0	0
Age continuous
Units: months
arithmetic mean (standard deviation)	54.4 ± 17.12	52.3 ± 17.02	53.3 ± 17.30	53.0 ± 16.91	-
Gender categorical
Units: Subjects
Female	197	189	206	178	770
Male	206	214	196	215	831
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	1	0	0	0	1
Not Hispanic or Latino	402	403	402	392	1599
Unknown or Not Reported	0	0	0	1	1
Race (NIH/OMB)
Units: Subjects
American Indian or Alaskan Native	0	0	0	0	0
Asian	364	364	362	355	1445
Native Hawaiian or Other Pacific Islander	0	0	0	0	0
Black or African American	0	0	0	0	0
White	38	36	37	35	146
Other	1	3	3	3	10
Region of Enrollment
Units: Subjects
Finland	39	39	39	38	155
Philippines	210	211	213	212	846
Thailand	154	153	150	143	600
Risk Status
Subjects with underlying conditions that posed high risk of influenza complications (at risk/not at risk)
Units: Subjects
At risk	10	20	18	13	61
Not at risk	393	383	384	380	1540

End points

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Reporting group title

aQIV/aQIV

Reporting group description

Subjects previously vaccinated with aQIV followed one year later with aQIV. aQIV = adjuvanted Quadrivalent Influenza Vaccine

Reporting group title

aQIV/QIV

Reporting group description

Subjects previously vaccinated with aQIV followed one year later with QIV QIV = Nonadjuvanted Quadrivalent Influenza Vaccine

Reporting group title

QIV/aQIV

Reporting group description

Subjects previously vaccinated with QIV followed one year later with aQIV aQIV = adjuvanted Quadrivalent Influenza Vaccine

Reporting group title

QIV/QIV

Reporting group description

Subjects previously vaccinated with QIV followed one year later with QIV QIV: Quadrivalent Influenza Vaccine

Primary: Geometric mean titers (GMT) and GMT ratio as determined by HI assay on Day 22 against homologous strains (aQIV-primed comparison) - Noninferiority analysis

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End point title

Geometric mean titers (GMT) and GMT ratio as determined by HI assay on Day 22 against homologous strains (aQIV-primed comparison) - Noninferiority analysis ^[1]

End point description

GMT and 95% CI were analyzed for Day 22 against homologous strains using ANCOVA with study specific covariates. Noninferiority criterion for the GMTr: Lower bound of two-sided 95% CI on the ratio of Arm A/Arm B HI GMT should not fall below 0.667. Strains tested: A/H1N1 California/07/2009; A/H3N2 Switzerland/9715293/2013; B/Victoria Brisbane/60/2008; B/Yamagata Phuket/3073/2013. Analysis Population: The immunogenicity per protocol set (PPS) consisting of all subjects who received a study vaccination and provided immunogenicity data, and who correctly received the study vaccine, had no major protocol deviations, and did not develop RT-PCR-confirmed influenza infection between baseline and Visit 2

End point type

Primary

End point timeframe

Day 22

Notes
[1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint reports results and statistics for the aQIV-primed groups: aQIV/aQIV and aQIV/QIV

End point values	aQIV/aQIV	aQIV/QIV
Number of subjects analysed	403	398
Units: geometric mean titer
number (confidence interval 95%)
A/H1N1	1219.00 (1137.35 to 1306.52)	1020.89 (953.22 to 1093.36)
A/H3N2	2355.52 (2226.19 to 2492.35)	2529.83 (2392.90 to 2674.59)
B/Yamagata	276.23 (252.73 to 301.92)	232.82 (213.25 to 254.19)
B/Victoria	388.35 (355.33 to 424.44)	328.42 (300.76 to 358.63)

A/H1N1, aQIV-aQIV and aQIV-QIV

Statistical analysis description

Comparison performed for strain A/ H1N1. Lower bound of two-sided 95% CI on the ratio of aQIV-aQIV/aQIV-QIV HI GMT should not fall below 0.667.

Comparison groups

aQIV/aQIV v aQIV/QIV

Number of subjects included in analysis

801

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Parameter type

GMT ratio

Point estimate

1.19

Confidence interval

level

95%

sides

2-sided

lower limit

1.1

upper limit

1.3

A/H3N2, aQIV-aQIV and aQIV-QIV

Statistical analysis description

Comparison performed for strain A/H3N2. Lower bound of two-sided 95% CI on the ratio of aQIV-aQIV/aQIV-QIV HI GMT should not fall below 0.667.

Comparison groups

aQIV/aQIV v aQIV/QIV

Number of subjects included in analysis

801

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Parameter type

GMT ratio

Point estimate

0.93

Confidence interval

level

95%

sides

2-sided

lower limit

0.9

upper limit

B/Yamagata, aQIV-aQIV and aQIV-QIV

Statistical analysis description

Comparison performed for strain B/Yamagata. Lower bound of two-sided 95% CI on the ratio of aQIV-aQIV/aQIV-QIV HI GMT should not fall below 0.667.

Comparison groups

aQIV/QIV v aQIV/aQIV

Number of subjects included in analysis

801

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Parameter type

GMT ratio

Point estimate

1.19

Confidence interval

level

95%

sides

2-sided

lower limit

1.1

upper limit

1.3

B/Victoria, aQIV-aQIV and aQIV-QIV

Statistical analysis description

Comparison performed for strain B/Victoria. Lower bound of two-sided 95% CI on the ratio of aQIV-aQIV/aQIV-QIV HI GMT should not fall below 0.667.

Comparison groups

aQIV/aQIV v aQIV/QIV

Number of subjects included in analysis

801

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Parameter type

GMT ratio

Point estimate

1.18

Confidence interval

level

95%

sides

2-sided

lower limit

1.1

upper limit

1.3

Primary: GMT and GMT ratio on as determined by HI assay Day 22 against homologous strains (aQIV-primed comparison) - Superiority Analysis

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End point title

GMT and GMT ratio on as determined by HI assay Day 22 against homologous strains (aQIV-primed comparison) - Superiority Analysis ^[2]

End point description

GMT and 95% CI were analyzed for Day 22 against homologous strains using ANCOVA with study specific covariates. Superiority criterion for the GMTr: Lower bound of two-sided 95% CI on the ratio of Arm A/Arm B HI GMT should exceed 1. Strains tested: A/H1N1 California/07/2009; A/H3N2 Switzerland/9715293/2013; B/Victoria Brisbane/60/2008; B/Yamagata Phuket/3073/2013. Analysis Population: The immunogenicity full analysis set (FAS) consisting of all subjects who received a study vaccination and provided immunogenicity data at both Visit 1 (baseline) and at least one post-vaccination visit.

End point type

Primary

End point timeframe

Day 22

Notes
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint reports results and statistics for the aQIV-primed groups: aQIV/aQIV and aQIV/QIV

End point values	aQIV/aQIV	aQIV/QIV
Number of subjects analysed	403	403
Units: geometric mean titer
number (confidence interval 95%)
A/H1N1	1218.91 (1137.02 to 1306.70)	1023.37 (955.72 to 1095.81)
A/H3N2	2345.71 (2216.84 to 2482.07)	2521.60 (2385.43 to 2665.56)
B/Yamagata	274.75 (251.09 to 300.65)	230.51 (210.97 to 251.86)
B/Victoria	387.35 (354.15 to 423.66)	326.68 (299.10 to 356.81)

A/H1N1, aQIV-aQIV and aQIV-QIV

Statistical analysis description

Comparison performed for strain A/ H1N1. Superiority criterion for the GMT ratio: Lower bound of two-sided 95% CI on the ratio of aQIV-aQIV/aQIV-QIV HI GMT should exceed 1

Comparison groups

aQIV/aQIV v aQIV/QIV

Number of subjects included in analysis

806

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

GMT ratio

Point estimate

1.19

Confidence interval

level

95%

sides

2-sided

lower limit

1.1

upper limit

1.3

A/H3N2, aQIV-aQIV and aQIV-QIV

Statistical analysis description

Comparison performed for strain A/H3N2. Superiority criterion for the GMT ratio: Lower bound of two-sided 95% CI on the ratio of aQIV-aQIV/aQIV-QIV HI GMT should exceed 1

Comparison groups

aQIV/aQIV v aQIV/QIV

Number of subjects included in analysis

806

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

GMT ratio

Point estimate

0.93

Confidence interval

level

95%

sides

2-sided

lower limit

0.9

upper limit

B/Yamagata, aQIV-aQIV and aQIV-QIV

Statistical analysis description

Comparison performed for strain B/Yamagata. Superiority criterion for the GMT ratio: Lower bound of two-sided 95% CI on the ratio of aQIV-aQIV/aQIV-QIV HI GMT should exceed 1

Comparison groups

aQIV/aQIV v aQIV/QIV

Number of subjects included in analysis

806

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

GMT ratio

Point estimate

1.19

Confidence interval

level

95%

sides

2-sided

lower limit

1.1

upper limit

1.3

B/Victoria, aQIV-aQIV and aQIV-QIV

Statistical analysis description

Comparison performed for strain B/Victoria. Superiority criterion for the GMT ratio: Lower bound of two-sided 95% CI on the ratio of aQIV-aQIV/aQIV-QIV HI GMT should exceed 1

Comparison groups

aQIV/aQIV v aQIV/QIV

Number of subjects included in analysis

806

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

GMT ratio

Point estimate

1.19

Confidence interval

level

95%

sides

2-sided

lower limit

1.1

upper limit

1.3

Secondary: Postvaccination HI GMTs and GMT ratio on Day 22 against Homologous Strains (QIV-primed Comparison)

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End point title

Postvaccination HI GMTs and GMT ratio on Day 22 against Homologous Strains (QIV-primed Comparison) ^[3]

End point description

End point type

Secondary

End point timeframe

Day 22

Notes
[3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint reports results and statistics for the QIV-primed groups: QIV/aQIV and QIV/QIV

End point values	QIV/aQIV	QIV/QIV
Number of subjects analysed	397	389
Units: geometric mean titer
number (confidence interval 95%)
A/H1N1	1206.20 (1123.80 to 1294.65)	866.51 (807.30 to 930.06)
A/H3N2	2369.95 (2236.39 to 2511.48)	2229.48 (2103.42 to 2363.10)
B/Yamagata	221.54 (202.12 to 242.82)	156.01 (142.32 to 171.02)
B/Victoria	330.94 (302.38 to 362.21)	244.03 (222.84 to 267.24)

A/H1N1, QIV-aQIV and QIV-QIV

Statistical analysis description

Comparison performed for strain A/H1N1. Lower bound of two-sided 95% CI on the ratio of QIV-aQIV/QIV-QIV HI GMT should not fall below 0.667.

Comparison groups

QIV/aQIV v QIV/QIV

Number of subjects included in analysis

786

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Parameter type

GMT ratio

Point estimate

1.39

Confidence interval

level

95%

sides

2-sided

lower limit

1.28

upper limit

1.51

A/H3N2, QIV-aQIV and QIV-QIV

Statistical analysis description

Comparison performed for strain A/H3N2. Lower bound of two-sided 95% CI on the ratio of QIV-aQIV/QIV-QIV HI GMT should not fall below 0.667.

Comparison groups

QIV/aQIV v QIV/QIV

Number of subjects included in analysis

786

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Parameter type

GMT ratio

Point estimate

1.06

Confidence interval

level

95%

sides

2-sided

lower limit

0.99

upper limit

1.14

B/Yamagata QIV-aQIV and QIV-QIV

Statistical analysis description

Comparison performed for strain B/Yamagata. Lower bound of two-sided 95% CI on the ratio of QIV-aQIV/QIV-QIV HI GMT should not fall below 0.667.

Comparison groups

QIV/aQIV v QIV/QIV

Number of subjects included in analysis

786

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Parameter type

GMT ratio

Point estimate

1.42

Confidence interval

level

95%

sides

2-sided

lower limit

1.27

upper limit

1.58

B/Victoria QIV-aQIV and QIV-QIV

Statistical analysis description

Comparison performed for strain B/Victoria strain. Lower bound of two-sided 95% CI on the ratio of QIV-aQIV/QIV-QIV HI GMT should not fall below 0.667.

Comparison groups

QIV/aQIV v QIV/QIV

Number of subjects included in analysis

786

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Parameter type

GMT ratio

Point estimate

1.36

Confidence interval

level

95%

sides

2-sided

lower limit

1.22

upper limit

1.51

Secondary: Postvaccination HI GMTs and GMTrs on Day 181 against homologous strains (aQIV-primed and QIV-primed comparison)

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End point title

Postvaccination HI GMTs and GMTrs on Day 181 against homologous strains (aQIV-primed and QIV-primed comparison)

End point description

End point type

Secondary

End point timeframe

Day 181

End point values	aQIV/aQIV	aQIV/QIV	QIV/aQIV	QIV/QIV
Number of subjects analysed	403	398	397	389
Units: geometric mean titer
number (confidence interval 95%)
A/H1N1	489.45 (449.93 to 532.45)	411.72 (378.83 to 447.46)	429.06 (393.73 to 467.57)	307.36 (282.02 to 334.98)
A/H3N2	1432.38 (1310.04 to 1546.52)	1438.40 (1325.53 to 1560.89)	1233.84 (1133.08 to 1343.56)	1222.21 (1121.92 to 1331.46)
B/Yamagata	97.01 (88.67 to 106.13)	86.43 (79.09 to 94.45)	73.37 (66.88 to 80.49)	56.57 (51.56 to 62.08)
B/Victoria	128.32 (115.17 to 142.97)	115.26 (103.57 to 128.26)	104.93 (94.02 to 117.10)	79.76 (71.41 to 89.09)

A/H1N1, aQIV/aQIV and aQIV/QIV

Statistical analysis description

Comparison performed for strain A/H1N1. Lower bound of two-sided 95% CI on the ratio of aQIV/aQIV:aQIV/QIV HI GMT should not fall below 0.667.

Comparison groups

aQIV/aQIV v aQIV/QIV

Number of subjects included in analysis

801

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Parameter type

GMT ratio

Point estimate

1.19

Confidence interval

level

95%

sides

2-sided

lower limit

1.07

upper limit

1.32

A/H3N2, aQIV/aQIV and aQIV/QIV

Statistical analysis description

Comparison performed for strain A/H3N2 Lower bound of two-sided 95% CI on the ratio of aQIV/aQIV:aQIV/QIV HI GMT should not fall below 0.667.

Comparison groups

aQIV/aQIV v aQIV/QIV

Number of subjects included in analysis

801

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Parameter type

GMT ratio

Point estimate

0.99

Confidence interval

level

95%

sides

2-sided

lower limit

0.9

upper limit

1.09

B/Yamagata, aQIV/aQIV and aQIV/QIV

Statistical analysis description

Comparison performed for strain B/Yamagata. Lower bound of two-sided 95% CI on the ratio of QIV/aQIV:aQIV/QIV HI GMT should not fall below 0.667.

Comparison groups

aQIV/aQIV v aQIV/QIV

Number of subjects included in analysis

801

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Parameter type

GMT ratio

Point estimate

1.12

Confidence interval

level

95%

sides

2-sided

lower limit

1.01

upper limit

1.25

B/Victoria, aQIV/aQIV and aQIV/QIV

Statistical analysis description

Comparison performed for strain B/Victoria. Lower bound of two-sided 95% CI on the ratio of aQIV/aQIV:aQIV/QIV HI GMT should not fall below 0.667.

Comparison groups

aQIV/aQIV v aQIV/QIV

Number of subjects included in analysis

801

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Parameter type

GMT ratio

Point estimate

1.11

Confidence interval

level

95%

sides

2-sided

lower limit

0.98

upper limit

1.27

A/H1N1, QIV/aQIV and QIV/QIV

Statistical analysis description

Comparison performed for strain A/H1N1. Lower bound of two-sided 95% CI on the ratio of QIV/aQIV:QIV/QIV HI GMT should not fall below 0.667.

Comparison groups

QIV/aQIV v QIV/QIV

Number of subjects included in analysis

786

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Parameter type

GMT ratio

Point estimate

1.4

Confidence interval

level

95%

sides

2-sided

lower limit

1.3

upper limit

1.5

A/H3N2, QIV/aQIV and QIV/QIV

Statistical analysis description

Comparison performed for strain A/H3N2. Lower bound of two-sided 95% CI on the ratio of QIV/aQIV:QIV/QIV HI GMT should not fall below 0.667.

Comparison groups

QIV/aQIV v QIV/QIV

Number of subjects included in analysis

786

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Parameter type

GMT ratio

Point estimate

1.01

Confidence interval

level

95%

sides

2-sided

lower limit

0.9

upper limit

1.1

B/Yamagata, QIV/aQIV and QIV/QIV

Statistical analysis description

Comparison performed for strain B/Yamagata. Lower bound of two-sided 95% CI on the ratio of QIV/aQIV:QIV/QIV HI GMT should not fall below 0.667.

Comparison groups

QIV/aQIV v QIV/QIV

Number of subjects included in analysis

786

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Parameter type

GMT ratio

Point estimate

1.3

Confidence interval

level

95%

sides

2-sided

lower limit

1.2

upper limit

1.4

B/Victoria, QIV/aQIV and QIV/QIV

Statistical analysis description

Comparison performed for strain B/Victoria. Lower bound of two-sided 95% CI on the ratio of QIV/aQIV:QIV/QIV HI GMT should not fall below 0.667.

Comparison groups

QIV/aQIV v QIV/QIV

Number of subjects included in analysis

786

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Parameter type

GMT ratio

Point estimate

1.32

Confidence interval

level

95%

sides

2-sided

lower limit

1.2

upper limit

1.5

Secondary: Postvaccination Seroconversion Rate (SCR) on Day 22 for the Homologous Strains (aQIV-primed and QIV-primed Comparison)

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End point title

Postvaccination Seroconversion Rate (SCR) on Day 22 for the Homologous Strains (aQIV-primed and QIV-primed Comparison)

End point description

The percentage of subjects achieving seroconversion at Day 22 after vaccination is reported for homologous strains. Seroconversion was defined in subjects seronegative at baseline (i.e. HI titer <1:10 on Day 1) as postvaccination HI titer ≥1:40 and defined in subjects seropositive at baseline (i.e. HI titer ≥1:10 on Day 1) as a minimum of a 4-fold increase in post-vaccination HI titer. Noninferiority criterion for the GMTr: Lower bound of two-sided 95% CI on the ratio of Arm A/Arm B HI GMT should not fall below 0.667. Strains tested: A/H1N1 California/07/2009; A/H3N2 Switzerland/9715293/2013; B/Victoria Brisbane/60/2008; B/Yamagata Phuket/3073/2013. Analysis Population: The immunogenicity per protocol set (PPS) consisting of all subjects who received a study vaccination and provided immunogenicity data, and who correctly received the study vaccine, had no major protocol deviations, and did not develop RT-PCR-confirmed influenza infection between baseline and Visit 2

End point type

Secondary

End point timeframe

Day 22

End point values	aQIV/aQIV	aQIV/QIV	QIV/aQIV	QIV/QIV
Number of subjects analysed	403	398	397	389
Units: percentage of subjects
number (confidence interval 95%)
A/H1N1	62.69 (57.75 to 67.43)	60.86 (55.86 to 65.69)	72.04 (67.35 to 76.40)	62.37 (57.34 to 67.21)
A/H3N2	68.91 (64.13 to 73.40)	68.01 (63.17 to 72.57)	72.80 (68.13 to 77.12)	76.74 (72.21 to 80.86)
B/Yamagata	76.37 (71.91 to 80.44)	72.04 (67.35 to 76.40)	79.44 (75.11 to 83.32)	66.49 (61.51 to 71.21)
B/Victoria	77.36 (72.95 to 81.36)	74.75 (70.17 to 78.95)	77.92 (73.49 to 81.92)	69.55 (64.66 to 74.14)

A/H1N1, aQIV/aQIV and aQIV/QIV

Statistical analysis description

Comparison performed for strain A/H1N1. The lower bound of two-sided 95% CI on the difference between SCR should not be below -10%.

Comparison groups

aQIV/aQIV v aQIV/QIV

Number of subjects included in analysis

801

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Parameter type

GMT ratio

Point estimate

1.8

Confidence interval

level

95%

sides

2-sided

lower limit

-4.9

upper limit

8.6

A/H3N2, aQIV/aQIV and aQIV/QIV

Statistical analysis description

Comparison performed for strain A/H3N2. The lower bound of two-sided 95% CI on the difference between SCR should not be below -10%.

Comparison groups

aQIV/aQIV v aQIV/QIV

Number of subjects included in analysis

801

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Parameter type

GMT ratio

Point estimate

0.9

Confidence interval

level

95%

sides

2-sided

lower limit

-5.6

upper limit

7.3

B/Yamagata, aQIV/aQIV and aQIV/QIV

Statistical analysis description

Comparison performed for strain B/Yamagata. The lower bound of two-sided 95% CI on the difference between SCR should not be below -10%.

Comparison groups

aQIV/aQIV v aQIV/QIV

Number of subjects included in analysis

801

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Parameter type

GMT ratio

Point estimate

4.3

Confidence interval

level

95%

sides

2-sided

lower limit

-1.8

upper limit

10.4

B/Victoria, aQIV/aQIV and aQIV/QIV

Statistical analysis description

Comparison performed for strain B/Victoria. The lower bound of two-sided 95% CI on the difference between SCR should not be below -10%.

Comparison groups

aQIV/aQIV v aQIV/QIV

Number of subjects included in analysis

801

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Parameter type

GMT ratio

Point estimate

2.6

Confidence interval

level

95%

sides

2-sided

lower limit

-3.3

upper limit

8.5

A/H1N1, QIV/aQIV and QIV/QIV

Statistical analysis description

Comparison performed for strain A/H1N1. The lower bound of two-sided 95% CI on the difference between SCR should not be below -10%.

Comparison groups

QIV/aQIV v QIV/QIV

Number of subjects included in analysis

786

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Parameter type

SCR difference

Point estimate

9.67

Confidence interval

level

95%

sides

2-sided

lower limit

3.11

upper limit

16.17

A/H3N2, QIV/aQIV and QIV/QIV

Statistical analysis description

Comparison performed for strain A/H3N2. The lower bound of two-sided 95% CI on the difference between SCR should not be below -10%.

Comparison groups

QIV/aQIV v QIV/QIV

Number of subjects included in analysis

786

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Parameter type

SCR difference

Point estimate

-3.95

Confidence interval

level

95%

sides

2-sided

lower limit

-10.02

upper limit

2.15

B/Yamagata, QIV/aQIV and QIV/QIV

Statistical analysis description

Comparison performed for strain B/Yamagata. The lower bound of two-sided 95% CI on the difference between SCR should not be below -10%.

Comparison groups

QIV/aQIV v QIV/QIV

Number of subjects included in analysis

786

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Parameter type

SCR difference

Point estimate

12.95

Confidence interval

level

95%

sides

2-sided

lower limit

6.73

upper limit

19.12

B/Victoria, QIV/aQIV and QIV/QIV

Statistical analysis description

Comparison performed for strain B/Victoria. The lower bound of two-sided 95% CI on the difference between SCR should not be below -10%.

Comparison groups

QIV/aQIV v QIV/QIV

Number of subjects included in analysis

786

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Parameter type

SCR difference

Point estimate

8.36

Confidence interval

level

95%

sides

2-sided

lower limit

2.17

upper limit

14.54

Secondary: Postvaccination HI Geometric Mean Ratio (GMR) against Homologous Strains

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End point title

Postvaccination HI Geometric Mean Ratio (GMR) against Homologous Strains

End point description

The GMR is the geometric mean of the fold increase in HI titer from Day 1 to Day 22 or Day 181. GMR and 95% CI were analyzed for the homologous strains using ANCOVA with study specific covariates. Strains tested: A/H1N1 California/07/2009; A/H3N2 Switzerland/9715293/2013; B/Victoria Brisbane/60/2008; B/Yamagata Phuket/3073/2013. Analysis Population: The immunogenicity per protocol set (PPS) consisting of all subjects who received a study vaccination and provided immunogenicity data, and who correctly received the study vaccine, had no major protocol deviations, and did not develop RT-PCR-confirmed influenza infection between baseline and Visit 2

End point type

Secondary

End point timeframe

Day 22, Day 181

End point values	aQIV/aQIV	aQIV/QIV	QIV/aQIV	QIV/QIV
Number of subjects analysed	403	398	397	389
Units: geometric mean ratio
number (confidence interval 95%)
A/H1N1 (Day 22/Day 1)	7.69 (7.17 to 8.24)	6.44 (6.01 to 6.90)	7.61 (7.09 to 8.17)	5.47 (5.09 to 5.87)
A/H1N1 (Day 181/Day 1)	3.11 (2.86 to 3.38)	2.61 (2.40 to 2.84)	2.72 (2.50 to 2.97)	1.95 (1.79 to 2.13)
A/H3N2 (Day 22/Day 1)	9.02 (8.53 to 9.55)	9.69 (9.17 to 10.25)	9.08 (8.57 to 9.62)	8.54 (8.06 to 9.05)
A/H3N2 (Day 181/Day 1)	5.44 (5.01 to 5.91)	5.50 (5.07 to 5.97)	4.72 (4.33 to 5.14)	4.67 (4.29 to 5.09)
B/Yamagata (Day 22/Day 1)	7.81 (7.14 to 8.54)	6.58 (6.03 to 7.19)	6.26 (5.71 to 6.86)	4.41 (4.02 to 4.83)
B/Yamagata (Day 181/Day 1)	2.74 (2.50 to 3.00)	2.44 (2.23 to 2.67)	2.07 (1.89 to 2.27)	1.60 (1.46 to 1.75)
B/Victoria (Day 22/Day 1)	7.86 (7.19 to 8.59)	6.64 (6.09 to 7.26)	6.70 (6.12 to 7.33)	4.94 (4.51 to 5.41)
B/Victoria (Day 181/Day 1)	2.59 (2.33 to 2.89)	2.33 (2.09 to 2.59)	2.12 (1.90 to 2.36)	1.61 (1.44 to 1.80)

No statistical analyses for this end point

Secondary: Percentage of Subjects With HI Titer ≥1:40 on Day 22 and Day 181 against Homologous Strains

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End point title

Percentage of Subjects With HI Titer ≥1:40 on Day 22 and Day 181 against Homologous Strains

End point description

The percentage of subjects achieving HI titer ≥1:40 at Day 22 and Day 181 after vaccination is reported for homologous strains. Strains tested: A/H1N1 California/07/2009; A/H3N2 Switzerland/9715293/2013; B/Victoria Brisbane/60/2008; B/Yamagata Phuket/3073/2013. Analysis Population: The Immunogenicity PPS consisting of all subjects who received a study vaccination and provided immunogenicity data, and who correctly received the study vaccine, had no major protocol deviations, and did not develop RT-PCR-confirmed influenza infection between baseline and Visit 2.

End point type

Secondary

End point timeframe

Day 22, Day 181

End point values	aQIV/aQIV	aQIV/QIV	QIV/aQIV	QIV/QIV
Number of subjects analysed	403	398	397	389
Units: percentage of subjects
number (confidence interval 95%)
A/H1N1 (Day 22)	100.0 (99.1 to 100.0)	100.0 (99.1 to 100.0)	100.0 (99.1 to 100.0)	99.7 (98.6 to 100.0)
A/H1N1 (Day 181)	100.0 (99.1 to 100.0)	99.2 (97.8 to 99.8)	99.2 (97.8 to 99.8)	95.9 (93.4 to 97.6)
A/H3N2 (Day 22)	100.0 (99.1 to 100.0)	100.0 (99.1 to 100.0)	100.0 (99.1 to 100.0)	100.0 (99.1 to 100.0)
A/H3N2 (Day 181)	99.8 (98.6 to 100.0)	100.0 (99.1 to 100.0)	100.0 (99.1 to 100.0)	98.7 (97.0 to 99.6)
B/Yamagata (Day 22)	98.5 (96.8 to 99.5)	98.7 (97.1 to 99.6)	98.5 (96.7 to 99.4)	96.6 (94.3 to 98.2)
B/Yamagata (Day 181)	94.3 (91.5 to 96.3)	93.9 (91.1 to 96.1)	83.9 (79.9 to 87.4)	76.1 (71.5 to 80.3)
B/Victoria (Day 22)	99.9 (98.6 to 100.0)	100.0 (99.1 to 100.0)	99.5 (98.2 to 99.9)	97.9 (95.9 to 99.1)
B/Victoria (Day 181)	95.3 (92.7 to 97.1)	93.9 (91.1 to 96.1)	86.7 (83.0 to 89.9)	76.9 (72.2 to 80.9)

No statistical analyses for this end point

Secondary: Percentage of Subjects With HI Titer ≥1:110, ≥1:151, ≥1:215, ≥1:330 and ≥1:629 on Day 22 for the Homologous Strains

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End point title

Percentage of Subjects With HI Titer ≥1:110, ≥1:151, ≥1:215, ≥1:330 and ≥1:629 on Day 22 for the Homologous Strains

End point description

The percentage of subjects achieving HI Titers ≥1:110, ≥1:151, ≥1:215, ≥1:330 and ≥1:629 at Day 22 after vaccination is reported for homologous strains. Strains tested: A/H1N1 California/07/2009; A/H3N2 Switzerland/9715293/2013; B/Victoria Brisbane/60/2008; B/Yamagata Phuket/3073/2013. Analysis Population: The Immunogenicity PPS consisting of all subjects who received a study vaccination and provided immunogenicity data, and who correctly received the study vaccine, had no major protocol deviations, and did not develop RT-PCR-confirmed influenza infection between baseline and Visit 2.

End point type

Secondary

End point timeframe

Day 22

End point values	aQIV/aQIV	aQIV/QIV	QIV/aQIV	QIV/QIV
Number of subjects analysed	403	398	397	389
Units: percentage of subjects
number (confidence interval 95%)
A/H1N1 ≥1: 110	100.00 (99.1 to 100.0)	100.0 (99.1 to 100.0)	99.7 (98.6 to 100.0)	97.7 (95.6 to 98.9)
A/H1N1 ≥1:151	100.0 (99.1 to 100.0)	100.0 (99.1 to 100.0)	99.5 (98.2 to 99.9)	97.4 (95.3 to 98.8)
A/H1N1 ≥1:215	99.8 (98.6 to 100.0)	99.2 (97.8 to 99.8)	97.5 (95.4 to 98.8)	93.8 (90.9 to 96.0)
A/H1N1 ≥1:330	97.3 (95.2 to 98.6)	93.7 (90.8 to 95.9)	93.2 (90.3 to 95.5)	82.5 (78.3 to 86.1)
A/H1N1 ≥1:629	94.8 (92.1 to 96.7)	87.6 (84.0 to 90.7)	87.9 (84.3 to 91.0)	74.2 (69.6 to 78.5)
A/H3N2 ≥1:110	99.8 (98.6 to 100.0)	100.0 (99.1 to 100.0)	100.0 (99.1 to 100.0)	99.5 (98.1 to 99.9)
A/H3N2 ≥1:151	99.8 (98.6 to 100.0)	100.0 (99.1 to 100.0)	100.0 (99.1 to 100.0)	99.5 (98.1 to 99.9)
A/H3N2 ≥1:215	99.5 (98.2 to 99.9)	100.0 (99.1 to 100.0)	100.0 (99.1 to 100.0)	97.7 (95.6 to 98.9)
A/H3N2 ≥1:330	99.3 (97.8 to 99.8)	99.7 (98.6 to 100.0)	99.5 (98.2 to 99.9)	95.9 (93.4 to 97.6)
A/H3N2 ≥1:629	99.0 (97.5 to 99.7)	99.7 (98.6 to 100.0)	99.2 (97.8 to 99.8)	95.1 (92.4 to 97.0)
B/Yamagata ≥1:110	90.8 (87.5 to 93.4)	88.4 (84.8 to 91.4)	82.7 (78.6 to 86.3)	68.3 (63.4 to 73.0)
B/Yamagata ≥1:151	87.6 (83.9 to 90.6)	81.6 (77.4 to 85.3)	75.9 (71.4 to 80.0)	59.9 (54.8 to 64.9)
B/Yamagata ≥1:215	69.9 (65.2 to 74.3)	64.2 (59.3 to 69.0)	53.3 (48.2 to 58.3)	38.5 (33.6 to 43.6)
B/Yamagata ≥1:330	44.0 (39.1 to 49.0)	34.3 (29.6 to 39.2)	25.1 (20.9 to 29.7)	14.9 (11.5 to 18.9)
B/Yamagata ≥1:629	27.9 (23.5 to 32.5)	20.9 (17.0 to 25.2)	14.2 (10.9 to 18.1)	7.3 (4.9 to 10.4)
B/Victoria ≥1:110	93.0 (90.1 to 95.3)	89.9 (86.5 to 92.7)	86.0 (82.8 to 89.8)	76.1 (71.5 to 80.3)
B/Victoria ≥1:151	91.3 (88.1 to 93.9)	87.9 (84.3 to 90.9)	83.0 (78.9 to 86.6)	70.6 (65.8 to 75.1)
B/Victoria ≥1:215	79.6 (75.3 to 83.4)	73.4 (69.1 to 78.0)	67.5 (62.6 to 72.1)	53.0 (47.9 to 58.1)
B/Victoria ≥1:330	58.7 (53.7 to 63.6)	48.7 (43.8 to 53.8)	41.9 (37.0 to 46.9)	32.0 (27.4 to 37.0)
B/Victoria ≥1:629	45.3 (40.3 to 50.3)	37.6 (32.8 to 42.6)	34.3 (29.6 to 39.2)	24.1 (19.9 to 28.8)

No statistical analyses for this end point

Secondary: Postvaccination HI GMTs on Day 1, Day 22, and Day 181 against Heterologous Strains

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End point title

Postvaccination HI GMTs on Day 1, Day 22, and Day 181 against Heterologous Strains

End point description

GMT and 95% CI were analyzed for Day 22 for the heterologous strains using ANCOVA with study specific covariates. The two heterologous strains selected for HI testing in this study were the H3N2 strain, A/HongKong/4801/2014 (X-263B), and the B/ Victoria lineage strain, B/Malaysia/2506/2004. The Immunogenicity PPS consisting of all subjects who received a study vaccination and provided immunogenicity data, and who correctly received the study vaccine, had no major protocol deviations, and did not develop RT-PCR-confirmed influenza infection between baseline and Visit 2.

End point type

Secondary

End point timeframe

Day 1, Day 22, Day 181

End point values	aQIV/aQIV	aQIV/QIV	QIV/aQIV	QIV/QIV
Number of subjects analysed	60	57	59	58
Units: geometric mean titer
number (confidence interval 95%)
A/H3N2 (Day 1)	97.7 (59.4 to 160.6)	156.6 (96.1 to 255.1)	40.9 (25.3 to 66.0)	91.6 (55.6 to 150.8)
A/H3N2 (Day 22)	2436.1 (2058.0 to 2883.6)	2415.2 (2049.9 to 2845.5)	2225.1 (1872.6 to 2643.8)	2097.2 (1769.7 to 2485.2)
A/H3N2 (Day 181)	898.1 (707.5 to 1139.9)	917.6 (728.2 to 1156.3)	953.2 (746.7 to 1216.6)	791.7 (621.5 to 1008.3)
B/Victoria (Day 1)	33.4 (24.6 to 45.3)	23.8 (17.6 to 32.2)	15.8 (11.8 to 21.2)	15.9 (11.7 to 21.6)
B/Victoria (Day 22)	327.1 (255.7 to 418.4)	248.4 (195.3 to 316.0)	283.2 (222.8 to 359.8)	204.8 (159.6 to 262.8)
B/Victoria (Day 181)	107.1 (79.3 to 144.6)	85.6 (63.9 to 114.7)	77.5 (57.9 to 103.9)	56.0 (41.2 to 76.0)

No statistical analyses for this end point

Secondary: Postvaccination HI GMRs for Day 22/Day 1 and Day 181/Day 1 for the Heterologous Strains

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End point title

Postvaccination HI GMRs for Day 22/Day 1 and Day 181/Day 1 for the Heterologous Strains

End point description

The GMR is the geometric mean of the fold increase in HI titer from Day 1 to Day 22 or Day 181. GMR and 95% CI were analyzed for the heterologous strains using ANCOVA with study specific covariates. The two heterologous strains selected for HI testing in this study were the H3N2 strain, A/Hong Kong/4801/2014 (X-263B), and the B Victoria lineage strain, B/Malaysia/2506/2004. Analysis Population: The Immunogenicity PPS consisting of all subjects who received a study vaccination and provided immunogenicity data, and who correctly received the study vaccine, had no major protocol deviations, and did not develop RT-PCR-confirmed influenza infection between baseline and Visit 2.

End point type

Secondary

End point timeframe

Day 22, Day 181

End point values	aQIV/aQIV	aQIV/QIV	QIV/aQIV	QIV/QIV
Number of subjects analysed	60	57	59	58
Units: geometric mean ratio
number (confidence interval 95%)
A/H3N2 (Day 22/Day 1)	14.67 (12.4 to 17.4)	14.55 (12.3 to 17.1)	13.40 (11.3 to 15.9)	12.63 (10.7 to 15.0)
A/H3N2 (Day 181/Day 1)	5.31 (4.2 to 6.7)	5.42 (4.3 to 6.8)	5.63 (4.4 to 7.2)	4.68 (3.7 to 6.0)
B/Victoria (Day 22/Day 1)	13.40 (10.5 to 17.1)	10.18 (8.0 to 13.0)	11.60 (9.1 to 14.7)	8.39 (6.5 to 10.8)
B/Victoria (Day 181/Day 1)	4.38 (3.2 to 5.9)	3.50 (2.6 to 4.7)	3.17 (2.4 to 4.3)	2.29 (1.7 to 3.1)

No statistical analyses for this end point

Secondary: Percentage of Subjects With HI Titer ≥1:40 and Seroconversion on Day 22 and Day 181 against Heterologous Strain

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End point title

Percentage of Subjects With HI Titer ≥1:40 and Seroconversion on Day 22 and Day 181 against Heterologous Strain

End point description

The percentage of subjects achieving HI titer ≥1:40 at Day 22 and Day 181 after vaccination and the percentage of subject who experienced seroconversion is reported for homologous strains. Seroconversion was defined in subjects seronegative at baseline (i.e. HI titer <1:10 on Day 1) as post-vaccination HI titer ≥1:40 and defined in subjects seropositive at baseline (i.e. HI titer ≥1:10 on Day 1) as a minimum of a 4-fold increase in post-vaccination HI titer. The two heterologous strains selected for HI testing in this study were the H3N2 strain, A/Hong Kong/4801/2014 (X-263B), and the B/ Victoria lineage strain, B/Malaysia/2506/2004. Analysis Population: The Immunogenicity PPS consisting of all subjects who received a study vaccination and provided immunogenicity data, and who correctly received the study vaccine, had no major protocol deviations, and did not develop RT-PCR-confirmed influenza infection between baseline and Visit 2.

End point type

Secondary

End point timeframe

Day 22, Day 181

End point values	aQIV/aQIV	aQIV/QIV	QIV/aQIV	QIV/QIV
Number of subjects analysed	60	57	59	58
Units: percentage of subjects
number (confidence interval 95%)
HI ≥1:40 A/H3N2 (Day 22)	100.00 (94.0 to 100.00)	100.00 (93.7 to 100.00)	100.00 (93.9 to 100.00)	100.00 (93.8 to 100.00)
HI ≥1:40 A/H3N2 (Day 181)	100.00 (93.8 to 100.00)	100.00 (93.68 to 100.00)	100.00 (93.8 to 100)	98.2 (90.4 to 100)
SCR A/H3N2 (Day 22)	78.3 (65.8 to 87.9)	73.7 (60.3 to 84.5)	83.1 (71.0 to 91.6)	69.0 (55.5 to 80.5)
HI ≥1:40 B/Victoria (Day 22)	98.3 (91.1 to 100.00)	100.00 (93.6 to 100.00)	96.6 (88.3 to 99.6)	98.3 (90.8 to 100)
HI ≥1:40 B/Victoria (Day 181)	91.4 (81.0 to 97.1)	83.6 (71.2 to 92.2)	74.1 (61.0 to 84.7)	64.3 (50.4 to 76.6)
SCR B/Victoria (Day 22)	75.0 (62.1 to 85.3)	82.1 (69.6 to 91.1)	81.4 (69.1 to 90.3)	77.6 (64.7 to 87.5)

No statistical analyses for this end point

Secondary: Postvaccination Microneutralization (MN) GMTs on Day 1, Day 22, and Day 181 against Homologous Strains

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End point title

Postvaccination Microneutralization (MN) GMTs on Day 1, Day 22, and Day 181 against Homologous Strains

End point description

To further characterize immune response, MN GMT and 95% CI were analyzed for Day 1, Day 22, and Day 181 for the homologous strains. Strains tested: A/H1N1 California/07/2009; A/H3N2 Switzerland/9715293/2013; B/Victoria Brisbane/60/2008; B/Yamagata Phuket/3073/2013. Analysis Population: The Immunogenicity PPS consisting of all subjects who received a study vaccination and provided immunogenicity data, and who correctly received the study vaccine, had no major protocol deviations, and did not develop RT-PCR-confirmed influenza infection between baseline and Visit 2.

End point type

Secondary

End point timeframe

Day 1, Day 22, Day 181

End point values	aQIV/aQIV	aQIV/QIV	QIV/aQIV	QIV/QIV
Number of subjects analysed	60	60	60	60
Units: geometric mean titer
number (confidence interval 95%)
A/H1N1 (Day 1)	264.36 (173.8 to 402.1)	198.13 (127.8 to 307.0)	104.28 (67.0 to 162.3)	140.38 (90.0 to 219.1)
A/H1N1 (Day 22)	2253.81 (1713.5 to 2964.5)	2295.46 (1729.5 to 3046.7)	2992.29 (2238.5 to 3999.9)	1543.54 (1156.5 to 2060.1)
A/H1N1 (Day 181)	727.04 (568.6 to 929.6)	725.35 (560.7 to 938.4)	686.98 (527.2 to 895.2)	412.34 (317.2 to 536.0)
A/H3N2 (Day 1)	160.88 (103.6 to 249.7)	113.74 (71.9 to 180.0)	133.25 (83.8 to 211.8)	97.47 (61.1 to 155.6)
A/H3N2 (Day 22)	5532.06 (4441.7 to 6890.0)	6649.94 (5275.3 to 8382.7)	5019.51 (3978.6 to 6332.8)	4696.37 (3699.4 to 5962.1)
A/H3N2 (Day 181)	2069.22 (1488.8 to 2875.9)	2127.88 (1500.4 to 3017.8)	2138.80 (1505.0 to 3039.5)	1696.57 (1178.4 to 2442.5)
B/Yamagata (Day 1)	29.82 (22.2 to 40.1)	37.99 (27.9 to 51.7)	21.57 (15.8 to 29.5)	21.07 (15.4 to 28.9)
B/Yamagata (Day 22)	388.29 (299.1 to 504.0)	301.39 (229.0 to 396.7)	247.31 (187.6 to 326.0)	197.51 (149.3 to 261.4)
B/Yamagata (Day 181)	107.05 (81.4 to 140.8)	103.59 (77.5 to 138.5)	82.90 (61.9 to 111.0)	56.03 (41.5 to 75.6)
B/Victoria (Day 1)	43.66 (33.1 to 57.6)	43.13 (32.3 to 57.6)	27.96 (20.9 to 37.4)	33.14 (24.7 to 44.4)
B/Victoria (Day 22)	355.63 (271.8 to 465.4)	346.99 (262.6 to 458.5)	338.49 (255.0 to 449.4)	193.09 (145.5 to 256.3)
B/Victoria (Day 181)	124.31 (95.3 to 162.1)	106.08 (80.2 to 140.3)	95.87 (72.1 to 127.5)	60.54 (45.4 to 80.7)

No statistical analyses for this end point

Secondary: Postvaccination MN GMR for Day 22/Day 1 and Day 181/Day 1 against Homologous Strains

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End point title

Postvaccination MN GMR for Day 22/Day 1 and Day 181/Day 1 against Homologous Strains

End point description

The GMR is the geometric mean of the fold increase in MN titer from Day 1 to Day 22 or Day 181. GMR and 95% CI were analyzed for the homologous strains using ANCOVA with study specific covariates. Strains tested: A/H1N1 California/07/2009; A/H3N2 Switzerland/9715293/2013; B/Victoria Brisbane/60/2008; B/Yamagata Phuket/3073/2013. Analysis Population: The Immunogenicity PPS consisting of all subjects who received a study vaccination and provided immunogenicity data, and who correctly received the study vaccine, had no major protocol deviations, and did not develop RT-PCR-confirmed influenza infection between baseline and Visit 2.

End point type

Secondary

End point timeframe

Day 22/Day 1 and Day 181/Day 1

End point values	aQIV/aQIV	aQIV/QIV	QIV/aQIV	QIV/QIV
Number of subjects analysed	60	60	60	60
Units: geometric mean ratio
number (confidence interval 95%)
A/H1N1 (Day 22/Day 1)	11.85 (9.0 to 15.6)	12.07 (9.1 to 16.0)	15.73 (11.8 to 21.0)	8.11 (6.1 to 10.8)
A/H1N1 (Day 181/Day 1)	3.67 (2.9 to 4.7)	3.66 (2.8 to 4.7)	3.47 (2.7 to 4.5)	2.08 (1.6 to 2.7)
A/H3N2 (Day 22/Day 1)	28.19 (22.6 to 35.1)	33.88 (26.9 to 42.7)	25.57 (20.3 to 32.3)	23.93 (18.8 to 30.4)
A/H3N2 (Day 181/Day 1)	10.63 (7.6 to 14.8)	10.93 (7.7 to 15.5)	10.99 (7.7 to 15.6)	8.72 (6.1 to 12.5)
B/Yamagata (Day 22/Day 1)	14.11 (10.9 to 18.3)	10.95 (8.3 to 14.4)	8.99 (6.8 to 11.8)	7.18 (5.4 to 9.5)
B/Yamagata (Day 181/Day 1)	3.97 (3.0 to 5.2)	3.84 (2.9 to 5.1)	3.07 (2.3 to 4.1)	2.08 (1.5 to 2.8)
B/Victoria (Day 22/Day 1)	9.43 (7.2 to 12.3)	9.20 (7.0 to 12.2)	8.97 (6.8 to 11.9)	5.12 (3.9 to 6.8)
B/Victoria (Day 181/Day 1)	3.25 (2.5 to 4.2)	2.77 (2.1 to 3.7)	2.51 (1.9 to 3.3)	1.58 (1.2 to 2.1)

No statistical analyses for this end point

Secondary: Postvaccination Anti-neuraminidase (NA) GMTs on Day 1, Day 22, and Day 181 for the Homologous Strains

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End point title

Postvaccination Anti-neuraminidase (NA) GMTs on Day 1, Day 22, and Day 181 for the Homologous Strains

End point description

To further characterize immune response, adjusted anti-NA GMT and 95% CI were analyzed for Day 1, Day 22, and Day 181 for the homologous strains. Strains tested: N1 (PR8 H6N1 California/07/2009), N2 (PR8 H6N2 Switzerl/9715293/2013); B/Victoria Brisbane/60/2008; B/Yamagata Phuket/3073/2013. Analysis Population: The Immunogenicity PPS consisting of all subjects who received a study vaccination and provided immunogenicity data, and who correctly received the study vaccine, had no major protocol deviations, and did not develop RT-PCR-confirmed influenza infection between baseline and Visit 2.

End point type

Secondary

End point timeframe

Day 1, Day 22, Day 181

End point values	aQIV/aQIV	aQIV/QIV	QIV/aQIV	QIV/QIV
Number of subjects analysed	56	62	59	60
Units: geometric mean titer
number (confidence interval 95%)
N1 (Day 1)	1174.69 (767.8 to 1797.3)	1209.21 (815.7 to 1792.6)	230.09 (154.7 to 342.2)	182.80 (122.7 to 272.2)
N1 (Day 22)	3403.72 (2821.4 to 4106.2)	3161.01 (2654.7 to 3763.9)	3588.43 (2994.0 to 4300.9)	2410.65 (2001.2 to 2903.9)
N1 (Day 181)	2477.65 (1958.9 to 3133.7)	1649.89 (1324.9 to 2054.5)	2018.32 (1610.4 to 2529.5)	870.73 (691.0 to 1097.2)
N2 (Day 1)	204.59 (121.3 to 345.2)	289.86 (178.6 to 470.4)	86.08 (52.8 to 140.3)	86.34 (52.9 to 140.9)
N2 (Day 22)	915.19 (753.5 to 1111.6)	1050.44 (876.7 to 1258.7)	1242.36 (1031.4 to 1496.5)	980.87 (813.8 to 1182.2)
N2 (Day 181)	505.91 (375.2 to 682.2)	565.69 (426.7 to 749.9)	516.51 (388.6 to 686.4)	369.04 (277.5 to 490.8)
B/Yamagata (Day 1)	290.06 (202.3 to 415.8)	282.17 (201.7 to 394.8)	148.35 (106.0 to 207.6)	126.07 (90.0 to 176.6)
B/Yamagata (Day 22)	1288.67 (1094.6 to 1517.2)	1250.88 (1074.3 to 1456.5)	1275.06 (1093.5 to 1486.7)	883.66 (756.1 to 1032.7)
B/Yamagata (Day 181)	727.17 (560.2 to 943.9)	596.62 (467.2 to 762.0)	511.73 (400.7 to 653.5)	391.23 (305.3 to 501.3)
B/Victoria (Day 1)	497.11 (344.3 to 717.7)	548.92 (390.7 to 771.2)	306.48 (217.6 to 431.7)	237.96 (168.7 to 335.6)
B/Victoria (Day 22)	3175.99 (2736.5 to 3686.0)	3336.65 (2906.2 to 3830.8)	3331.87 (2894.6 to 3835.2)	2418.50 (2094.6 to 2792.74)
B/Victoria (Day 181)	1424.38 (1108.1 to 1831.0)	1587.86 (1256.5 to 2006.6)	1443.37 (1140.1 to 1827.3)	1030.77 (810.3 to 1311.3)

No statistical analyses for this end point

Secondary: Postvaccination Anti-NA GMR for Day 22/Day 1 and Day 181/Day 1 against Homologous Strains

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End point title

Postvaccination Anti-NA GMR for Day 22/Day 1 and Day 181/Day 1 against Homologous Strains

End point description

The GMR is the geometric mean of the fold increase in anti-NA titer from Day 1 to Day 22 or Day 181. GMR and 95% CI were analyzed for the homologous strains using ANCOVA with study specific covariates. Strains tested: N1 (PR8 H6N1 California/07/2009), N2 (PR8 H6N2 Switzerl/9715293/2013); B/Victoria Brisbane/60/2008; B/Yamagata Phuket/3073/2013.

End point type

Secondary

End point timeframe

Day 22, Day 181

End point values	aQIV/aQIV	aQIV/QIV	QIV/aQIV	QIV/QIV
Number of subjects analysed	56	62	59	60
Units: geometric mean ratio
number (confidence interval 95%)
N1 (Day 22/Day 1)	5.40 (4.5 to 6.5)	5.02 (4.2 to 6.0)	5.70 (4.8 to 6.8)	3.83 (3.2 to 4.6)
N1 (Day 181/Day 1)	3.95 (3.1 to 5.0)	2.63 (2.1 to 3.3)	3.22 (2.6 to 4.0)	1.39 (1.1 to 1.8)
N2 (Day 22/Day 1)	4.51 (3.7 to 5.5)	5.18 (4.3 to 6.2)	6.13 (5.1 to 7.4)	4.84 (4.0 to 5.8)
N2 (Day 181/Day 1)	2.45 (1.8 to 3.3)	2.74 (2.1 to 3.6)	2.50 (1.9 to 3.3)	1.79 (1.3 to 2.4)
B/Yamagata (Day 22/Day 1)	5.75 (4.9 to 6.8)	5.59 (4.8 to 6.5)	5.69 (4.9 to 6.6)	3.95 (3.4 to 4.6)
B/Yamagata (Day 181/Day 1)	3.29 (2.5 to 4.3)	2.70 (2.1 to 3.4)	2.32 (1.81 to 3.0)	1.77 (1.4 to 2.3)
B/Victoria (Day 22/Day 1)	6.81 (5.9 to 7.9)	7.15 (6.2 to 8.2)	7.14 (6.2 to 8.2)	5.18 (4.5 to 6.0)
B/Victoria (Day 181/Day 1)	3.05 (2.4 to 3.9)	3.40 (2.7 to 4.3)	3.09 (2.4 to 3.9)	2.21 (1.7 to 2.8)

No statistical analyses for this end point

Secondary: Percentage of Subjects with Solicited AEs

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End point title

Percentage of Subjects with Solicited AEs

End point description

Safety was assessed in terms of percentage of subjects reporting solicited AEs up to 7 days after vaccination.

End point type

Secondary

End point timeframe

Day 1 to Day 7 after vaccination

End point values	aQIV/aQIV	aQIV/QIV	QIV/aQIV	QIV/QIV
Number of subjects analysed	403	403	402	393
Units: percentage of subjects
number (not applicable)
Any Solicited AEs	64.76	50.12	53.48	40.71
Local Solicited AEs	44.67	37.97	36.82	29.52
Systemic Solicited AEs	39.21	24.81	30.85	18.83
Other (antipyretic/analgesic use)	27.54	10.17	16.92	10.43

No statistical analyses for this end point

Secondary: Percentage of Subjects with Unsolicited AEs

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End point title

Percentage of Subjects with Unsolicited AEs

End point description

Safety of revaccination was assessed in terms of percentage of subjects reporting unsolicited AEs up to 12 months after last vaccination. Analysis Population: The unsolicited safety set consisting of all subjects who received a study vaccination with documented safety assessments for unsolicited AE data (including those where it was reported/confirmed that no events had occurred).

End point type

Secondary

End point timeframe

Day 1 to Day 22 after vaccination

End point values	aQIV/aQIV	aQIV/QIV	QIV/aQIV	QIV/QIV
Number of subjects analysed	403	403	402	393
Units: percentage of subjects
number (not applicable)
Unsolicited AEs	54.09	55.33	55.97	52.16
Related Unsolicited AEs	6.20	3.97	5.72	3.82

No statistical analyses for this end point

Secondary: Percentage of subjects with Serious Adverse Events (SAE), AEs Leading to Withdrawal, New Onset of Chronic Disease (NOCD), Adverse Event of Special Interest (AESI) and Medically Attended AEs

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End point title

Percentage of subjects with Serious Adverse Events (SAE), AEs Leading to Withdrawal, New Onset of Chronic Disease (NOCD), Adverse Event of Special Interest (AESI) and Medically Attended AEs

End point description

Safety of revaccination was assessed in terms of percentage of subjects reporting SAEs, AEs leading to withdrawal, NOCD, AESI and medically attended AE up to 12 months after last vaccination. Analysis Population: The unsolicited safety set consisting of all subjects who received a study vaccination with documented safety assessments for unsolicited AE data (including those where it was reported/confirmed that no events had occurred).

End point type

Secondary

End point timeframe

Day 1 to Day 366

End point values	aQIV/aQIV	aQIV/QIV	QIV/aQIV	QIV/QIV
Number of subjects analysed	403	403	402	393
Units: percentage of subjects
number (not applicable)
SAE	2.48	2.73	1.74	2.04
AE leading to withdrawal	0	0	0	0
NOCD	0.50	0	0	0
AESI	0	0	0	0.25
Medically Attended AE	51.61	54.34	53.98	48.60

No statistical analyses for this end point

Secondary: Percentage of Subjects With Diagnosis of Failure to Thrive or Short Stature

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End point title

Percentage of Subjects With Diagnosis of Failure to Thrive or Short Stature

End point description

Safety of revaccination was assessed in terms of percentage of subjects reporting diagnosis of failure to thrive or short stature up to 12 months after last vaccination. Analysis Population: The unsolicited safety set consisting of all subjects who received a study vaccination with documented safety assessments for unsolicited AE data (including those where it was reported/confirmed that no events had occurred).

End point type

Secondary

End point timeframe

Day 1 to Day 366

End point values	aQIV/aQIV	aQIV/QIV	QIV/aQIV	QIV/QIV
Number of subjects analysed	403	403	402	393
Units: percentage of subjects
number (not applicable)
Diagnosis of Failure to Thrive or Short Stature	0.25	0.74	0.25	0.76

No statistical analyses for this end point

Secondary: Safety Endpoint: Percentage of Subjects With Otitis Media, or Pneumonia, or Influenza-like Illness

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End point title

Safety Endpoint: Percentage of Subjects With Otitis Media, or Pneumonia, or Influenza-like Illness

End point description

Safety of revaccination was assessed in terms of percentage of subjects reporting otitis media, or pneumonia, or influenza-like illness up to 12 months after last vaccination. Analysis Population: The unsolicited safety set consisting of all subjects who received a study vaccination with documented safety assessments for unsolicited AE data (including those where it was reported/confirmed that no events had occurred).

End point type

Secondary

End point timeframe

Day 1 to Day 366

End point values	aQIV/aQIV	aQIV/QIV	QIV/aQIV	QIV/QIV
Number of subjects analysed	403	403	402	393
Units: percentage of subjects
number (not applicable)
otitis media, any event	3.23	3.47	3.73	2.80
pneumonia, any event	1.49	1.49	0.75	1.78
influenza-like illness	7.94	10.17	9.20	7.89

No statistical analyses for this end point

Secondary: Immunogenicity Endpoint: Percentage of subjects with MN Titer ≥1:20, ≥1:40, ≥1:80, ≥1:160, ≥1:320 and ≥1:640 on Day 22 and Day 181 against homologous strains

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End point title

Immunogenicity Endpoint: Percentage of subjects with MN Titer ≥1:20, ≥1:40, ≥1:80, ≥1:160, ≥1:320 and ≥1:640 on Day 22 and Day 181 against homologous strains

End point description

The percentage of subjects achieving MN titer ≥1:20, ≥1:40, ≥1:80 ≥1:160, ≥1:320 and ≥1:640 at Day 22 and Day 181 after vaccination is reported against homologous strains. Strains tested: A/H1N1 California/07/2009; A/H3N2 Switzerland/9715293/2013; B/Victoria Brisbane/60/2008; B/Yamagata Phuket/3073/2013. Analysis Population: The Immunogenicity PPS consisting of all subjects who received a study vaccination and provided immunogenicity data, and who correctly received the study vaccine, had no major protocol deviations, and did not develop RT-PCR-confirmed influenza infection between baseline and Visit 2.

End point type

Secondary

End point timeframe

Day 22, Day 181

End point values	aQIV/aQIV	aQIV/QIV	QIV/aQIV	QIV/QIV
Number of subjects analysed	60	59	60	59
Units: percentage of subjects
number (confidence interval 95%)
A/ H1N1, ≥1:20 (Day 22)	100.00 (93.94 to 100.00)	100.00 (93.94 to 100.00)	100.00 (94.04 to 100.00)	100.00 (93.94 to 100.00)
A/ H1N1, ≥1:40 (Day 22)	98.31 (90.91 to 99.96)	100.00 (93.94 to 100.00)	100.00 (94.04 to 100.00)	100.00 (93.94 to 100.00)
A/H1N1, ≥1:80 (Day 22)	98.31 (90.91 to 99.96)	100.00 (93.94 to 100.00)	100.00 (94.04 to 100.00)	98.31 (90.91 to 99.96)
A/H1N1, ≥1:160 (Day 22)	98.31 (90.91 to 99.96)	100.00 (93.94 to 100.00)	100.00 (94.04 to 100.00)	94.92 (85.85 to 98.94)
A/H1N1, ≥1:320 (Day 22)	96.61 (88.29 to 99.59)	100.00 (93.94 to 100.00)	100.00 (94.04 to 100.00)	94.92 (85.85 to 98.94)
A/H1N1, ≥1:640 (Day 22)	96.61 (88.29 to 99.59)	98.31 (90.91 to 99.96)	91.67 (81.61 to 97.24)	81.36 (69.09 to 90.31)
A/H1N1, ≥1:20 (Day 181)	100.00 (94.04 to 100.00)	100.00 (93.84 to 100.00)	100.00 (93.84 to 100.00)	98.28 (90.76 to 99.96)
A/H1N1, ≥1:40 (Day 181)	100.00 (94.04 to 100.00)	100.00 (93.84 to 100.00)	100.00 (93.84 to 100.00)	96.55 (88.09 to 99.58)
A/H1N1, ≥1:80 (Day 181)	100.00 (94.04 to 100.00)	100.00 (93.84 to 100.00)	100.00 (93.84 to 100.00)	93.10 (83.27 to 98.09)
A/H1N1, ≥1:160 (Day 181)	96.67 (88.47 to 99.59)	98.28 (90.76 to 99.96)	94.83 (85.62 to 98.92)	81.03 (68.59 to 90.13)
A/H1N1, ≥1:320 (Day 181)	91.67 (81.61 to 97.24)	91.38 (81.02 to 97.14)	84.48 (72.58 to 92.65)	63.79 (50.12 to 76.01)
A/H1N1, ≥1:640 (Day 181)	80.00 (67.67 to 89.22)	63.79 (50.12 to 76.01)	55.17 (41.54 to 68.26)	48.28 (34.95 to 61.78)
A/H3N2, ≥1:20 (Day 22)	100.00 (94.04 to 100.00)	100.00 (93.94 to 100.00)	100.00 (94.04 to 100.00)	98.28 (90.76 to 99.96)
A/H3N2, ≥1:40 (Day 22)	100.00 (94.04 to 100.00)	100.00 (93.94 to 100.00)	100.00 (94.04 to 100.00)	98.28 (90.76 to 99.96)
A/H3N2, ≥1:80 (Day 22)	100.00 (94.04 to 100.00)	100.00 (93.94 to 100.00)	100.00 (94.04 to 100.00)	98.28 (90.76 to 99.96)
A/H3N2, ≥1:160 (Day 22)	100.00 (94.04 to 100.00)	100.00 (93.94 to 100.00)	100.00 (94.04 to 100.00)	98.28 (90.76 to 99.96)
A/H3N2, ≥1:320 (Day 22)	100.00 (94.04 to 100.00)	100.00 (93.94 to 100.00)	100.00 (94.04 to 100.00)	96.55 (88.09 to 99.58)
A/H3N2, ≥1:640 (Day 22)	100.00 (94.04 to 100.00)	100.00 (93.94 to 100.00)	100.00 (94.04 to 100.00)	94.83 (85.62 to 98.92)
A/H3N2, ≥1:20 (Day 181)	100.00 (94.04 to 100.00)	98.28 (90.76 to 99.96)	100.00 (93.84 to 100.00)	98.21 (90.45 to 99.95)
A/H3N2, ≥1:40 (Day 181)	100.00 (94.04 to 100.00)	98.28 (90.76 to 99.96)	100.00 (93.84 to 100.00)	96.43 (87.69 to 99.56)
A/H3N2, ≥1:80 (Day 181)	100.00 (94.04 to 100.00)	98.28 (90.76 to 99.96)	100.00 (93.84 to 100.00)	91.07 (80.38 to 97.04)
A/H3N2, ≥1:160 (Day 181)	96.67 (88.47 to 99.59)	98.28 (90.76 to 99.96)	96.55 (88.09 to 99.58)	89.29 (78.12 to 95.97)
A/H3N2, ≥1:320 (Day 181)	91.67 (81.61 to 97.24)	94.83 (85.62 to 98.92)	93.10 (83.27 to 98.09)	85.71 (73.78 to 93.62)
A/H3N2, ≥1:640 (Day 181)	86.67 (75.41 to 94.06)	86.21 (74.62 to 93.85)	84.48 (72.58 to 92.65)	83.93 (71.67 to 92.38)
B/Yamagata, ≥1:20 (Day 22)	100.00 (94.04 to 100.00)	100.00 (93.94 to 100.00)	96.67 (88.47 to 99.59)	96.55 (88.09 to 99.58)
B/Yamagata, ≥1:40 (Day 22)	98.33 (91.06 to 99.96)	98.31 (90.91 to 99.96)	96.67 (88.47 to 99.59)	93.10 (83.27 to 98.09)
B/Yamagata, ≥1:80 (Day 22)	95.00 (86.08 to 98.96)	96.61 (88.29 to 99.59)	95.00 (86.08 to 98.96)	89.66 (78.83 to 96.11)
B/Yamagata, ≥1:160 (Day 22)	91.67 (81.61 to 97.24)	86.44 (75.02 to 93.96)	78.33 (65.80 to 87.93)	70.69 (57.27 to 81.91)
B/Yamagata, ≥1:320 (Day 22)	75.00 (62.14 to 85.28)	72.88 (59.73 to 83.64)	65.00 (51.60 to 76.87)	50.00 (36.58 to 63.42)
B/Yamagata, ≥1:640 (Day 22)	58.33 (44.88 to 70.93)	47.46 (34.30 to 60.88)	31.67 (20.26 to 44.96)	24.14 (13.87 to 37.17)
B/Yamagata, ≥1:20 (Day 181)	98.33 (91.06 to 99.96)	96.55 (88.09 to 99.58)	93.10 (83.27 to 98.09)	80.36 (67.57 to 89.77)
B/Yamagata, ≥1:40 (Day 181)	93.33 (83.80 to 98.15)	93.10 (83.27 to 98.09)	79.31 (66.65 to 88.83)	71.43 (57.79 to 82.70)
B/Yamagata, ≥1:80 (Day 181)	71.67 (58.56 to 82.55)	72.41 (59.10 to 83.34)	56.90 (43.23 to 69.84)	46.43 (32.99 to 60.26)
B/Yamagata, ≥1:160 (Day 181)	45.00 (32.12 to 58.39)	48.28 (34.95 to 61.78)	32.76 (21.01 to 46.34)	17.86 (8.91 to 30.40)
B/Yamagata, ≥1:320 (Day 181)	25.00 (14.72 to 37.86)	24.14 (13.87 to 37.17)	15.52 (7.35 to 27.42)	7.14 (1.98 to 17.29)
B/Yamagata, ≥1:640 (Day 181)	3.33 (0.41 to 11.53)	8.62 (2.86 to 18.98)	5.17 (1.08 to 14.38)	3.57 (0.44 to 12.31)
B/Victoria, ≥1:20 (Day 22)	98.31 (90.91 to 99.96)	100.00 (93.94 to 100.00)	100.00 (94.04 to 100.00)	98.31 (90.91 to 99.96)
B/Victoria, ≥1:40 (Day 22)	94.92 (85.85 to 98.94)	100.00 (93.94 to 100.00)	96.67 (88.47 to 99.59)	93.22 (83.54 to 98.12)
B/Victoria, ≥1:80 (Day 22)	91.53 (81.32 to 97.19)	96.61 (88.29 to 99.59)	90.00 (79.49 to 96.24)	84.75 (73.01 to 92.78)
B/Victoria, ≥1:160 (Day 22)	86.44 (75.02 to 93.96)	86.44 (75.02 to 93.96)	81.67 (69.56 to 90.48)	69.49 (56.13 to 80.81)
B/Victoria, ≥1:320 (Day 22)	74.58 (61.56 to 85.02)	67.80 (54.36 to 79.38)	58.33 (44.88 to 70.93)	35.59 (23.55 to 49.13)
B/Victoria, ≥1:640 (Day 22)	49.15 (35.89 to 62.50)	42.37 (29.61 to 55.93)	33.33 (21.69 to 46.69)	22.03 (12.29 to 34.73)
B/Victoria, ≥1:20 (Day 181)	100.00 (94.04 to 100.00)	100.00 (93.84 to 100.00)	98.28 (90.76 to 99.96)	96.43 (87.69 to 99.56)
B/Victoria, ≥1:40 (Day 181)	86.67 (75.41 to 94.06)	87.93 (76.70 to 95.01)	74.14 (60.96 to 84.74)	60.71 (46.75 to 73.50)
B/Victoria, ≥1:80 (Day 181)	78.33 (65.80 to 87.93)	63.79 (50.12 to 76.01)	44.83 (31.74 to 58.46)	41.07 (28.10 to 55.02)
B/Victoria, ≥1:160 (Day 181)	58.33 (44.88 to 70.93)	43.10 (30.16 to 56.77)	27.59 (16.66 to 40.90)	23.21 (12.98 to 36.42)
B/Victoria, ≥1:320 (Day 181)	31.67 (20.26 to 44.96)	20.69 (11.17 to 33.35)	18.97 (9.87 to 31.41)	8.93 (2.96 to 19.62)
B/Victoria, ≥1:640 (Day 181)	8.33 (2.76 to 18.39)	15.52 (7.35 to 27.42)	12.07 (4.99 to 23.30)	5.36 (1.12 to 14.87)

No statistical analyses for this end point

Secondary: Immunogenicity Endpoint: Percentage of subjects achieving anti-NA titers ≥1:20, ≥1:40, ≥1:80, ≥1:160, ≥1:320 and ≥1:640 on Days 22 and 181 against homologous strains

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End point title

Immunogenicity Endpoint: Percentage of subjects achieving anti-NA titers ≥1:20, ≥1:40, ≥1:80, ≥1:160, ≥1:320 and ≥1:640 on Days 22 and 181 against homologous strains

End point description

The percentage of subjects achieving anti-NA titers ≥1:20, ≥1:40, ≥1:80, ≥1:160, ≥1:320 and ≥1:640 on Days 22 and 181 after vaccination is reported against homologous strains. Strains tested: N1 (PR8 H6N1 California/07/2009), N2 (PR8 H6N2 Switzerl/9715293/2013); B/Victoria Brisbane/60/2008; B/Yamagata Phuket/3073/2013. Analysis Population: The Immunogenicity PPS consisting of all subjects who received a study vaccination and provided immunogenicity data, and who correctly received the study vaccine, had no major protocol deviations, and did not develop RT-PCR-confirmed influenza infection between baseline and Visit 2.

End point type

Secondary

End point timeframe

Day 22, Day 181

End point values	aQIV/aQIV	aQIV/QIV	QIV/aQIV	QIV/QIV
Number of subjects analysed	56	62	59	60
Units: percentage of subjects
number (confidence interval 95%)
N1, ≥1:20 (Day 22)	100.00 (93.62 to 100.00)	100.00 (94.22 to 100.00)	100.00 (93.94 to 100.00)	100.00 (94.04 to 100.00)
N1, ≥1:40 (Day 22)	100.00 (93.62 to 100.00)	100.00 (94.22 to 100.00)	100.00 (93.94 to 100.00)	98.33 (91.06 to 99.96)
N1, ≥1:80 (Day 22)	100.00 (93.62 to 100.00)	100.00 (94.22 to 100.00)	100.00 (93.94 to 100.00)	98.33 (91.06 to 99.96)
N1, ≥1:160 (Day 22)	100.00 (93.62 to 100.00)	100.00 (94.22 to 100.00)	100.00 (93.94 to 100.00)	93.33 (83.80 to 98.15)
N1, ≥1:320 (Day 22)	100.00 (93.62 to 100.00)	100.00 (94.22 to 100.00)	100.00 (93.94 to 100.00)	88.33 (77.43 to 95.18)
N1,≥1:640 (Day 22)	100.00 (93.62 to 100.00)	100.00 (94.22 to 100.00)	98.31 (90.91 to 99.96)	85.00 (73.43 to 92.90)
N1, ≥1:20 (Day 181)	100.00 (93.51 to 100.00)	100.00 (94.13 to 100.00)	100.00 (93.84 to 100.00)	93.33 (83.80 to 98.15)
N1, ≥1:40 (Day 181)	100.00 (93.51 to 100.00)	100.00 (94.13 to 100.00)	100.00 (93.84 to 100.00)	91.67 (81.61 to 97.24)
N1, ≥1:80 (Day 181)	100.00 (93.51 to 100.00)	100.00 (94.13 to 100.00)	100.00 (93.84 to 100.00)	86.67 (75.41 to 94.06)
N1, ≥1:160 (Day 181)	100.00 (93.51 to 100.00)	100.00 (94.13 to 100.00)	96.55 (88.09 to 99.58)	81.67 (69.56 to 90.48)
N1, ≥1:320 (Day 181)	100.00 (93.51 to 100.00)	96.72 (88.65 to 99.60)	93.10 (83.27 to 98.09)	70.00 (56.79 to 81.15)
N1, ≥1:640 (Day 181)	100.00 (93.51 to 100.00)	93.44 (84.05 to 98.18)	72.41 (59.10 to 83.34)	51.67 (38.39 to 64.77)
N2, ≥1:20 (Day 22)	100.00 (93.62 to 100.00)	100.00 (94.22 to 100.00)	100.00 (93.94 to 100.00)	100.00 (94.04 to 100.00)
N2, ≥1:40 (Day 22)	100.00 (93.62 to 100.00)	100.00 (94.22 to 100.00)	100.00 (93.94 to 100.00)	100.00 (94.04 to 100.00)
N2, ≥1:80 (Day 22)	98.21 (90.45 to 99.95)	100.00 (94.22 to 100.00)	98.31 (90.91 to 99.96)	96.67 (88.47 to 99.59)
N2, ≥1:160 (Day 22)	98.21 (90.45 to 99.95)	100.00 (94.22 to 100.00)	98.31 (90.91 to 99.96)	90.00 (79.49 to 96.24)
N2, ≥1:320 (Day 22)	94.64 (85.13 to 98.88)	96.77 (88.83 to 99.61)	94.92 (85.85 to 98.94)	85.00 (73.43 to 92.90)
N2, ≥1:640 (Day 22)	85.71 (73.78 to 93.62)	88.71 (78.11 to 95.34)	79.66 (67.17 to 89.02)	68.33 (55.04 to 79.74)
N2, ≥1:20 (Day 181)	100.00 (93.51 to 100.00)	100.00 (94.04 to 100.00)	100.00 (93.84 to 100.00)	90.00 (79.49 to 96.24)
N2, ≥1:40 (Day 181)	98.18 (90.28 to 99.95)	98.33 (91.06 to 99.96)	89.66 (78.83 to 96.11)	88.33 (77.43 to 95.18)
N2, ≥1:80 (Day 181)	94.55 (84.88 to 98.86)	98.33 (91.06 to 99.96)	86.21 (74.62 to 93.85)	80.00 (67.67 to 89.22)
N2, ≥1:160 (Day 181)	85.45 (73.34 to 93.50)	95.00 (86.08 to 98.96)	81.03 (68.59 to 90.13)	70.00 (56.79 to 81.15)
N2, ≥1:320 (Day 181)	80.00 (67.03 to 89.57)	85.00 (73.43 to 92.90)	67.24 (53.66 to 78.99)	61.67 (48.21 to 73.93)
N2, ≥1:640 (Day 181)	70.91 (57.10 to 82.37)	81.67 (69.56 to 90.48)	55.17 (41.54 to 68.26)	50.00 (36.81 to 63.19)
B/Yamagata, ≥1:20 (Day 22)	100.00 (93.62 to 100.00)	100.00 (94.13 to 100.00)	100.00 (93.94 to 100.00)	100.00 (94.04 to 100.00)
B/Yamagata, ≥1:40 (Day 22)	100.00 (93.62 to 100.00)	100.00 (94.13 to 100.00)	100.00 (93.94 to 100.00)	100.00 (94.04 to 100.00)
B/Yamagata, ≥1:80 (Day 22)	98.21 (90.45 to 99.95)	100.00 (94.13 to 100.00)	100.00 (93.94 to 100.00)	100.00 (94.04 to 100.00)
B/Yamagata, ≥1:160 (Day 22)	98.21 (90.45 to 99.95)	100.00 (94.13 to 100.00)	100.00 (93.94 to 100.00)	98.33 (91.06 to 99.96)
B/Yamagata, ≥1:320 (Day 22)	98.21 (90.45 to 99.95)	100.00 (94.13 to 100.00)	96.61 (88.29 to 99.59)	88.33 (77.43 to 95.18)
B/Yamagata, ≥1:640 (Day 22)	91.07 (80.38 to 97.04)	91.80 (81.90 to 97.28)	89.83 (79.17 to 96.18)	66.67 (53.31 to 78.31)
B/Yamagata, ≥1:20 (Day 181)	100.00 (93.51 to 100.00)	98.33 (91.06 to 99.96)	100.00 (93.84 to 100.00)	100.00 (94.04 to 100.00)
B/Yamagata, ≥1:40 (Day 181)	100.00 (93.51 to 100.00)	98.33 (91.06 to 99.96)	98.28 (90.76 to 99.96)	96.67 (88.47 to 99.59)
B/Yamagata, ≥1:80 (Day 181)	100.00 (93.51 to 100.00)	98.33 (91.06 to 99.96)	96.55 (88.09 to 99.58)	90.00 (79.49 to 96.24)
B/Yamagata, ≥1:160 (Day 181)	98.18 (90.28 to 99.95)	96.67 (88.47 to 99.59)	91.38 (81.02 to 97.14)	81.67 (69.56 to 90.48)
B/Yamagata, ≥1:320 (Day 181)	92.73 (82.41 to 97.98)	86.67 (75.41 to 94.06)	84.48 (72.58 to 92.65)	65.00 (51.60 to 76.87)
B/Yamagata, ≥1:640 (Day 181)	72.73 (59.04 to 83.86)	61.67 (48.21 to 73.93)	51.72 (38.22 to 65.05)	40.00 (27.56 to 53.46)
B/Victoria, ≥1:20 (Day 22)	100.00 (93.62 to 100.00)	100.00 (94.22 to 100.00)	100.00 (93.94 to 100.00)	100.00 (94.04 to 100.00)
B/Victoria, ≥1:40 (Day 22)	100.00 (93.62 to 100.00)	100.00 (94.22 to 100.00)	100.00 (93.94 to 100.00)	100.00 (94.04 to 100.00)
B/Victoria, ≥1:80 (Day 22)	100.00 (93.62 to 100.00)	100.00 (94.22 to 100.00)	100.00 (93.94 to 100.00)	100.00 (94.04 to 100.00)
B/Victoria, ≥1:160 (Day 22)	100.00 (93.62 to 100.00)	100.00 (94.22 to 100.00)	100.00 (93.94 to 100.00)	100.00 (94.04 to 100.00)
B/Victoria, ≥1:320 (Day 22)	100.00 (93.62 to 100.00)	100.00 (94.22 to 100.00)	100.00 (93.94 to 100.00)	98.33 (91.06 to 99.96)
B/Victoria, ≥1:640 (Day 22)	100.00 (93.62 to 100.00)	100.00 (94.22 to 100.00)	100.00 (93.94 to 100.00)	91.67 (81.61 to 97.24)
B/Victoria, ≥1:20 (Day 181)	100.00 (93.51 to 100.00)	100.00 (94.13 to 100.00)	100.00 (93.84 to 100.00)	100.00 (94.04 to 100.00)
B/Victoria, ≥1:40 (Day 181)	100.00 (93.51 to 100.00)	100.00 (94.13 to 100.00)	100.00 (93.84 to 100.00)	100.00 (94.04 to 100.00)
B/Victoria, ≥1:80 (Day 181)	100.00 (93.51 to 100.00)	100.00 (94.13 to 100.00)	100.00 (93.84 to 100.00)	100.00 (94.04 to 100.00)
B/Victoria, ≥1:160 (Day 181)	100.00 (93.51 to 100.00)	100.00 (94.13 to 100.00)	96.55 (88.09 to 99.58)	96.67 (88.47 to 99.59)
B/Victoria, ≥1:320 (Day 181)	94.55 (84.88 to 98.86)	100.00 (94.13 to 100.00)	96.55 (88.09 to 99.58)	83.33 (71.48 to 91.71)
B/Victoria, ≥1:640 (Day 181)	89.09 (77.75 to 95.89)	95.08 (86.29 to 98.97)	81.03 (68.59 to 90.13)	70.00 (56.79 to 81.15)

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Day 1 to Day 366

Adverse event reporting additional description

The overall safety set included all subjects who were in the solicited safety set and/or in the unsolicited safety set. Assessment of revaccination safety included: SAEs collected between Day 1 to Day 366 Non-serious AEs included solicited AEs collected between Day 1 to Day 7 after last vaccination, and unsolicited AEs collected between Day 1 to

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

19.1

Reporting group title

aQIV-aQIV

Reporting group description

Subjects previously vaccinated with aQIV followed by one year later by aQIV. aQIV = adjuvanted Quadrivalent Influenza Vaccine

Reporting group title

aQIV-QIV

Reporting group description

Subjects previously vaccinated with aQIV followed one year by QIV QIV: Nonadjuvanted Quadrivalent Influenza Vaccine

Reporting group title

QIV-aQIV

Reporting group description

Subjects previously vaccinated with QIV followed one year later by aQIV aQIV: adjuvanted Quadrivalent Influenza Vaccine

Reporting group title

QIV-QIV

Reporting group description

Subjects previously vaccinated with QIV followed one year later QIV QIV: Quadrivalent Influenza Vaccine

Serious adverse events	aQIV-aQIV	aQIV-QIV	QIV-aQIV	QIV-QIV
Total subjects affected by serious adverse events
subjects affected / exposed	10 / 403 (2.48%)	11 / 403 (2.73%)	7 / 402 (1.74%)	8 / 393 (2.04%)
number of deaths (all causes)	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0
Injury, poisoning and procedural complications
Animal bite
subjects affected / exposed	1 / 403 (0.25%)	1 / 403 (0.25%)	0 / 402 (0.00%)	1 / 393 (0.25%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Fall
subjects affected / exposed	0 / 403 (0.00%)	1 / 403 (0.25%)	0 / 402 (0.00%)	0 / 393 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Jaw fracture
subjects affected / exposed	1 / 403 (0.25%)	0 / 403 (0.00%)	0 / 402 (0.00%)	0 / 393 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Wound secretion
subjects affected / exposed	0 / 403 (0.00%)	1 / 403 (0.25%)	0 / 402 (0.00%)	0 / 393 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Congenital, familial and genetic disorders
Spina bifida occulta
subjects affected / exposed	0 / 403 (0.00%)	0 / 403 (0.00%)	0 / 402 (0.00%)	1 / 393 (0.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Kawasaki's disease
subjects affected / exposed	0 / 403 (0.00%)	0 / 403 (0.00%)	0 / 402 (0.00%)	1 / 393 (0.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Febrile convulsion
subjects affected / exposed	1 / 403 (0.25%)	0 / 403 (0.00%)	0 / 402 (0.00%)	0 / 393 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Iron deficiency anaemia
subjects affected / exposed	0 / 403 (0.00%)	0 / 403 (0.00%)	0 / 402 (0.00%)	1 / 393 (0.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lymphadenitis
subjects affected / exposed	0 / 403 (0.00%)	0 / 403 (0.00%)	0 / 402 (0.00%)	1 / 393 (0.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	1 / 403 (0.25%)	0 / 403 (0.00%)	0 / 402 (0.00%)	0 / 393 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Immune system disorders
Anaphylactic reaction
subjects affected / exposed	0 / 403 (0.00%)	0 / 403 (0.00%)	0 / 402 (0.00%)	1 / 393 (0.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Aphthous ulcer
subjects affected / exposed	0 / 403 (0.00%)	0 / 403 (0.00%)	0 / 402 (0.00%)	1 / 393 (0.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dyspepsia
subjects affected / exposed	1 / 403 (0.25%)	0 / 403 (0.00%)	0 / 402 (0.00%)	0 / 393 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastritis
subjects affected / exposed	2 / 403 (0.50%)	0 / 403 (0.00%)	0 / 402 (0.00%)	0 / 393 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Amoebic dysentery
subjects affected / exposed	1 / 403 (0.25%)	0 / 403 (0.00%)	0 / 402 (0.00%)	0 / 393 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Appendiceal abscess
subjects affected / exposed	0 / 403 (0.00%)	1 / 403 (0.25%)	0 / 402 (0.00%)	0 / 393 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	0 / 403 (0.00%)	1 / 403 (0.25%)	1 / 402 (0.25%)	0 / 393 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dengue fever
subjects affected / exposed	1 / 403 (0.25%)	0 / 403 (0.00%)	0 / 402 (0.00%)	0 / 393 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
External ear cellulitis
subjects affected / exposed	0 / 403 (0.00%)	1 / 403 (0.25%)	0 / 402 (0.00%)	0 / 393 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	0 / 403 (0.00%)	4 / 403 (0.99%)	4 / 402 (1.00%)	1 / 393 (0.25%)
occurrences causally related to treatment / all	0 / 0	0 / 4	0 / 4	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Herpangina
subjects affected / exposed	0 / 403 (0.00%)	0 / 403 (0.00%)	1 / 402 (0.25%)	0 / 393 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	1 / 403 (0.25%)	1 / 403 (0.25%)	0 / 402 (0.00%)	1 / 393 (0.25%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory tract infection
subjects affected / exposed	0 / 403 (0.00%)	1 / 403 (0.25%)	0 / 402 (0.00%)	0 / 393 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tonsillitis
subjects affected / exposed	0 / 403 (0.00%)	0 / 403 (0.00%)	1 / 402 (0.25%)	1 / 393 (0.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	1 / 403 (0.25%)	0 / 403 (0.00%)	0 / 402 (0.00%)	1 / 393 (0.25%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	aQIV-aQIV	aQIV-QIV	QIV-aQIV	QIV-QIV
Total subjects affected by non serious adverse events
subjects affected / exposed	289 / 403 (71.71%)	269 / 403 (66.75%)	274 / 402 (68.16%)	229 / 393 (58.27%)
Nervous system disorders
Somnolence
subjects affected / exposed	79 / 403 (19.60%)	45 / 403 (11.17%)	55 / 402 (13.68%)	25 / 393 (6.36%)
occurrences all number	154	89	111	51
General disorders and administration site conditions
Influenza like illness
subjects affected / exposed	32 / 403 (7.94%)	41 / 403 (10.17%)	37 / 402 (9.20%)	31 / 393 (7.89%)
occurrences all number	36	43	38	34
Injection site erythema
subjects affected / exposed	81 / 403 (20.10%)	57 / 403 (14.14%)	51 / 402 (12.69%)	39 / 393 (9.92%)
occurrences all number	157	114	94	69
Injection site induration
subjects affected / exposed	62 / 403 (15.38%)	55 / 403 (13.65%)	38 / 402 (9.45%)	24 / 393 (6.11%)
occurrences all number	117	111	62	38
Injection site pain
subjects affected / exposed	163 / 403 (40.45%)	137 / 403 (34.00%)	134 / 402 (33.33%)	120 / 393 (30.53%)
occurrences all number	300	245	254	191
Pyrexia
subjects affected / exposed	96 / 403 (23.82%)	46 / 403 (11.41%)	72 / 402 (17.91%)	51 / 393 (12.98%)
occurrences all number	135	80	104	77
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	22 / 403 (5.46%)	8 / 403 (1.99%)	14 / 402 (3.48%)	16 / 393 (4.07%)
occurrences all number	38	14	29	30
Vomiting
subjects affected / exposed	29 / 403 (7.20%)	15 / 403 (3.72%)	19 / 402 (4.73%)	13 / 393 (3.31%)
occurrences all number	37	26	33	20
Psychiatric disorders
Eating disorder
subjects affected / exposed	66 / 403 (16.38%)	28 / 403 (6.95%)	52 / 402 (12.94%)	24 / 393 (6.11%)
occurrences all number	147	64	121	65
Irritability
subjects affected / exposed	60 / 403 (14.89%)	44 / 403 (10.92%)	50 / 402 (12.44%)	36 / 393 (9.16%)
occurrences all number	126	79	98	73
Infections and infestations
Nasopharyngitis
subjects affected / exposed	21 / 403 (5.21%)	19 / 403 (4.71%)	26 / 402 (6.47%)	16 / 393 (4.07%)
occurrences all number	24	23	30	16
Upper respiratory tract infection
subjects affected / exposed	78 / 403 (19.35%)	100 / 403 (24.81%)	99 / 402 (24.63%)	73 / 393 (18.58%)
occurrences all number	107	139	138	91

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Were there any global substantial amendments to the protocol? Yes

29 Feb 2016

• During the conduct of the study there was a transition in the Sponsor responsibilities from Novartis to Seqirus. • The study protocol was aligned with the final SAP. • A secondary immunogenicity objective was added to further characterize the immune response using MN assay on Days 22 and 181 in a subset of subjects. • Additional immunogenicity analysis was included to characterize immune response against heterologous influenza strains in a subset of subjects.

08 Feb 2017

• Immune response evaluation using anti-NA assay in a subset of subjects for each vaccine group was added as secondary objective (as per Pediatric Investigation Plan commitment to the European Medicines Agency Paediatric Committee). • Inclusion of additional safety evaluations such as occurrence of all-cause mortality, hospitalizations, ILI syndrome, all–cause pneumonia, and otitis media. • In order to align the analysis with the parent study V118_05, an additional subgroup analysis by age group (<24 and ≥24 months of age) was added. • The maximal duration of laboratory samples storage (up to 15 years) was clarified.

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: Geometric mean titers (GMT) and GMT ratio as determined by HI assay on Day 22 against homologous strains (aQIV-primed comparison) - Noninferiority analysis

Primary: Geometric mean titers (GMT) and GMT ratio as determined by HI assay on Day 22 against homologous strains (aQIV-primed comparison) - Noninferiority analysis

Primary: GMT and GMT ratio on as determined by HI assay Day 22 against homologous strains (aQIV-primed comparison) - Superiority Analysis

Primary: GMT and GMT ratio on as determined by HI assay Day 22 against homologous strains (aQIV-primed comparison) - Superiority Analysis

Secondary: Postvaccination HI GMTs and GMT ratio on Day 22 against Homologous Strains (QIV-primed Comparison)

Secondary: Postvaccination HI GMTs and GMT ratio on Day 22 against Homologous Strains (QIV-primed Comparison)

Secondary: Postvaccination HI GMTs and GMTrs on Day 181 against homologous strains (aQIV-primed and QIV-primed comparison)

Secondary: Postvaccination HI GMTs and GMTrs on Day 181 against homologous strains (aQIV-primed and QIV-primed comparison)

Secondary: Postvaccination Seroconversion Rate (SCR) on Day 22 for the Homologous Strains (aQIV-primed and QIV-primed Comparison)

Secondary: Postvaccination Seroconversion Rate (SCR) on Day 22 for the Homologous Strains (aQIV-primed and QIV-primed Comparison)

Secondary: Postvaccination HI Geometric Mean Ratio (GMR) against Homologous Strains

Secondary: Postvaccination HI Geometric Mean Ratio (GMR) against Homologous Strains

Secondary: Percentage of Subjects With HI Titer ≥1:40 on Day 22 and Day 181 against Homologous Strains

Secondary: Percentage of Subjects With HI Titer ≥1:40 on Day 22 and Day 181 against Homologous Strains

Secondary: Percentage of Subjects With HI Titer ≥1:110, ≥1:151, ≥1:215, ≥1:330 and ≥1:629 on Day 22 for the Homologous Strains

Secondary: Percentage of Subjects With HI Titer ≥1:110, ≥1:151, ≥1:215, ≥1:330 and ≥1:629 on Day 22 for the Homologous Strains

Secondary: Postvaccination HI GMTs on Day 1, Day 22, and Day 181 against Heterologous Strains

Secondary: Postvaccination HI GMTs on Day 1, Day 22, and Day 181 against Heterologous Strains

Secondary: Postvaccination HI GMRs for Day 22/Day 1 and Day 181/Day 1 for the Heterologous Strains

Secondary: Postvaccination HI GMRs for Day 22/Day 1 and Day 181/Day 1 for the Heterologous Strains

Secondary: Percentage of Subjects With HI Titer ≥1:40 and Seroconversion on Day 22 and Day 181 against Heterologous Strain

Secondary: Percentage of Subjects With HI Titer ≥1:40 and Seroconversion on Day 22 and Day 181 against Heterologous Strain

Secondary: Postvaccination Microneutralization (MN) GMTs on Day 1, Day 22, and Day 181 against Homologous Strains

Secondary: Postvaccination Microneutralization (MN) GMTs on Day 1, Day 22, and Day 181 against Homologous Strains

Secondary: Postvaccination MN GMR for Day 22/Day 1 and Day 181/Day 1 against Homologous Strains

Secondary: Postvaccination MN GMR for Day 22/Day 1 and Day 181/Day 1 against Homologous Strains

Secondary: Postvaccination Anti-neuraminidase (NA) GMTs on Day 1, Day 22, and Day 181 for the Homologous Strains

Secondary: Postvaccination Anti-neuraminidase (NA) GMTs on Day 1, Day 22, and Day 181 for the Homologous Strains

Secondary: Postvaccination Anti-NA GMR for Day 22/Day 1 and Day 181/Day 1 against Homologous Strains

Secondary: Postvaccination Anti-NA GMR for Day 22/Day 1 and Day 181/Day 1 against Homologous Strains

Secondary: Percentage of Subjects with Solicited AEs

Secondary: Percentage of Subjects with Solicited AEs

Secondary: Percentage of Subjects with Unsolicited AEs

Secondary: Percentage of Subjects with Unsolicited AEs

Secondary: Percentage of subjects with Serious Adverse Events (SAE), AEs Leading to Withdrawal, New Onset of Chronic Disease (NOCD), Adverse Event of Special Interest (AESI) and Medically Attended AEs

Secondary: Percentage of subjects with Serious Adverse Events (SAE), AEs Leading to Withdrawal, New Onset of Chronic Disease (NOCD), Adverse Event of Special Interest (AESI) and Medically Attended AEs

Secondary: Percentage of Subjects With Diagnosis of Failure to Thrive or Short Stature

Secondary: Percentage of Subjects With Diagnosis of Failure to Thrive or Short Stature

Secondary: Safety Endpoint: Percentage of Subjects With Otitis Media, or Pneumonia, or Influenza-like Illness

Secondary: Safety Endpoint: Percentage of Subjects With Otitis Media, or Pneumonia, or Influenza-like Illness

Secondary: Immunogenicity Endpoint: Percentage of subjects with MN Titer ≥1:20, ≥1:40, ≥1:80, ≥1:160, ≥1:320 and ≥1:640 on Day 22 and Day 181 against homologous strains

Secondary: Immunogenicity Endpoint: Percentage of subjects with MN Titer ≥1:20, ≥1:40, ≥1:80, ≥1:160, ≥1:320 and ≥1:640 on Day 22 and Day 181 against homologous strains

Secondary: Immunogenicity Endpoint: Percentage of subjects achieving anti-NA titers ≥1:20, ≥1:40, ≥1:80, ≥1:160, ≥1:320 and ≥1:640 on Days 22 and 181 against homologous strains

Secondary: Immunogenicity Endpoint: Percentage of subjects achieving anti-NA titers ≥1:20, ≥1:40, ≥1:80, ≥1:160, ≥1:320 and ≥1:640 on Days 22 and 181 against homologous strains

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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