immunogenicity, safety and reactogenicity study of …...study number: 116023 (flu d-qiv-009 ext...

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GSK Medicine: Fluarix Quadrivalent (GSK2321138A)

Study Number: 116023 (FLU D-QIV-009 EXT 004)

Title: Immunogenicity, safety and reactogenicity study of GSK Biologicals’ quadrivalent seasonal influenza candidate vaccine GSK2321138A, administered to children who previously participated in study 115345. GSK2321138A (FLU D-QIV): GlaxoSmithKline (GSK) Biologicals’ quadrivalent seasonal influenza candidate vaccine.

Rationale: The purpose of this study was to evaluate the priming effect of FLU D-QIV vaccine by assessing the immune response after 1 dose of FLU D-QIV in children who were unprimed and in children who had received 2 doses of FLU D-QIV the year before in the primary study [115345 (FLU D-QIV-004 PRI)]. Subjects who received 2-dose FLU D-QIV vaccination in primary study 115345 were considered as primed and received a revaccination dose of the FLU D-QIV vaccine at Day 0 in this study (116023). Subjects who received 2 doses of non-influenza comparator vaccine(s) in primary study 115345 were considered as unprimed and received a primary course of 2 doses of the FLU D-QIV vaccine in this study (116023) at Days 0 and 28.

Phase: III

Study Period: 06 October 2012 to 05 June 2013

Study Design: Open-label, multi-centre, multi-country study with 2 parallel groups (1:1)

Centres: 33 centres (8 centres in Czech Republic, 3 centres in Poland, 12 centres in Spain, 10 centres in United Kingdom)

Indication: Immunization against influenza A and B in children aged 17 to 48 months

Treatment: The study groups were as follows:

FLU D-QIV-1: Subjects in this group were previously primed with 2 doses of FLU D-QIV vaccine in the primary study 115345 and received 1 dose of FLU D-QIV at Day 0 in the current study.

FLU D-QIV-2: Subjects in this group were unprimed with respect to FLU D-QIV in the primary study 115345 and received 2 doses of FLU D-QIV at Days 0 and 28 in the current study.

The vaccine was administered intramuscularly in the deltoid region of the arm.

Objectives: To assess the immune response in terms of haemagglutination inhibition (HI) antibody titre at Day 7 after one dose of FLU D-QIV vaccine (2012-2013 formulation) in vaccine-primed and vaccine-unprimed subjects, for all strains included in the vaccine.

Primary Outcome/Efficacy Variable:

Serum HI antibody titres at Days 0 and 7 against each of the four vaccine strains after one dose of FLU D-QIV. Derived variables:

‒ Seropositivity rates at Days 0 and 7. ‒ Geometric Mean Titres (GMTs) of HI antibody titres at Days 0 and 7. ‒ Seroconversion rate (SCR)* at Day 7. ‒ Mean Geometric Increase (MGI)** at Day 7. ‒ Seroprotection rate (SPR)*** at Days 0 and 7.

*SCR was defined as the percentage of vaccinees that had either a pre-vaccination titre <1:10 and a post-vaccination titre

1:40 or a pre-vaccination titre 1:10 and at least a four-fold increase in post-vaccination titre. **MGI was defined as the geometric mean of the within subject ratios of the post-vaccination reciprocal HI titre to the Day 0 reciprocal HI titre.

***SPR was defined as the percentage of vaccinees with a serum HI titre 1:40 that usually is accepted as indicating protection in adults.

Secondary Outcome/Efficacy Variable(s): Immunogenicity:

Serum HI antibody titres at Days 0 and 7 against each of the four vaccine strains after one dose of FLU D-QIV. Derived variables:

‒ GMT ratios of primed versus unprimed subjects at Day 7. ‒ SCR difference between primed and unprimed subjects at Day 7. ‒ SPR difference between primed and unprimed subjects at Day 7. ‒ Percentage of subjects with HI antibody titres < 1:10, 1:10 to < 1:40 and ≥ 1:40 at Days 0 and 7.

Immunogenicity in the Micro-neutralising/Anti-neuraminidase (MN/AN$) subset* of subjects:

Serum neutralising antibody titres and anti-neuraminidase antibody titres at Days 0 and 7 against each of the four vaccine strains.

Derived variable: ‒ GMTs at Days 0 and 7. ‒ Vaccine Response Rates (VRRs)** at Day 7. ‒ MGIs*** at Day 7.

* The MN/AN subset included 226 subjects in total, approximately 56 in each age stratum (17 to 29 months old and 30 to 48 months old) of each study group (FLU D-QIV-1 and FLU D-QIV-2 groups). $Neuraminidase inhibitor antibodies For neutralising antibodies: ** VRR was defined as the percentage of vaccinees who had either a pre-vaccination titre <cut-off and a post-vaccination titre ≥ 4-fold of half of the cut-off or a pre-vaccination titre ≥cut-off and at least a 4-fold increase in post-vaccination titres. *** MGI was defined as the fold increase in GMTs post-vaccination compared to Day 0. Safety:

Occurrence of each solicited local Adverse Event (AE): ‒ Percentage, duration and intensity during the 7-day follow-up period (i.e. day of vaccination and 6 subsequent days)

after the first vaccination.

Occurrence of each solicited general AE: ‒ Percentage, duration, intensity and relationship to vaccination during the 7-day follow-up period (i.e. day of

vaccination and 6 subsequent days) after the first vaccination.

Occurrence of unsolicited AEs: ‒ Percentage, intensity and relationship to vaccination during the 28-day follow up period (i.e. day of vaccination and

27 subsequent days) after the first vaccination.

Occurrence of AEs with Medically Attended Visit (MAV): ‒ Percentage, intensity and relationship to vaccination of AEs with MAV during the entire study period.

Occurrence of Serious Adverse Events (SAEs) and Potential Immune-Mediated Diseases (pIMDs): ‒ Percentage and relationship to vaccination of SAEs and pIMDs during the entire study period.

Statistical Methods: Analyses were performed on the Total Vaccinated cohort, the According-to-Protocol (ATP) cohort for immunogenicity and ATP cohort for immunogenicity (ATP-I) excluding subjects who had an RT-PCR confirmed influenza infection in study 115345.

The Total Vaccinated cohort included all subjects with at least one vaccine administration documented.

The ATP cohort for immunogenicity included all evaluable subjects (i.e., those meeting all eligibility criteria, complying with the procedures and intervals defined in the protocol, with no elimination criteria) who received the study vaccine according to their treatment assignment, for whom the assay results for antibodies against at least one study vaccine strain after vaccination and for whom data concerning immunogenicity outcome measures were available.

The ATP-I excluding subjects who had an RT-PCR confirmed influenza infection in study 115345 consisted of all evaluable subjects from the ATP-I, excluding subjects who had an RT-PCR confirmed influenza infection in study 115345. These subjects were identified as having an influenza episode [per Flu D-QIV-004 (115345) protocol definition] which occurred during the influenza surveillance period, had nasal swab taken within 7 days of the start of the influenza episode, and confirmed by RT-PCR.

Analysis of Immunogenicity The analysis was performed on the ATP cohort for immunogenicity and the ATP-I excluding subjects with a RT-PCR-confirmed influenza infection in study 115345. For the humoral response in terms of HI antibodies for all vaccine strains, the following parameters were calculated with 95% confidence interval (CI), by group for all subjects:

Seropositivity rates at Days 0 and 7.

GMTs at Days 0 and 7.

SCR at Day 7.

SPR at Days 0 and 7.

MGI at Day 7.

Percentage of subjects with HI antibody titres <1:10, 1:10 - <1:40 and ≥ 1:40 at Days 0 and 7. Additionally, the percentage of subjects with HI antibody titres ≥1:60 and ≥1:80 at Days 0 and 7 were also calculated with 95% confidence interval (CI), by group for all subjects on ATP-I excluding subjects with a RT-PCR-confirmed influenza infection in study 115345. For the humoral response in terms of neutralising and anti-neuraminidase antibodies for all vaccine strains, the following parameters were calculated with 95% CI, by group and by each age stratum for a subset of subjects:

GMTs at Days 0 and 7.

VRR at Day 7.

MGI at Day 7. For the humoral response in terms of HI antibodies for all vaccine strains, the following parameters were calculated with 95% CI between FLU D-QIV-1 and FLU D-QIV-2 groups for all subjects at Day 7:

GMT ratio.

SCR difference.

SPR difference. Analysis of Safety The analysis was performed on the Total Vaccinated cohort. The percentages of subjects reporting each individual solicited local and general symptom during the 7 day (Days 0 –6) follow-up period after first vaccination were tabulated with exact 95% CI. The same tabulation was performed for grade 3 solicited symptoms and for general symptoms assessed by the investigator as causally related to the study vaccination. The duration of solicited local/general symptoms during the 7 day (days 0-6) follow up period after first vaccination were also tabulated. The percentages of subjects with at least one report of an unsolicited AE classified by Medical Dictionary for Regulatory Activities (MedDRA) Preferred Term during the 28-day (Days 0-27) follow-up period after first vaccination were tabulated. The same tabulation was performed for grade 3 unsolicited AEs and for unsolicited AEs assessed by the investigator to be causally related to vaccination. The percentage of subjects reporting AE with MAVs during the entire study period were tabulated and classified according to MedDRA Preferred Term. The same tabulation was performed for grade 3 AE with MAVs and for AE with MAVs assessed by the investigator to be causally related to vaccination. The percentage of subjects reporting SAEs and pIMDs (including related pIMDs) during the entire study period were summarized and classified according to MedDRA Preferred Term. Fatal SAEs and SAEs assessed by the investigators to be causally related to vaccination were also reported

Study Population: Healthy male and female children aged 17 to 48 months who received a 2-dose vaccination in the primary study 115345. Written informed consent was obtained from the parent(s)/LAR(s) of the subject.

Number of Subjects: FLU D-QIV-1 Group FLU D-QIV-2 Group

Planned, N 226 226

Enrolled, N (Total Vaccinated cohort) 241 229

Completed, n (%) 238 (98.8) 221 (96.5)

Total Number Subjects Withdrawn, n (%) 3 (1.2) 8 (3.5)

Withdrawn due to Adverse Events, n (%) 0 (0.0) 0 (0.0)

Withdrawn due to Lack of Efficacy, n (%) Not Applicable Not Applicable

Withdrawn for other reasons, n (%) 3 (1.2) 8 (3.5)

Demographics FLU D-QIV-1 Group FLU D-QIV-2 Group

N (Total Vaccinated cohort) 241 229

Sex, n (%) Females

114 (47.3) 96 (41.9)

Males 127 (52.7) 133 (58.1)

Mean Age, years (SD) 33.2 (7.54) 32.5 (7.39)

Median 32.0 31.0

Minimum, Maximum 18,47 17, 47

White Caucasian, n (%) 236 (97.9) 224 (97.8)

Primary Outcome Results: Seropositivity rates and GMTs for HI antibodies titres at Day 0 and Day 7 post vaccination Dose 1 (ATP cohort for immunogenicity)

≥ 1:10 GMT

95% CI 95% CI

HI Antibody Group Timing N n % LL UL Value LL UL A/Christchurch/16/2010 (H1N1) FLU D-QIV-1 PRE 221 189 85.5 80.2 89.9 43.1 33.8 54.9

PI(D7) 224 220 98.2 95.5 99.5 445.6 376.9 526.7

FLU D-QIV-2 PRE 202 64 31.7 25.3 38.6 14.5 11.5 18.2

PI(D7) 209 137 65.6 58.7 72.0 45.8 32.0 65.5 A/Victoria/361/2011 (H3N2) FLU D-QIV-1 PRE 221 131 59.3 52.5 65.8 12.3 10.7 14.1

PI(D7) 224 218 97.3 94.3 99.0 135.3 113.6 161.2

FLU D-QIV-2 PRE 202 79 39.1 32.3 46.2 16.4 13.2 20.4 PI(D7) 209 99 47.4 40.4 54.4 47.5 32.6 69.3

B/Brisbane/60/2008 (Victoria) FLU D-QIV-1 PRE 221 187 84.6 79.2 89.1 28.5 23.8 34.1

PI(D7) 224 224 100 98.4 100 193.9 168.7 222.8 FLU D-QIV-2 PRE 202 58 28.7 22.6 35.5 10.0 8.4 11.9

PI(D7) 209 174 83.3 77.5 88.0 47.1 35.2 63.0

B/Hubei-Wujiagang/158/2009 FLU D-QIV-1 PRE 221 134 60.6 53.9 67.1 11.9 10.6 13.3

(Yamagata) PI(D7) 224 222 99.1 96.8 99.9 182.6 159.0 209.6

FLU D-QIV-2 PRE 202 36 17.8 12.8 23.8 6.5 5.9 7.2 PI(D7) 209 144 68.9 62.1 75.1 26.1 20.9 32.7

GMT = geometric mean antibody titre calculated on all subjects N = number of subjects with available results n/% = number/percentage of subjects with titre equal to or above specified value 95% CI = 95% confidence interval; LL = Lower Limit, UL = Upper Limit PRE = Pre-vaccination at Day 0, PI(D7) = Post-vaccination Dose 1 at Day 7

Primary Outcome Results: Seropositivity rates, SPR and GMTs for HI antibodies titres at Day 0 and Day 7 post vaccination Dose 1 (ATP-I excluding subjects who had an RT-PCR confirmed influenza infection in study 115345)

≥ 1:10 ≥ 1:40 GMT

95% CI 95% CI 95% CI

HI Antibody Group Timing N n % LL UL n % LL UL value LL UL

A/Christchurch/16/2010 (H1N1)

FLU D-QIV-1 PRE 210 178 84.8 79.2 89.3 87 41.4 34.7 48.4 44.0 34.2 56.7

PI(D7) 213 209 98.1 95.3 99.5 206 96.7 93.3 98.7 442.3 372.0 525.9

FLU D-QIV-2 PRE 173 54 31.2 24.4 38.7 51 29.5 22.8 36.9 14.3 11.2 18.3

PI(D7) 179 113 63.1 55.6 70.2 59 33.0 26.1 40.4 42.7 29.0 63.0

A/Victoria/361/2011 (H3N2)

FLU D-QIV-1 PRE 210 120 57.1 50.2 63.9 29 13.8 9.4 19.2 11.0 9.8 12.5

PI(D7) 213 207 97.2 94.0 99.0 182 85.4 80.0 89.9 125.9 105.4 150.4

FLU D-QIV-2 PRE 173 52 30.1 23.3 37.5 48 27.7 21.2 35.1 11.9 9.6 14.7

PI(D7) 179 72 40.2 33.0 47.8 54 30.2 23.5 37.5 28.7 19.7 41.9 B/Brisbane/60/2008 (Victoria)

FLU D-QIV-1 PRE 210 177 84.3 78.6 88.9 68 32.4 26.1 39.2 27.8 23.2 33.2

PI(D7) 213 213 100 98.3 100 206 96.7 93.3 98.7 193.3 167.6 222.8

FLU D-QIV-2 PRE 173 50 28.9 22.3 36.3 35 20.2 14.5 27.0 10.3 8.5 12.5

PI(D7) 179 145 81.0 74.5 86.5 70 39.1 31.9 46.7 46.1 33.5 63.4

B/Hubei-Wujiagang/158/2009 (Yamagata)

FLU D-QIV-1 PRE 210 127 60.5 53.5 67.1 27 12.9 8.6 18.2 11.9 10.6 13.4

PI(D7) 213 211 99.1 96.6 99.9 205 96.2 92.7 98.4 184.1 159.8 212.1

FLU D-QIV-2 PRE 173 31 17.9 12.5 24.5 10 5.8 2.8 10.4 6.5 5.8 7.2

PI(D7) 179 120 67.0 59.6 73.9 70 39.1 31.9 46.7 25.2 19.8 32.0

GMT = geometric mean antibody titre calculated on all subjects N = number of subjects with available results n/% = number/percentage of subjects with titre equal to or above specified value 95% CI = 95% confidence interval; LL = Lower Limit, UL = Upper Limit PRE = Pre-vaccination at Day 0, PI(D7) = Post-vaccination Dose 1 at Day 7

Primary Outcome Results: SCR for HI antibodies titres at Day 7 post vaccination Dose 1 (ATP cohort for immunogenicity) SCR

95% CI

HI Antibody Group N n % LL UL

A/Christchurch/16/2010 (H1N1) FLU D-QIV-1 221 170 76.9 70.8 82.3 FLU D-QIV-2 202 65 32.2 25.8 39.1

A/Victoria/361/2011 (H3N2) FLU D-QIV-1 221 180 81.4 75.7 86.3

FLU D-QIV-2 202 73 36.1 29.5 43.2 B/Brisbane/60/2008 (Victoria) FLU D-QIV-1 221 169 76.5 70.3 81.9

FLU D-QIV-2 202 78 38.6 31.9 45.7

B/Hubei-Wujiagang/158/2009 (Yamagata) FLU D-QIV-1 221 208 94.1 90.2 96.8

FLU D-QIV-2 202 77 38.1 31.4 45.2

Seroconversion defined as: For initially seronegative subjects, antibody titre ≥ 1:40 after vaccination For initially seropositive subjects, antibody titre after vaccination ≥ 4 fold the pre-vaccination antibody titre N = Number of subjects with pre- and post-vaccination results available n/% = number/percentage of seroconverted subjects 95% CI = 95% confidence interval, LL = Lower Limit, UL = Upper Limit

Primary Outcome Results: SCR for HI antibodies titres at day 7 post vaccination Dose 1 (ATP-I excluding subjects who had an RT-PCR confirmed influenza infection in study 115345)

SCR

95% CI

HI Antibody Group N n % LL UL

A/Christchurch/16/2010 (H1N1) FLU D-QIV-1 210 160 76.2 69.8 81.8

FLU D-QIV-2 173 54 31.2 24.4 38.7


FLU D-QIV-2 173 49 28.3 21.7 35.7

B/Brisbane/60/2008 (Victoria) FLU D-QIV-1 210 162 77.1 70.9 82.6

FLU D-QIV-2 173 66 38.2 30.9 45.8


FLU D-QIV-2 173 65 37.6 30.3 45.2

Seronegative subjects=antibody titre < 1:10 prior to vaccination Seropositive subjects=antibody titre ≥ 1:10 prior to vaccination SCR defined as: For initially seronegative subjects, antibody titre ≥ 1:40 at post-vaccination For initially seropositive subjects, antibody titre at post-vaccination ≥ 4 fold the pre-vaccination antibody titre N = Number of subjects with both pre- and post-vaccination results available n/% = Number/percentage of seroconverted subjects 95% CI = 95% confidence interval, LL = Lower Limit, UL = Upper Limit

Primary Outcome Results: MGI for HI antibodies titres at Day 7 post vaccination Dose 1 (ATP cohort for immunogenicity)

MGI 95% CI

HI Antibody Group N Value LL UL

A/Christchurch/16/2010 (H1N1) FLU D-QIV-1 221 10.3 8.5 12.4

FLU D-QIV-2 202 3.2 2.6 3.9 A/Victoria/361/2011 (H3N2) FLU D-QIV-1 221 10.9 9.4 12.6

FLU D-QIV-2 202 2.9 2.4 3.6

B/Brisbane/60/2008 (Victoria) FLU D-QIV-1 221 6.7 5.9 7.6 FLU D-QIV-2 202 4.6 3.8 5.5

B/Hubei-Wujiagang/158/2009 (Yamagata) FLU D-QIV-1 221 15.2 13.3 17.3

FLU D-QIV-2 202 4.0 3.3 4.9

MGI = Mean Geometric increase in serum HI GMTs post-vaccination N = Number of subjects with pre- and post-vaccination results available 95% CI = 95% confidence interval, LL = Lower Limit, UL = Upper Limit

Primary Outcome Results: MGI for HI antibodies titres at day 7 post vaccination Dose 1 (ATP-I excluding subjects who had an RT-PCR confirmed influenza infection in study 115345)

MGI

95% CI

HI Antibody Group N Value LL UL A/Christchurch/16/2010 (H1N1) FLU D-QIV-1 210 10.0 8.1 12.2

FLU D-QIV-2 173 3.1 2.5 3.9

A/Victoria/361/2011 (H3N2) FLU D-QIV-1 210 11.2 9.7 13.1

FLU D-QIV-2 173 2.4 2.0 3.0

B/Brisbane/60/2008 (Victoria) FLU D-QIV-1 210 6.9 6.0 7.8

FLU D-QIV-2 173 4.5 3.7 5.4


FLU D-QIV-2 173 4.0 3.2 4.9

MGI = Mean Geometric increase in serum HI GMTs post-vaccination N = Number of subjects with pre- and post-vaccination results available

95% CI = 95% confidence interval, LL = Lower Limit, UL = Upper Limit

Primary Outcome Results: SPR for HI antibodies titres at Day 0 and Day 7 post vaccination Dose 1 (ATP cohort for immunogenicity)

SPR

95% CI

HI Antibody Group Timing N n % LL UL A/Christchurch/16/2010 (H1N1) FLU D-QIV-1

PRE 221 89 40.3 33.7 47.1

PI(D7) 224 217 96.9 93.7 98.7

FLU D-QIV-2 PRE 202 61 30.2 24.0 37.0

PI(D7) 209 72 34.4 28.0 41.3 A/Victoria/361/2011 (H3N2) FLU D-QIV-1 PRE 221 37 16.7 12.1 22.3

PI(D7) 224 193 86.2 80.9 90.4

FLU D-QIV-2 PRE 202 74 36.6 30.0 43.7 PI(D7) 209 81 38.8 32.1 45.7

B/Brisbane/60/2008 (Victoria) FLU D-QIV-1 PRE 221 72 32.6 26.4 39.2

PI(D7) 224 217 96.9 93.7 98.7

FLU D-QIV-2 PRE 202 39 19.3 14.1 25.4 PI(D7) 209 84 40.2 33.5 47.2

B/Hubei-Wujiagang/158/2009 (Yamagata) FLU D-QIV-1 PRE 221 27 12.2 8.2 17.3

PI(D7) 224 216 96.4 93.1 98.4 FLU D-QIV-2 PRE 202 12 5.9 3.1 10.1

PI(D7) 209 83 39.7 33.0 46.7

SPR = Seroprotection rate N = Number of subjects with available results n/% = number/percentage of subjects with HI titre ≥ 1:40 95% CI = 95% confidence interval, LL = Lower Limit, UL = Upper Limit PRE = Pre-vaccination at Day 0 PI(D7) = Post-vaccination Dose 1 at Day 7 Secondary Outcome Results: GMT ratios of HI antibodies titres at Day 7 post vaccination Dose 1 (ATP cohort for immunogenicity)

Adjusted GMT ratio (FLU D-QIV-1 / FLU D-QIV-2)

FLU D-QIV-1 FLU D-QIV-2 95% CI

HI Antibody N Adjusted GMT N Adjusted GMT Value LL UL

A/Christchurch/16/2010 (H1N1) 224 428.4 209 47.8 8.97 6.21 12.96 A/Victoria/361/2011 (H3N2) 224 131.9 209 48.9 2.70 1.81 4.02

B/Brisbane/60/2008 (Victoria) 224 189.8 209 48.2 3.94 2.89 5.37

B/Hubei-Wujiagang/158/2009 (Yamagata) 224 179.0 209 26.7 6.71 5.21 8.63

Adjusted GMT = geometric mean antibody titre adjusted for Age (Months) N = Number of subjects with both pre- and post-vaccination results available 95% CI = 95% confidence interval for the adjusted GMT ratio (ANCOVA model: adjustment for Age (Months)-pooled variance; LL = lower limit, UL = upper limit

Secondary Outcome Results: GMT ratios of HI antibodies titres at Day 7 post vaccination Dose 1 (ATP-I excluding subjects who had an RT-PCR confirmed influenza infection in study 115345)

Adjusted GMT ratio (FLU D-QIV-1 / FLU D-QIV-2)

FLU D-QIV-1 FLU D-QIV-2 95% CI

HI Antibody N Adjusted GMT N Adjusted GMT Value LL UL

A/Christchurch/16/2010 (H1N1) 210 291.7 173 72.8 4.01 2.96 5.42 A/Victoria/361/2011 (H3N2) 210 129.1 173 27.7 4.66 3.67 5.92

B/Brisbane/60/2008 (Victoria) 210 125.7 173 75.9 1.66 1.30 2.11


Adjusted GMT = geometric mean antibody titre adjusted for Age (Months) N = Number of subjects with both pre- and post-vaccination results available 95% CI = 95% confidence interval for the adjusted GMT ratio (Ancova model: adjustment for Age (Months) - pooled variance); LL = lower limit, UL = upper limit

Secondary Outcome Results: Difference in SCR for HI antibodies at Day 7 post vaccination Dose 1 (ATP cohort for immunogenicity)

Difference in SCR (FLU D-QIV-1 minus FLU D-QIV-2)

FLU D-QIV-1 FLU D-QIV-2 95% CI HI Antibody N n % N n % % LL UL A/Christchurch/16/2010 (H1N1) 221 170 76.9 202 65 32.2 44.74 35.87 52.84

A/Victoria/361/2011 (H3N2) 221 180 81.4 202 73 36.1 45.31 36.58 53.30

B/Brisbane/60/2008 (Victoria) 221 169 76.5 202 78 38.6 37.86 28.83 46.26

B/Hubei-Wujiagang/158/2009 (Yamagata) 221 208 94.1 202 77 38.1 56.00 48.32 63.04

SCR defined as: For initially seronegative subjects: post-vaccination antibody titre ≥ 1:40 at PI(D7) For initially seropositive subjects: antibody titre at PI(D7) ≥ 4 fold the pre-vaccination antibody titre N = number of subjects with pre- and post-vaccination results available n/% = number/percentage of subjects with a vaccine response 95% CI = Standardized asymptotic 95% confidence interval; LL = lower limit, UL = upper limit

Secondary Outcome Results: Difference in SCR for HI antibodies at Day 7 post vaccination Dose 1 (ATP-I excluding subjects who had an RT-PCR confirmed influenza infection in study 115345)

Difference in SCR (FLU D-QIV-1 minus FLU D-QIV-2)

FLU D-QIV-1 FLU D-QIV-2 95% CI HI Antibody N n % N n % % LL UL

A/Christchurch/16/2010 (H1N1) 210 160 76.2 173 54 31.2 44.98 35.57 53.50

A/Victoria/361/2011 (H3N2) 210 173 82.4 173 49 28.3 54.06 45.09 61.98

B/Brisbane/60/2008 (Victoria) 210 162 77.1 173 66 38.2 38.99 29.47 47.81 B/Hubei-Wujiagang/158/2009 (Yamagata) 210 197 93.8 173 65 37.6 56.24 47.99 63.76

Seroconversion defined as : For initially seronegative subjects: post-vaccination antibody titre ≥ 1:40 at PI(D7) For initially seropositive subjects : antibody titre at PI(D7) ≥ 4 fold the pre-vaccination antibody titre N = number of subjects with pre- and post-vaccination results available n/% = number/percentage of seroprotected subjects 95% CI = Standardized asymptotic 95% confidence interval; LL = lower limit, UL = upper limit

Secondary Outcome Results: Difference in SPR for HI antibodies at Day 7 post vaccination Dose 1 (ATP cohort for immunogenicity)

Difference in SPR (FLU D-QIV-1 minus FLU D-QIV-2)

FLU D-QIV-1 FLU D-QIV-2 95% CI HI Antibody N % N % % LL UL

A/Christchurch/16/2010 (H1N1) 224 96.9 209 34.4 62.43 55.27 68.89

A/Victoria/361/2011 (H3N2) 224 86.2 209 38.8 47.40 39.08 55.06 B/Brisbane/60/2008 (Victoria) 224 96.9 209 40.2 56.68 49.44 63.43


N = number of subjects with available results % = percentage of subjects for each strain, HI titre ≥ 1:40 95% CI = 95% Standardized asymptotic confidence interval; LL = lower limit, UL = upper limit

Secondary Outcome Results: Difference in SPR for HI antibodies at Day 7 post vaccination Dose 1 (ATP-I excluding subjects who had an RT-PCR confirmed influenza infection in study 115345)

Difference in SPR (FLU D-QIV-1 minus FLU D-QIV-2)

FLU D-QIV-1 FLU D-QIV-2 95% CI HI Antibody Type N n % N n % % LL UL

A/Christchurch/16/2010 (H1N1) 1:40 213 206 96.7 179 59 33.0 63.75 56.08 70.59

A/Victoria/361/2011 (H3N2) 1:40 213 182 85.4 179 54 30.2 55.28 46.58 62.99

B/Brisbane/60/2008 (Victoria) 1:40 213 206 96.7 179 70 39.1 57.61 49.81 64.81 B/Hubei-Wujiagang/158/2009 (Yamagata) 1:40 213 205 96.2 179 70 39.1 57.14 49.28 64.39

N = number of subjects with available results n/% = number/percentage of subjects with HI titre ≥ 1:40 95% CI = Standardized asymptotic 95% confidence interval; LL = lower limit, UL = upper limit

Secondary Outcome Results: Number (%) of subjects with HI antibody titres <1:10, 1:10 to <1:40 and ≥1:40 at Day 0 and Day 7 post vaccination Dose 1 (ATP cohort for immunogenicity)

< 1:10 1:10 -< 1:40 ≥1: 40

HI Antibody Group Timing N n % n % n %

A/Christchurch/16/2010 H1N1 FLU D-QIV-1 PRE 221 32 14.5 100 45.2 89 40.3

P1D7 224 4 1.8 3 1.3 217 96.9

FLU D-QIV-2 PRE 202 138 68.3 3 1.5 61 30.2

P1D7 209 72 34.4 65 31.1 72 34.4

A/Victoria/361/2011 (H3N2) FLU D-QIV-1 PRE 221 90 40.7 94 42.5 37 16.7

P1D7 224 6 2.7 25 11.2 193 86.2

FLU D-QIV-2 PRE 202 123 60.9 5 2.5 74 36.6

P1D7 209 110 52.6 18 8.6 81 38.8

B/Brisbane/60/2008 (Victoria) FLU D-QIV-1 PRE 221 34 15.4 115 52.0 72 32.6

P1D7 224 0 0.0 7 3.1 217 96.9

FLU D-QIV-2 PRE 202 144 71.3 19 9.4 39 19.3

P1D7 209 35 16.7 90 43.1 84 40.2


FLU D-QIV-1 PRE 221 87 39.4 107 48.4 27 12.2

P1D7 224 2 0.9 6 2.7 216 96.4 FLU D-QIV-2 PRE 202 166 82.2 24 11.9 12 5.9

P1D7 209 65 31.1 61 29.2 83 39.7

N = number of subjects with available results n/% = number/percentage of subjects with titre within the specified range PRE = Pre-vaccination at Day 0, P1 (D7) = Post-vaccination Dose 1 at Day 7

Secondary Outcome Results: Number (%) of subjects with HI antibody titres <1:10, 1:10 to <1:40, ≥1:40, ≥1:60 and ≥1:80 at Day 0 and Day 7 post vaccination Dose 1 (ATP-I excluding subjects who had an RT-PCR confirmed influenza infection in study 115345)

<1:10 ≥1:10 ≥1:40 ≥1:60 ≥1:80 HI Antibody Group Timing N n % n % n % n % n %

A/Christchurch/16/2010 (H1N1) FLU D-QIV-1 PRE 210 32 15.2 178 84.8 87 41.4 73 34.8 73 34.8

PI(D7) 213 4 1.9 209 98.1 206 96.7 204 95.8 204 95.8

FLU D-QIV-2 PRE 173 119 68.8 54 31.2 51 29.5 47 27.2 47 27.2

PI(D7) 179 66 36.9 113 63.1 59 33.0 57 31.8 57 31.8

A/Victoria/361/2011 (H3N2) FLU D-QIV-1 PRE 210 90 42.9 120 57.1 29 13.8 12 5.7 12 5.7

PI(D7) 213 6 2.8 207 97.2 182 85.4 147 69.0 147 69.0

FLU D-QIV-2 PRE 173 121 69.9 52 30.1 48 27.7 36 20.8 36 20.8

PI(D7) 179 107 59.8 72 40.2 54 30.2 52 29.1 52 29.1

B/Brisbane/60/2008 (Victoria) FLU D-QIV-1 PRE 210 33 15.7 177 84.3 68 32.4 40 19.0 40 19.0

PI(D7) 213 0 0.0 213 100 206 96.7 182 85.4 182 85.4

FLU D-QIV-2 PRE 173 123 71.1 50 28.9 35 20.2 27 15.6 27 15.6

PI(D7) 179 34 19.0 145 81.0 70 39.1 51 28.5 51 28.5

B/Hubei-Wujiagang/158/2009 (Yamagata) FLU D-QIV-1 PRE 210 83 39.5 127 60.5 27 12.9 7 3.3 7 3.3

PI(D7) 213 2 0.9 211 99.1 205 96.2 177 83.1 177 83.1

FLU D-QIV-2 PRE 173 142 82.1 31 17.9 10 5.8 4 2.3 4 2.3

PI(D7) 179 59 33.0 120 67.0 70 39.1 44 24.6 44 24.6

N = number of subjects with available results n/% = number/percentage of subjects with titre within the specified range PRE = Pre-vaccination at Day 0, PI(D7) = Post-vaccination Dose 1 at Day 7

Secondary Outcome Results: Seropositivity rates and GMTs for neutralizing antibodies titres (H1N1 - H3N2 - Victoria) at Day 0 and Day 7 post vaccination Dose 1 (ATP cohort for immunogenicity)

≥ 1:28 GMT

95% CI 95% CI

MN Antibody Group Timing N n % LL UL Value LL UL


FLU D-QIV-1 PRE 97 86 88.7 80.6 94.2 138.2 97.4 196.2

PI(D7) 107 106 99.1 94.9 100 1500.9 1172.7 1920.9

FLU D-QIV-2 PRE 90 34 37.8 27.8 48.6 48.3 33.9 68.7

PI(D7) 96 50 52.1 41.6 62.4 139.4 78.8 246.8


FLU D-QIV-1 PRE 99 93 93.9 87.3 97.7 66.5 55.9 79.2

PI(D7) 104 104 100 96.5 100 422.9 342.3 522.4

FLU D-QIV-2 PRE 96 66 68.8 58.5 77.8 82.8 60.6 113.1

PI(D7) 100 73 73.0 63.2 81.4 325.1 187.1 564.7

≥ 1:28 GMT

95% CI 95% CI

Antibody Group Sub-group Timing N n % LL UL value LL UL

A/Christchurch/16/2 010 (H1N1)

FLU D-QIV-1 17-29M PRE 47 40 85.1 71.7 93.8 76.8 48.8 120.9

PI(D7) 53 52 98.1 89.9 100 1112.0 746.0 1657.8

30-48M PRE 50 46 92.0 80.8 97.8 240.0 146.2 394.1

PI(D7) 54 54 100 93.4 100 2014.5 1517.5 2674.4

FLU D-QIV-2 17-29M PRE 44 10 22.7 11.5 37.8 29.0 18.7 44.9

PI(D7) 48 18 37.5 24.0 52.6 53.0 26.9 104.2

30-48M PRE 46 24 52.2 36.9 67.1 78.8 46.6 133.1

PI(D7) 48 32 66.7 51.6 79.6 366.9 155.6 865.4


FLU D-QIV-1 17-29M PRE 49 46 93.9 83.1 98.7 58.1 46.3 72.9

PI(D7) 51 51 100 93.0 100 370.5 272.7 503.2

30-48M PRE 50 47 94.0 83.5 98.7 76.0 58.2 99.1

PI(D7) 53 53 100 93.3 100 480.3 356.7 646.8

FLU D-QIV-2 17-29M PRE 47 30 63.8 48.5 77.3 74.5 45.8 121.5

PI(D7) 50 33 66.0 51.2 78.8 217.5 97.0 488.0

30-48M PRE 49 36 73.5 58.9 85.1 91.5 60.8 137.7

PI(D7) 50 40 80.0 66.3 90.0 485.8 226.2 1043.7

B/Brisbane/60/2008) (Victoria)

FLU D-QIV-1 17-29M PRE 53 30 56.6 42.3 70.2 29.2 21.7 39.2

PI(D7) 53 53 100 93.3 100 156.3 119.7 204.2

30-48M PRE 54 36 66.7 52.5 78.9 50.9 33.1 78.2

PI(D7) 54 54 100 93.4 100 239.1 166.7 343.0

FLU D-QIV-2 17-29M PRE 54 9 16.7 7.9 29.3 19.8 15.9 24.8

PI(D7) 53 11 20.8 10.8 34.1 35.5 20.0 62.9

30-48M PRE 55 15 27.3 16.1 41.0 24.7 18.8 32.6

PI(D7) 55 21 38.2 25.4 52.3 61.8 31.6 120.8

17-29M = 17-29 months old subjects 30-48M = 30-48 months old subjects GMT = geometric mean antibody titre calculated on all subjects N = number of subjects with available results n/% = number/percentage of subjects with titre equal to or above specified value 95% CI = 95% confidence interval; LL = Lower Limit, UL = Upper Limit PRE = Pre-vaccination at Day 0 PI(D7) = Post-vaccination Dose 1 at Day 7

Secondary Outcome Results: Seropositivity rates and GMTs for neutralising antibodies titres (H1N1 - H3N2 - Victoria) at Day 0 and Day 7 post vaccination Dose 1 (ATP-I excluding subjects who had an RT-PCR confirmed influenza infection in study 115345)

≥ 1:28 GMT

95% CI 95% CI

MN Antibody Group Timing N n % LL UL value LL UL


FLU D-QIV-1 PRE 90 79 87.8 79.2 93.7 141.4 97.6 205.0

PI(D7) 100 99 99.0 94.6 100 1461.3 1132.8 1885.1

FLU D-QIV-2 PRE 72 27 37.5 26.4 49.7 47.3 32.1 69.6

PI(D7) 76 37 48.7 37.0 60.4 138.4 71.9 266.4

A/Victoria/361/2011 (H3N2) FLU D-QIV-1 PRE 92 86 93.5 86.3 97.6 60.0 51.2 70.4

PI(D7) 97 97 100 96.3 100 374.6 305.4 459.4

FLU D-QIV-2 PRE 76 46 60.5 48.6 71.6 59.6 42.5 83.7

B/Brisbane/60/2008 (Victoria)

FLU D-QIV-1 PRE 107 66 61.7 51.8 70.9 38.6 29.7 50.3

PI(D7) 107 107 100 96.6 100 193.7 154.7 242.6

FLU D-QIV-2 PRE 109 24 22.0 14.6 31.0 22.2 18.6 26.5

PI(D7) 108 32 29.6 21.2 39.2 47.0 30.3 72.9

GMT = geometric mean antibody titre calculated on all subjects N = number of subjects with available results n/% = number/percentage of subjects with titre within the specified range 95% CI = 95% confidence interval; LL = Lower Limit, UL = Upper Limit PRE = Pre-vaccination at Day 0, P1 (D7) = Post-vaccination Dose 1 at Day 7

Secondary Outcome Results: Seropositivity rates and GMTs for neutralising antibodies titres (H1N1 - H3N2 - Victoria) at Day 0 and Day 7 post Dose 1 - by age strata (ATP cohort for immunogenicity)

PI(D7) 80 53 66.3 54.8 76.4 177.7 97.4 324.2


PI(D7) 100 100 100 96.4 100 189.9 151.2 238.5

FLU D-QIV-2 PRE 89 21 23.6 15.2 33.8 23.5 19.1 28.9

PI(D7) 88 27 30.7 21.3 41.4 52.0 31.3 86.3

GMT = geometric mean antibody titre calculated on all subjects N = number of subjects with available results n/% = number/percentage of subjects with titre within the specified range 95% CI = 95% confidence interval; LL = Lower Limit, UL = Upper Limit PRE = Pre-vaccination at Day 0, PI(D7) = Post-vaccination Dose 1 at Day 7

Secondary Outcome Results: Seropositivity rates and GMTs for neutralizing antibodies titres (Yamagata) at Day 0 and Day 7 post vaccination Dose 1 (ATP cohort for immunogenicity)

≥ 1:57 GMT

95% CI 95% CI

MN Antibody Group Timing N n % LL UL Value LL UL


FLU D-QIV-1 PRE 107 35 32.7 24.0 42.5 36.9 34.2 39.8

PI(D7) 107 107 100 96.6 100 182.7 157.7 211.8

FLU D-QIV-2 PRE 107 8 7.5 3.3 14.2 30.8 29.0 32.6

PI(D7) 107 35 32.7 24.0 42.5 51.7 42.2 63.4

GMT = geometric mean antibody titre calculated on all subjects N = number of subjects with available results n/% = number/percentage of subjects with titre within the specified range 95% CI = 95% confidence interval; LL = Lower Limit, UL = Upper Limit PRE = Pre-vaccination at Day 0, P1 (D7) = Post-vaccination Dose 1 at Day 7 Secondary Outcome Results: Seropositivity rates and GMTs for neutralising antibodies titres (Yamagata) at Day 0 and Day 7 post Dose 1 - by age strata (ATP cohort for immunogenicity)

≥ 1:57 GMT

95% CI 95% CI

MN Antibody Group Sub-group Timing N n % LL UL value LL UL B/Hubei- Wujiagang/158/2009) (Yamagata)

FLU D-QIV-1 17-29M PRE 53 16 30.2 18.3 44.3 35.6 32.3 39.2

PI(D7) 53 53 100 93.3 100 156.9 129.4 190.3

30-48M PRE 54 19 35.2 22.7 49.4 38.3 34.0 43.1

PI(D7) 54 54 100 93.4 100 212.2 170.1 264.7

FLU D-QIV-2 17-29M PRE 53 2 3.8 0.5 13.0 29.6 28.0 31.4

PI(D7) 52 13 25.0 14.0 38.9 45.6 33.7 61.7

30-48M PRE 54 6 11.1 4.2 22.6 32.0 28.9 35.4

PI(D7) 55 22 40.0 27.0 54.1 58.3 44.1 77.0


Secondary Outcome Results: Seropositivity rates and GMTs for neutralising antibodies titres (Yamagata) at Day 0 and Day 7 post vaccination Dose 1 (ATP-I excluding subjects who had an RT-PCR confirmed influenza infection in study 115345)

≥ 1:57 GMT

95% CI 95% CI

MN Antibody Group Timing N n % LL UL value LL UL B/Hubei-Wujiagang/158/2009 (Yamagata)

FLU D-QIV-1 PRE 100 33 33.0 23.9 43.1 37.1 34.2 40.2

PI(D7) 100 100 100 96.4 100 177.5 154.2 204.5

FLU D-QIV-2 PRE 87 7 8.0 3.3 15.9 30.9 28.9 32.9

PI(D7) 88 27 30.7 21.3 41.4 49.8 40.5 61.1


Secondary Outcome Results: VRR for neutralising antibody titres at Day 7 post vaccination Dose 1 (ATP cohort for immunogenicity)

Vaccine response

95% CI

MN Antibody Group N n % LL UL


FLU D-QIV-1 97 74 76.3 66.6 84.3

FLU D-QIV-2 89 36 40.4 30.2 51.4


FLU D-QIV-2 94 48 51.1 40.5 61.5


FLU D-QIV-2 108 24 22.2 14.8 31.2

Vaccine response for A/Christchurch/16/2010 (H1N1), A/Victoria/361/2011 (H3N2) and B/Brisbane/60/2008 (Victoria) neutralizing antibody was defined as: For initially seronegative subjects, antibody titre ≥ 1:56 after vaccination and For initially seropositive subjects, antibody titre after vaccination ≥ 4 fold the pre-vaccination antibody titre N = Number of subjects with pre- and post-vaccination results available n/% = number/percentage of seroconverted subjects 95% CI = 95% confidence interval, LL = Lower Limit, UL = Upper Limit

Secondary Outcome Results: VRR for neutralising antibodies titres (H1N1 - H3N2 - Victoria) at day 7 post vaccination Dose 1 - by age strata (ATP cohort for immunogenicity)

Vaccine response

95% CI

MN Antibody Group Sub-group N n % LL UL

A/Christchurch/16/2010 (H1N1) FLU D-QIV-1 17-29M 47 39 83.0 69.2 92.4

30-48M 50 35 70.0 55.4 82.1

FLU D-QIV-2 17-29M 44 12 27.3 15.0 42.8

30-48M 45 24 53.3 37.9 68.3 A/Victoria/361/2011 (H3N2) FLU D-QIV-1 17-29M 48 36 75.0 60.4 86.4

30-48M 49 36 73.5 58.9 85.1

FLU D-QIV-2 17-29M 46 19 41.3 27.0 56.8

30-48M 48 29 60.4 45.3 74.2

B/Brisbane/60/2008 (Victoria) FLU D-QIV-1 17-29M 53 41 77.4 63.8 87.7

30-48M 54 37 68.5 54.4 80.5

FLU D-QIV-2 17-29M 53 9 17.0 8.1 29.8

30-48M 55 15 27.3 16.1 41.0

17-29M = 17-29 months old subjects 30-48M = 30-48 months old subjects Vaccine response defined as: For initially seronegative subjects, antibody titre ≥ 1:56 after vaccination For initially seropositive subjects, antibody titre after vaccination ≥ 4 fold the pre-vaccination antibody titre N = Number of subjects with pre- and post-vaccination results available n/% = Number/percentage of seroconverted subjects 95% CI = 95% confidence interval, LL = Lower Limit, UL = Upper Limit

Secondary Outcome Results: VRR for neutralising antibodies titres at day 7 post vaccination Dose 1 (ATP-I excluding subjects who had an RT-PCR confirmed influenza infection in study 115345)

Vaccine response

95% CI



FLU D-QIV-2 71 28 39.4 28.0 51.7


FLU D-QIV-2 74 31 41.9 30.5 53.9


FLU D-QIV-2 88 21 23.9 15.4 34.1

Vaccine response for A/Christchurch/16/2010 (H1N1), A/Victoria/361/2011 (H3N2) and B/Brisbane/60/2008 (Victoria) was defined as: For initially seronegative subjects, antibody titre ≥ 1:56 after vaccination For initially seropositive subjects, antibody titre after vaccination ≥ 4 fold the pre-vaccination antibody titre N = Number of subjects with pre- and post-vaccination results available n/% = Number/percentage of seroconverted subjects 95% CI = 95% confidence interval, LL = Lower Limit, UL = Upper Limit

Secondary Outcome Results: VRR for neutralising antibody titres (Yamagata) at Day 7 post vaccination Dose 1 (ATP cohort for immunogenicity) Vaccine response



FLU D-QIV-2 105 15 14.3 8.2 22.5

Vaccine response for B/Hubei-Wujiagang/158/2009 (Yamagata) neutralizing antibody was defined as: For initially seronegative subjects, antibody titre ≥ 1:114 after vaccination; For initially seropositive subjects, antibody titre after vaccination ≥ 4 fold the pre-vaccination antibody titre N = Number of subjects with pre- and post-vaccination results available n/% = number/percentage of seroconverted subjects 95% CI = 95% confidence interval, LL = Lower Limit, UL = Upper Limit

Secondary Outcome Results: VRR for neutralising antibodies titres (Yamagata) at day 7 post Dose 1 - by age strata (ATP cohort for immunogenicity)

Vaccine response

95% CI

MN Antibody Group Sub-group N n % LL UL


FLU D-QIV-1 17-29M 53 17 32.1 19.9 46.3

30-48M 54 28 51.9 37.8 65.7

FLU D-QIV-2 17-29M 51 6 11.8 4.4 23.9

30-48M 54 9 16.7 7.9 29.3


Secondary Outcome Results: VRR for neutralising antibodies titres (Yamagata) at day 7 post Dose 1 (ATP-I excluding subjects who had an RT-PCR confirmed influenza infection in study 115345)

Vaccine response

95% CI

MN Antibody Group N n % LL UL B/Hubei-Wujiagang/158/2009 (Yamagata) FLU D-QIV-1 100 42 42.0 32.2 52.3

FLU D-QIV-2 86 11 12.8 6.6 21.7

Vaccine response for B/Hubei-Wujiagang/158/2009 (Yamagata) neutralizing antibody was defined as: For initially seronegative subjects, antibody titre ≥ 1:114 after vaccination For initially seropositive subjects, antibody titre after vaccination ≥ 4 fold the pre-vaccination antibody titre N = Number of subjects with pre- and post-vaccination results available n/% = Number/percentage of seroconverted subjects 95% CI = 95% confidence interval, LL = Lower Limit, UL = Upper Limit

Secondary Outcome Results: MGI for neutralising antibodies titres at Day 7 post vaccination Dose 1 (ATP cohort for immunogenicity)

MGI

95% CI

MN Antibody Group N Value LL UL A/Christchurch/16/2010 (H1N1) FLU D-QIV-1 97 10.6 8.2 13.7

FLU D-QIV-2 89 3.1 2.3 4.2


FLU D-QIV-2 94 4.5 3.2 6.2 B/Brisbane/60/2008 (Victoria) FLU D-QIV-1 107 5.0 4.3 5.8

FLU D-QIV-2 108 2.1 1.6 2.8

B/Hubei-Wujiagang/158/2009 (Yamagata) FLU D-QIV-1 107 5.0 4.3 5.7 FLU D-QIV-2 105 1.7 1.4 2.0

MGI = Mean Geometric increase in serum MN GMTs post-vaccination N = Number of subjects with pre- and post-vaccination results available 95% CI = 95% confidence interval, LL = Lower Limit, UL = Upper Limit

Secondary Outcome Results: MGI for neutralising antibodies titres at Day 7 post vaccination Dose 1 - by age strata (ATP cohort for immunogenicity)

MGI

95% CI MN Antibody Group Sub-group N Value LL UL

A/Christchurch/16/2010 (H1N1) FLU D-QIV-1 17-29M 47 13.1 9.2 18.8

30-48M 50 8.7 6.0 12.5

FLU D-QIV-2 17-29M 44 2.0 1.4 3.0

30-48M 45 4.7 3.0 7.3

A/Victoria/361/2011 (H3N2) FLU D-QIV-1 17-29M 48 6.1 4.8 7.7

30-48M 49 6.7 5.1 8.8

FLU D-QIV-2 17-29M 46 3.4 2.1 5.4

30-48M 48 5.9 3.8 9.2

B/Brisbane/60/2008 (Victoria) FLU D-QIV-1 17-29M 53 5.4 4.4 6.5

30-48M 54 4.7 3.8 5.8

FLU D-QIV-2 17-29M 53 1.8 1.2 2.6

30-48M 55 2.5 1.6 3.8 B/Hubei-Wujiagang/158/2009 FLU D-QIV-1 17-29M 53 4.4 3.8 5.2

(Yamagata) 30-48M 54 5.5 4.5 6.9

FLU D-QIV-2 17-29M 51 1.5 1.2 2.0

30-48M 54 1.8 1.4 2.4

17-29M = 17-29 months old subjects 30-48M = 30-48 months old subjects N = Number of subjects with pre- and post-vaccination results available MGI = Mean Geometric increase in serum neutralising GMTs post-vaccination 95% CI = 95% confidence interval, LL = Lower Limit, UL = Upper Limit

Secondary Outcome Results: MGI for neutralising antibodies titres at day 7 post vaccination Dose 1 (ATP-I excluding subjects who had an RT-PCR confirmed influenza infection in study 115345)

MGI

95% CI

MN Antibody Group N Value LL UL

A/Christchurch/16/2010 (H1N1) FLU D-QIV-1 90 10.0 7.7 13.1

FLU D-QIV-2 71 3.1 2.2 4.3


FLU D-QIV-2 74 3.4 2.4 4.9

B/Brisbane/60/2008 (Victoria) FLU D-QIV-1 100 5.1 4.4 5.9

FLU D-QIV-2 88 2.2 1.6 3.0


MGI = Mean Geometric increase in serum MN GMTs post-vaccination N = Number of subjects with pre- and post-vaccination results available

95% CI = 95% confidence interval, LL = Lower Limit, UL = Upper Limit Secondary Outcome Results: Seropositivity rates and GMTs for anti-neuraminidase antibodies titres (H1N1 - Victoria - Yamagata) at Day 0 and Day 7 post vaccination Dose 1 (ATP cohort for immunogenicity)

≥ 1:20 GMT

95% CI 95% CI

NI Antibody Group Timing N n % LL UL Value LL UL


FLU D-QIV-1 PRE 106 50 47.2 37.4 57.1 34.6 25.3 47.3

PI(D7) 106 105 99.1 94.9 100 293.9 247.2 349.3

FLU D-QIV-2 PRE 106 35 33.0 24.2 42.8 24.1 18.6 31.1

PI(D7) 109 44 40.4 31.1 50.2 41.3 28.9 59.0


PI(D7) 106 105 99.1 94.9 100 90.6 74.1 110.8

FLU D-QIV-2 PRE 106 23 21.7 14.3 30.8 14.3 12.4 16.5

PI(D7) 109 28 25.7 17.8 34.9 27.6 19.4 39.1


FLU D-QIV-1 PRE 106 71 67.0 57.2 75.8 25.3 21.6 29.6

PI(D7) 106 106 100 96.6 100 222.0 185.7 265.4

FLU D-QIV-2 PRE 106 34 32.1 23.3 41.8 15.4 13.2 18.0

PI(D7) 109 68 62.4 52.6 71.5 40.6 29.5 55.7

GMT = geometric mean antibody titre calculated on all subjects N = number of subjects with available results n/% = number/percentage of subjects with titre within the specified range 95% CI = 95% confidence interval; LL = Lower Limit, UL = Upper Limit PRE = Pre-vaccination at Day 0, P1 (D7) = Post-vaccination Dose 1 at Day 7

Secondary Outcome Results: Seropositivity rates and GMTs for Anti-neuraminidase antibodies titres (H1N1 - Victoria - Yamagata) at Day 0 and Day 7 post vaccination Dose 1 - by age strata (ATP cohort for immunogenicity)

≥ 1:20 GMT

95% CI 95% CI

NI Antibody Group Sub-group Timing N n % LL UL value LL UL


FLU D-QIV-1 17-29M PRE 53 19 35.8 23.1 50.2 21.6 15.0 31.3

PI(D7) 53 52 98.1 89.9 100 246.3 189.1 320.8

30-48M PRE 53 31 58.5 44.1 71.9 55.5 34.2 89.9

PI(D7) 53 53 100 93.3 100 350.7 281.1 437.4

FLU D-QIV-2 17-29M PRE 52 10 19.2 9.6 32.5 15.8 11.9 21.1

PI(D7) 54 14 25.9 15.0 39.7 22.9 14.9 35.1

30-48M PRE 54 25 46.3 32.6 60.4 36.1 24.2 53.9

PI(D7) 55 30 54.5 40.6 68.0 73.7 42.9 126.7

B/Brisbane/60/2008 (Victoria)

FLU D-QIV-1 17-29M PRE 53 11 20.8 10.8 34.1 13.2 11.0 16.0

PI(D7) 53 52 98.1 89.9 100 68.8 53.3 88.9

30-48M PRE 53 18 34.0 21.5 48.3 22.8 16.0 32.4

PI(D7) 53 53 100 93.3 100 119.2 88.2 161.1

FLU D-QIV-2 17-29M PRE 52 8 15.4 6.9 28.1 13.1 10.9 15.7

PI(D7) 54 10 18.5 9.3 31.4 21.1 13.4 33.2

30-48M PRE 54 15 27.8 16.5 41.6 15.7 12.6 19.4

PI(D7) 55 18 32.7 20.7 46.7 35.9 21.0 61.4

B/Hubei- Wujiagang/158/2009 (Yamagata)

FLU D-QIV-1 17-29M PRE 53 32 60.4 46.0 73.5 20.5 16.9 24.9

PI(D7) 53 53 100 93.3 100 181.4 143.3 229.5

30-48M PRE 53 39 73.6 59.7 84.7 31.1 24.4 39.7

PI(D7) 53 53 100 93.3 100 271.8 208.6 354.3

FLU D-QIV-2 17-29M PRE 52 13 25.0 14.0 38.9 13.2 11.1 15.8

PI(D7) 54 29 53.7 39.6 67.4 29.3 19.5 44.0

30-48M PRE 54 21 38.9 25.9 53.1 17.9 13.8 23.1

PI(D7) 55 39 70.9 57.1 82.4 55.8 34.4 90.5


Secondary Outcome Results: Seropositivity rates and GMTs for anti-neuraminidase antibodies titres (H1N1 - Victoria - Yamagata) at Day 0 and Day 7 post vaccination Dose 1 (ATP-I excluding subjects who had an RT-PCR confirmed influenza infection in study 115345)

≥ 1:20 GMT

95% CI 95% CI

NI Antibody Group Timing N n % LL UL value LL UL

A/Christchurch/16/2010 (H1N1) FLU D-QIV-1 PRE 99 46 46.5 36.4 56.8 34.8 25.1 48.1 PI(D7) 99 98 99.0 94.5 100 287.1 239.8 343.6

FLU D-QIV-2 PRE 86 28 32.6 22.8 43.5 23.5 17.8 31.1

PI(D7) 89 33 37.1 27.1 48.0 38.3 25.7 57.1 B/Brisbane/60/2008 (Victoria) FLU D-QIV-1 PRE 99 26 26.3 17.9 36.1 16.8 13.7 20.7

PI(D7) 99 98 99.0 94.5 100 89.2 72.5 109.7

FLU D-QIV-2 PRE 86 21 24.4 15.8 34.9 15.0 12.7 17.6

PI(D7) 89 24 27.0 18.1 37.4 29.1 19.6 43.2 B/Hubei-Wujiagang/158/2009 (Yamagata)

FLU D-QIV-1 PRE 99 66 66.7 56.5 75.8 25.1 21.3 29.5

PI(D7) 100 100 100 96.4 100 216.5 180.5 259.6

FLU D-QIV-2 PRE 86 28 32.6 22.8 43.5 15.4 12.9 18.3 PI(D7) 89 53 59.6 48.6 69.8 39.7 27.9 56.6

GMT = geometric mean antibody titre calculated on all subjects N = number of subjects with available results n/% = number/percentage of subjects with titre within the specified range 95% CI = 95% confidence interval; LL = Lower Limit, UL = Upper Limit PRE = Pre-vaccination at Day 0, PI(D7) = Post-vaccination Dose 1 at Day 7 Secondary Outcome Results: Seropositivity rates and GMTs for anti-neuraminidase antibodies titres (H3N2) at Day 0 and Day 7 post vaccination Dose 1 (ATP cohort for immunogenicity)

≥ 1:40 GMT

95% CI 95% CI

NI Antibody Group Timing N n % LL UL Value LL UL


FLU D-QIV-1

PRE 107 68 63.6 53.7 72.6 38.4 33.7 43.7

PI(D7) 107 104 97.2 92.0 99.4 189.4 155.9 230.2

FLU D-QIV-2

PRE 106 58 54.7 44.8 64.4 58.8 47.2 73.4

PI(D7) 109 71 65.1 55.4 74.0 114.2 84.1 155.2

GMT = geometric mean antibody titre calculated on all subjects N = number of subjects with available results n/% = number/percentage of subjects with titre within the specified range 95% CI = 95% confidence interval; LL = Lower Limit, UL = Upper Limit PRE = Pre-vaccination at Day 0, P1 (D7) = Post-vaccination Dose 1 at Day 7 Secondary Outcome Results: Seropositivity rates and GMTs for Anti-neuraminidase antibodies titres (H3N2) at Day 0 and Day 7 post vaccination Dose 1 - by age strata (ATP cohort for immunogenicity)

≥ 1:40 GMT

95% CI 95% CI NI Antibody Group Sub-group Timing N n % LL UL value LL UL


FLU D-QIV-1 17-29M PRE 53 30 56.6 42.3 70.2 34.7 29.2 41.2

PI(D7) 53 51 96.2 87.0 99.5 158.0 117.8 211.8

30-48M PRE 54 38 70.4 56.4 82.0 42.4 34.9 51.6

PI(D7) 54 53 98.1 90.1 100 226.4 174.9 292.9

FLU D-QIV-2 17-29M PRE 52 24 46.2 32.2 60.5 49.8 35.9 69.3

PI(D7) 54 33 61.1 46.9 74.1 85.3 55.4 131.4

30-48M PRE 54 34 63.0 48.7 75.7 69.0 51.1 93.2

PI(D7) 55 38 69.1 55.2 80.9 152.2 98.5 235.1


Secondary Outcome Results: Seropositivity rates and GMTs for anti-neuraminidase antibodies titres (H3N2) at Day 0 and Day 7 post vaccination Dose 1 (ATP-I excluding subjects who had an RT-PCR confirmed influenza infection in study 115345)

≥ 1:40 GMT

95% CI 95% CI

NI Antibody Group Timing N n % LL UL value LL UL

A/Victoria/361/2011 (H3N2) FLU D-QIV-1 PRE 100 61 61.0 50.7 70.6 35.0 31.3 39.1

PI(D7) 100 97 97.0 91.5 99.4 175.8 143.9 214.7 FLU D-QIV-2 PRE 86 40 46.5 35.7 57.6 45.9 36.7 57.4

PI(D7) 89 53 59.6 48.6 69.8 84.5 60.7 117.6


Secondary Outcome Results: VRR for anti-neuraminidase antibody titres (H1N1 - Victoria - Yamagata) at Day 7 post vaccination Dose 1 (ATP cohort for immunogenicity)

Vaccine response

NI Antibody Group N n % LL UL


FLU D-QIV-2 106 31 29.2 20.8 38.9


FLU D-QIV-2 106 24 22.6 15.1 31.8


FLU D-QIV-2 106 29 27.4 19.1 36.9

Vaccine response for A/Christchurch/16/2010 (H1N1), B/Brisbane/60/2008 (Victoria), B/Hubei-Wujiagang/158/2009 (Yamagata) anti-neuraminidase was defined as: For initially seronegative subjects, antibody titre ≥ 1:40 after vaccination; For initially seropositive subjects, antibody titre after vaccination ≥ 4 fold the pre-vaccination antibody titre N = Number of subjects with pre- and post-vaccination results available n/% = Number/percentage of seroconverted subjects 95% CI = 95% confidence interval, LL = Lower Limit, UL = Upper Limit

Secondary Outcome Results: VRR for Anti-neuraminidase antibodies titres (H1N1 - Victoria - Yamagata) at day 7 post vaccination Dose 1 - by age strata (ATP cohort for immunogenicity)

Vaccine response

95% CI

NI Antibody Group Sub-group N n % LL UL

A/Christchurch/16/2010 (H1N1) FLU D-QIV-1 17-29M 53 43 81.1 68.0 90.6

30-48M 52 32 61.5 47.0 74.7

FLU D-QIV-2 17-29M 52 11 21.2 11.1 34.7

30-48M 54 20 37.0 24.3 51.3 B/Brisbane/60/2008 (Victoria) FLU D-QIV-1 17-29M 53 40 75.5 61.7 86.2

30-48M 52 39 75.0 61.1 86.0

FLU D-QIV-2 17-29M 52 8 15.4 6.9 28.1

30-48M 54 16 29.6 18.0 43.6

B/Hubei-Wujiagang/158/2009 (Yamagata) FLU D-QIV-1 17-29M 53 46 86.8 74.7 94.5

30-48M 52 44 84.6 71.9 93.1

FLU D-QIV-2 17-29M 52 10 19.2 9.6 32.5

30-48M 54 19 35.2 22.7 49.4


Secondary Outcome Results: VRR for anti-neuraminidase antibodies titres (H1N1 - Victoria - Yamagata) at day 7 post vaccination Dose 1 (ATP-I excluding subjects who had an RT-PCR confirmed influenza infection in study 115345)

Vaccine response

95% CI NI Antibody Group N n % LL UL


FLU D-QIV-2 86 23 26.7 17.8 37.4


FLU D-QIV-2 86 20 23.3 14.8 33.6 B/Hubei-Wujiagang/158/2009 (Yamagata) FLU D-QIV-1 99 85 85.9 77.4 92.0

FLU D-QIV-2 86 23 26.7 17.8 37.4

Vaccine response for A/Christchurch/16/2010 (H1N1), B/Brisbane/60/2008 (Victoria), B/Hubei-Wujiagang/158/2009 (Yamagata) anti-neuraminidase was defined as: For initially seronegative subjects, antibody titre ≥ 1:40 after vaccination For initially seropositive subjects, antibody titre after vaccination ≥ 4 fold the pre-vaccination antibody titre N = Number of subjects with pre- and post-vaccination results available n/% = Number/percentage of seroconverted subjects 95% CI = 95% confidence interval, LL = Lower Limit, UL = Upper Limit

Secondary Outcome Results: VRR for anti-neuraminidase antibody titres (H3N2) at Day 7 post vaccination Dose 1 (ATP cohort for immunogenicity)

Vaccine response

NI Antibody Group N n % LL UL


FLU D-QIV-2 106 31 29.2 20.8 38.9

Vaccine response for A/Victoria/361/2011 (H3N2) anti-neuraminidase is defined as: For initially seronegative subjects, antibody titre ≥1: 80 after vaccination; For initially seropositive subjects, antibody titre after vaccination ≥ 4 fold the pre-vaccination antibody titre N = Number of subjects with pre- and post-vaccination results available n/% = Number/percentage of seroconverted subjects 95% CI = 95% confidence interval, LL = Lower Limit, UL = Upper Limit

Secondary Outcome Results: VRR for Anti-neuraminidase antibodies titres (H3N2) at day 7 post vaccination Dose 1 - by age strata (ATP cohort for immunogenicity)

Vaccine response

95% CI

NI Antibody Group Sub-group N n % LL UL

A/Victoria/361/2011 (H3N2) FLU D-QIV-1 17-29M 53 36 67.9 53.7 80.1

30-48M 54 39 72.2 58.4 83.5

FLU D-QIV-2 17-29M 52 8 15.4 6.9 28.1

30-48M 54 23 42.6 29.2 56.8


Secondary Outcome Results: VRR for anti-neuraminidase antibodies titres (H3N2) at day 7 post vaccination Dose 1 (ATP-I excluding subjects who had an RT-PCR confirmed influenza infection in study 115345)

Vaccine response

95% CI

NI Antibody Group N n % LL UL A/Victoria/361/2011 (H3N2) FLU D-QIV-1 100 70 70.0 60.0 78.8

FLU D-QIV-2 86 22 25.6 16.8 36.1

Vaccine response defined as: For initially seronegative subjects, antibody titre ≥ 1:80 after vaccination For initially seropositive subjects, antibody titre after vaccination ≥ 4 fold the pre-vaccination antibody titre N = Number of subjects with pre- and post-vaccination results available n/% = Number/percentage of seroconverted subjects 95% CI = 95% confidence interval, LL = Lower Limit, UL = Upper Limit

Secondary Outcome Results: MGI for anti-neuraminidase antibodies titres at Day 7 post vaccination Dose 1 (ATP cohort for immunogenicity)

MGI

95% CI

NI Antibody Group N Value LL UL A/Christchurch/16/2010 (H1N1) FLU D-QIV-1 105 8.3 6.5 10.7

FLU D-QIV-2 106 1.8 1.5 2.1



FLU D-QIV-2 106 2.7 2.1 3.4


MGI = Mean Geometric increase in serum NI GMTs post-vaccination N = Number of subjects with pre- and post-vaccination results available 95% CI = 95% confidence interval, LL = Lower Limit, UL = Upper Limit

Secondary Outcome Results: MGI for Anti-neuraminidase antibodies titres at Day 7 post vaccination Dose 1 - by age strata (ATP cohort for immunogenicity)

MGI

95% CI

NI Antibody Group Sub-group N Value LL UL

A/Christchurch/16/2010 (H1N1) FLU D-QIV-1 17-29M 53 11.4 8.2 15.8

30-48M 52 6.0 4.1 8.8

FLU D-QIV-2 17-29M 52 1.5 1.2 1.9

30-48M 54 2.1 1.7 2.7

B/Brisbane/60/2008 (Victoria) FLU D-QIV-1 17-29M 53 5.2 4.3 6.3

30-48M 52 5.1 4.1 6.5

FLU D-QIV-2 17-29M 52 1.5 1.1 2.1

30-48M 54 2.3 1.6 3.4 B/Hubei-Wujiagang/158/2009 (Yamagata) FLU D-QIV-1 17-29M 53 8.8 7.2 10.8

30-48M 52 8.7 6.9 11.0

FLU D-QIV-2 17-29M 52 2.2 1.5 3.2

30-48M 54 3.2 2.3 4.5

A/Victoria/361/2011 (H3N2) FLU D-QIV-1 17-29M 53 4.6 3.6 5.8

30-48M 54 5.3 4.2 6.8

FLU D-QIV-2 17-29M 52 1.7 1.4 2.0

30-48M 54 2.3 1.9 2.8

17-29M = 17-29 months old subjects 30-48M = 30-48 months old subjects N = Number of subjects with pre- and post-vaccination results available MGI = Mean Geometric increase in serum Anti-neuraminidase GMTs post-vaccination 95% CI = 95% confidence interval, LL = Lower Limit, UL = Upper Limit

Secondary Outcome Results: MGI for anti-neuraminidase antibodies titres at Day 7 post vaccination Dose 1 (ATP-I excluding subjects who had an RT-PCR confirmed influenza infection in study 115345)

MGI

95% CI

NI Antibody Group N Value LL UL

A/Christchurch/16/2010( H1N1) FLU D-QIV-1 98 8.1 6.2 10.5


FLU D-QIV-2 86 1.9 1.5 2.5


FLU D-QIV-2 86 2.6 2.0 3.5

A/Victoria/361/2011(H3N2) FLU D-QIV-1 100 5.0 4.2 6.0

FLU D-QIV-2 86 1.8 1.6 2.2

MGI = Mean Geometric increase in serum NI GMTs post-vaccination N = Number of subjects with pre- and post-vaccination results available

95% CI = 95% confidence interval, LL = Lower Limit, UL = Upper Limit Secondary Outcome Results: Number (%) of subjects reporting solicited local symptoms during the 7-day (Days 0-6) post-dose 1 vaccination period (Total Vaccinated cohort)

FLU D-QIV-1 Group FLU D-QIV-2 Group

95 % CI 95 % CI Symptom Intensity N n % LL UL N n % LL UL

Pain Any 239 96 40.2 33.9 46.7 228 61 26.8 21.1 33.0

Grade 3 239 2 0.8 0.1 3.0 228 1 0.4 0.0 2.4

Redness Any 239 82 34.3 28.3 40.7 228 48 21.1 15.9 26.9 > 50 mm 239 2 0.8 0.1 3.0 228 0 0.0 0.0 1.6

Swelling Any 239 49 20.5 15.6 26.2 228 25 11.0 7.2 15.8

> 50 mm 239 2 0.8 0.1 3.0 228 0 0.0 0.0 1.6

N= number of subjects with the documented dose n/%= number/percentage of subjects reporting at least once the symptom 95%CI = Exact 95% confidence interval; LL = lower limit, UL = upper limit Any = occurrence of any local symptom regardless of their intensity grade Grade 3 pain = Cried when limb was moved/spontaneously painful

Secondary Outcome Results: Number (%) of subjects reporting solicited general symptoms during the 7-day (Days 0-6) post-dose 1 vaccination period (Total Vaccinated cohort)

FLU D-QIV-1 Group FLU D-QIV-2 Group

95 % CI 95 % CI

Symptom Intensity/Relationship N n % LL UL N n % LL UL Drowsiness Any 238 54 22.7 17.5 28.5 224 44 19.6 14.7 25.5

Grade 3 238 5 2.1 0.7 4.8 224 1 0.4 0.0 2.5

Related 238 36 15.1 10.8 20.3 224 28 12.5 8.5 17.6

Irritability/Fussiness Any 238 77 32.4 26.5 38.7 224 59 26.3 20.7 32.6

Grade 3 238 5 2.1 0.7 4.8 224 5 2.2 0.7 5.1

Related 238 51 21.4 16.4 27.2 224 43 19.2 14.3 25.0

Loss of Appetite Any 238 51 21.4 16.4 27.2 224 46 20.5 15.4 26.4 Grade 3 238 8 3.4 1.5 6.5 224 5 2.2 0.7 5.1

Related 238 31 13.0 9.0 18.0 224 31 13.8 9.6 19.1

Temperature/(Axillary) 37.5°C 238 13 5.5 2.9 9.2 224 26 11.6 7.7 16.5

>39.0 °C 238 2 0.8 0.1 3.0 224 1 0.4 0.0 2.5

Related 238 6 2.5 0.9 5.4 224 15 6.7 3.8 10.8

N= number of subjects with the documented dose n/%= number/percentage of subjects reporting the symptom at least once 95%CI= Exact 95% confidence interval; LL = lower limit, UL = upper limit Any = occurrence of any general symptom regardless of their intensity grade or relationship to vaccination Grade 3 irritability/fussiness = crying that could not be comforted/prevented normal activity Grade 3 drowsiness = drowsiness that prevented normal activity Grade 3 loss of appetite = did not eat at all Related = symptom assessed by the investigator as causally related to the vaccination Secondary Outcome Results: Number of days with symptoms during the 7-day (Days 0-6) post-vaccination Dose 1 period (Total Vaccinated cohort)

Solicited symptom Group N Mean Median

Drowsiness FLU D-QIV-1 54 2.5 1.0 FLU D-QIV-2 44 1.4 1.0

Irritability/fussiness FLU D-QIV-1 77 2.2 2.0

FLU D-QIV-2 59 2.0 2.0

Loss of appetite FLU D-QIV-1 51 2.9 2.0 FLU D-QIV-2 46 2.1 2.0

Pain FLU D-QIV-1 96 1.7 1.0

FLU D-QIV-2 61 1.6 1.0 Redness FLU D-QIV-1 82 2.1 2.0

FLU D-QIV-2 48 2.2 2.0

Swelling FLU D-QIV-1 49 2.1 2.0

FLU D-QIV-2 25 1.8 1.0 Temperature FLU D-QIV-1 13 1.9 1.0

FLU D-QIV-2 26 2.0 2.0

N = Number of subjects with the symptom and without the missing confirmed grade

Secondary Outcome Results: Number (%) of subjects with AE with MAVs during the entire study period (Total Vaccinated cohort)

Most frequent AE with MAVs – On-Therapy (Occurring within entire study period)

FLU D-QIV-1 Group N = 241


Subjects with any AE with MAV(s), n (%) 149 (61.8) 130 (56.8)

Subjects with grade 3 AE with MAV(s), n (%) 5 (2.1) 8 (3.5)

Subjects with related AE with MAV(s), n (%) 0 (0.0) 1 (0.4) Bronchitis 34 (14.1) 21 (9.2)

Upper respiratory tract infection 34 (14.1) 26 (11.4)

Nasopharyngitis 32 (13.3) 28 (12.2) Pharyngitis 19 (7.9) 18 (7.9)

Tonsillitis 18 (7.5) 13 (5.7)

Otitis media 16 (6.6) - Viral infection 15 (6.2) 10 (4.4)

Conjunctivitis 10 (4.1) 10 (4.4)

Cough 10 (4.1) 14 (6.1)

Pyrexia 8 (3.3) - Gastroenteritis 8 (3.3) 11 (4.8)

Rhinitis 8 (3.3) 11 (4.8)

N = number of subjects with at least one administered dose n/% = number/percentage of subjects reporting the symptom at least once Grade 3 = event that prevented normal activities Related = event assessed by the investigator as causally related to the study vaccination Counting rule applied: As there were more than 30 subjects per treatment group and ≤ 3 groups, only 10 most frequent events in each treatment group were listed. - : Implies that event was not reported in the particular group or that the adverse event was reported in the particular group but did not fall within the pre-defined counting rule of 10 most frequent events for that group.

Secondary Outcome Results: Number (%) of subjects with pIMDs during the entire study period (Total Vaccinated cohort)

All pIMDs



Subjects with any pIMD(s), n (%) 0 (0.0) 0 (0.0) Subjects with related pIMD(s), n (%) 0 (0.0) 0 (0.0)

N = number of subjects with at least one administered dose n/% = number/percentage of subjects reporting the symptom at least once Related = event assessed by the investigator as causally related to the study vaccination

Safety Results: Number (%) of subjects with unsolicited AEs during the 28-day (Days 0-27) follow up period after the first vaccination (Total Vaccinated cohort)

Most Frequent Unsolicited Adverse Events – On-Therapy (Occurring within Days 0 –27 following the first vaccination)



Subjects with any AE(s), n (%) 66 (27.4 ) 66 (28.8 )

Subjects with grade 3 AE(s), n (%) 6 (2.5 ) 7 (3.1 )

Subjects with related AE(s), n (%) 5 (2.1 ) 3 (1.3 )

Cough 9 (3.7) 13 (5.7)

Bronchitis 11 (4.6) 5 (2.2)

Nasopharyngitis 6 (2.5) 10 (4.4)

Upper respiratory tract infection 4 (1.7) 8 (3.5)

Pharyngitis 5 (2.1) 6 (2.6)

Vomiting 4 (1.7) 5 (2.2)

Tonsillitis 6 (2.5) -

Pyrexia 3 (1.2) 5 (2.2)

Viral infection 6 (2.5) -

Diarrhoea 3 (1.2) 4 (1.7)

Otitis media 3 (1.2) 4 (1.7)

Rhinitis - 5 (2.2)

N = number of subjects with the administered dose n/% = number/percentage of subjects reporting the symptom at least once Grade 3 = event that prevented normal activities Related = event assessed by the investigator as causally related to the study vaccination Counting rule applied: As there were more than 30 subjects per treatment group and ≤ 3 groups, only the 10 most frequent events in each treatment group were listed. -: Implies that adverse event was not reported in the particular group or that the adverse event was reported in the particular group but did not fall within the pre-defined counting rule of 10 most frequent events for that group.

Safety Results: Number (%) of subjects with SAEs during the entire study period (Total Vaccinated cohort)

Serious Adverse Events, n (%) [n considered by the investigator to be related to study medication]

All SAEs FLU D-QIV-1 Group

N = 241 FLU D-QIV-2 Group

N = 229

Subjects with any SAEs, n (%) [n assessed by the investigator as related]

7 (2.9) [0] 8 (3.5) [0]

Gastroenteritis 0 (0.0) [0] 2 (0.9) [0]

Thermal burn 1 (0.4) [0] 0 (0.0) [0]

Inguinal hernia 0 (0.0) [0] 1 (0.4) [0]

Bronchiolitis 0 (0.0) [0] 1 (0.4) [0]

Bronchitis 1 (0.4) [0] 0 (0.0) [0]

Bronchopneumonia 1 (0.4) [0] 0 (0.0) [0]

Laryngitis 1 (0.4) [0] 0 (0.0) [0]

Lymphadenitis bacterial 0 (0.0) [0] 1 (0.4) [0]

Otitis media 1 (0.4) [0] 0 (0.0) [0]

Otitis media acute 1 (0.4) [0] 0 (0.0) [0]

Pharyngitis 0 (0.0)[0] 1 (0.4) [0]

Pneumonia bacterial 0 (0.0) [0] 1 (0.4) [0]

Rhinitis 1 (0.4) [0] 0 (0.0) [0]

Sinusitis 1 (0.4) [0] 0 (0.0) [0]

Arthralgia 1 (0.4) [0] 0 (0.0) [0]

Adenoidal hypertrophy 0 (0.0) [0] 1 (0.4) [0]

Upper respiratory tract inflammation 1 (0.4) [0] 0 (0.0) [0]

Urticaria 1 (0.4) [0] 0 (0.0) [0]

Fatal SAEs FLU D-QIV-1 Group

N = 241 FLU D-QIV-2 Group

N = 229

Subjects with fatal SAEs, n (%) [n assessed by the investigator as related]

0 (0.0) [0] 0 (0.0) [0]

Conclusion: For the ATP-I, the geometric mean titre (GMT) for HI antibodies titres at Day 0 ranged between 11.9 and 43.1 in the FLU D-QIV-1 Group (vaccine-primed group), in contrast to between 6.5 and 16.4 in the FLU D-QIV-2 group (vaccine-unprimed group). Post-vaccination, at Day 7, the GMTs ranged between 135.3 and 445.6 in the FLU D-QIV-1 Group, and between 26.1 and 47.5 in the FLU D-QIV-2 Group. In the ATP-I, the SPRs at Day 0 post-vaccination dose 1, across the 4 vaccine strains (A/Christchurch/16/2010, A/Victoria/361/2011, B/Brisbane/60/2008 and B/Hubei-Wujiagang/158/2009) ranged between 12.2% and 40.3% in the FLU D-QIV-1 Group and between 5.9% and 36.6% in the FLU D-QIV-2 Group. At Day 7 post-vaccination dose 1, the SPRs ranged between 86.2% and 96.9% in the FLU D-QIV-1 Group and between 34.4% and 40.2% in the FLU D-QIV-2 Group. The SCRs at Day 7 post-vaccination dose 1, across the 4 vaccine-strains ranged between 76.5% and 94.1% in the FLU D-QIV-1 Group and between 32.2% and 38.6% in the FLU D-QIV-2 Group. At the same time point, the MGI ranged between 6.7 and 15.2 in the FLU D-QIV-1 Group and between 2.9 and 4.6 in the FLU D-QIV-2 Group across the 4 vaccine-strains. Additionally, the protocol-specified analysis of immunogenicity parameters using the ATP-I excluding subjects who had an RT-PCR confirmed influenza infection in study 115345, yielded results which were very similar to the results of the ATP-I analysis inclusive of all eligible subjects. During the 28-day follow-up period after first vaccination, at least one unsolicited adverse event was reported by 66 (27.4%) subjects in FLU D-QIV-1 Group and 66 (28.8%) subjects in FLU D-QIV-2 Group. During the same time period, 6 (2.5%) subjects in FLU D-QIV-1 Group and 7 (3.1%) subjects in FLU D-QIV-2 Group reported grade 3 unsolicited AEs and 5 (2.1%) subjects in FLU D-QIV-1 Group and 3 (1.3%) subjects in FLU D-QIV-2 Group reported unsolicited AEs assessed by the investigator as causally related to study vaccination. During the entire study period, at least 1 SAE was reported by 7 subjects in FLU D-QIV-1 Group and 8 subjects in FLU D-QIV-2 Group. None of them was assessed by the investigator as causally related to study vaccination. There were no fatal SAEs reported throughout the study.

Date updated: 23 February 2017

immunogenicity, safety and reactogenicity study of …...study number: 116023 (flu d-qiv-009 ext...

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