(flu d-qiv) · occurrence of myalgia during the 7-day post-vaccination period (day 0 – day 6)...

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GSK Medicine: GlaxoSmithKline (GSK) Biologicals’ Quadrivalent Inactivated Split Virion Influenza Vaccine 2014/2015, GSK2321138A (FLU D-QIV)

Study Number: 201251 (FLU D-QIV-015)

Title: Safety and immunogenicity study of GSK Biologicals’ Quadrivalent Influenza Vaccine (GSK2321138A) manufactured with a new process in adults and children. Influsplit Tetra™ (D-QIV_IP): GlaxoSmithKline (GSK) Biologicals’ quadrivalent seasonal influenza candidate vaccine (Fluarix Tetra™, Fluarix Quadrivalent®) produced by investigational process.

Rationale: The purpose of this study was to assess the acceptable safety profile and the immunogenic non-inferiority of the FLU D-QIV vaccine manufactured with this investigational process (FLU D-QIV Investigational Process [IP]) compared to FLU D-QIV manufactured with the current licensed process (FLU D-QIV Licensed Process [LP]). Influsplit Tetra™ (D-QIV_LP): GlaxoSmithKline (GSK) Biologicals’ quadrivalent seasonal influenza candidate vaccine (Fluarix Tetra™, Fluarix Quadrivalent®) produced by currently licensed process.

Phase: IIIA

Study Period: 18 August 2014 to 18 April 2015

Study Design: Double-blind, controlled, multi-country, self-contained study with staggered enrolment of adult (18-49 years) and pediatric treatment groups (6 months to 17 years).

Centres: 53 centers [1 center in Bangladesh, 11 centers in C’zech Republic, 7 centers in France, 18 centers in Germany, 6 centers in Poland, 6 centers in Spain and 4 centers in the United States (US)]

Indication: Active immunization of adults and children against influenza

Treatment: The study groups were as follows:

D-QIV_IP Adult Group: Subjects aged 18-49 years received 1 dose of D-QIV_IP vaccine at Day 0.

D-QIV_LP Adult Group: Subjects aged 18-49 years received 1 dose of D-QIV_LP vaccine at Day 0.

D-QIV_IP 3-17y Group: Subjects aged 3-17 years received 1 or 2 doses of D-QIV_IP vaccine depending on vaccine-priming status*.

D-QIV_LP 3-17y Group: Subjects aged 3-17 years received 1 or 2 doses of D-QIV_LP vaccine depending on vaccine-priming status*.

D-QIV_IP 6-35m Group: Subjects aged 6-35 months received 1 or 2 doses of D-QIV_IP vaccine depending on vaccine-priming status*.

D-QIV_LP 6-35m Group: Subjects aged 6-35 months received 1 or 2 doses of D-QIV_IP vaccine depending on vaccine-priming status*.

Dose 1 of all vaccines were administered intramuscularly (IM) in the anterolateral region of left thigh for subjects below 12 months of age and in the deltoid region of left or non-dominant arm in subjects ≥ 12 months of age. Dose 2 of all vaccines were administered IM in the anterolateral region of right thigh for subjects below 12 months of age and in the deltoid region of right or dominant arm in subjects ≥ 12 months of age. Note: First the adult groups were enrolled. Upon endorsement from the Internal Safety Review Committee (iSRC) based on the safety data reported within the 7-day post-vaccination period of the adults, enrolment of the pediatric cohort aged 3-17 years commenced. Enrolment of the 6-35 months old cohort started only after the first 100 subjects 3-17 years old were vaccinated and no life-threatening related SAE(s) were reported within 2 days post-Dose 1 vaccination in these first 100 pediatric subjects. *Vaccine-primed subjects are subjects aged 6 months to 8 years (inclusive), who had received at least 1 dose of the seasonal influenza vaccine 2013-2014 or a total of 2 or more doses of seasonal influenza vaccine since 01 July 2010 or a total of 2 or more doses of seasonal influenza vaccine before July 1, 2010 and 1 or more doses of monovalent 2009 (H1N1) vaccine or a total of 1 or more doses of

seasonal influenza vaccine before July 1, 2010 and 1 or more doses of seasonal influenza since July 1, 2010. All subjects aged 9 years of age are considered vaccine-primed and received only 1 dose of seasonal influenza vaccine in this study. Subjects 6 months to 8 years of age, inclusive, who did not meet these criteria were considered as vaccine-unprimed subjects.

Objectives: Adults 18-49 years old:

To describe the safety of 1 dose of D-QIV_IP vaccine and 1 dose of D-QIV_LP vaccine in terms of solicited adverse events

(AEs) 7 days after vaccination, including the symptoms of Oculorespiratory Syndrome (ORS)# over 3 days post-vaccination, and in terms of unsolicited AEs 21 days after vaccination in subjects aged 18-49 years.

Children 3-17 years old:

To demonstrate the immunogenic non-inferiority of D-QIV_IP as compared to D-QIV_LP in terms of haemagglutination inhibition (HI) geometric mean titer (GMT) ratio at 28 days after completion of the vaccination series in subjects aged 3-17 years. Non-inferiority criterion (for each of the 4 strains): upper limit (UL) of the 95% confidence interval (CI) of the GMT ratio (D-QIV_LP/D-QIV_IP) is ≤ 1.5.

To describe the safety of D-QIV_IP vaccine and D-QIV_LP vaccine in terms of solicited AEs 7 days after vaccination, including the symptoms of ORS over 3 days post-vaccination, and in terms of unsolicited AEs 28 days after vaccination in subjects aged 3-17 years.

Children 6-35 months old:

To demonstrate the immunogenic non-inferiority of D-QIV_IP as compared to D-QIV_LP in terms of HI GMT ratio at 28 days after completion of the vaccination series in subjects aged 6-35 months. Non-inferiority criterion (for each of the 4 strains): UL of the 95% CI for the GMT ratio (D-QIV_LP/ D-QIV_IP) is ≤ 1.5.

To demonstrate there is no significant increase of fever in subjects who reported fever ≥ 38ºC (100.4ºF) after Dose 1 or Dose 2 (overall per subject) with D-QIV_IP compared to D-QIV_LP within 7 days post-vaccination in subjects aged 6-35 months. Success criterion: UL of the 95% CI for relative risk (RR) of fever ≥ 38ºC (100.4ºF) (FLU D-QIV IP/FLU D-QIV LP) is ≤ 2.0.

#Oculorespiratory syndrome (ORS) was defined as the occurrence within 24 hours after vaccination of one or more of the following newly onset symptoms: bilateral red eyes, cough, wheeze, chest tightness, difficulty breathing, difficulty swallowing, hoarseness, sore throat, facial swelling.

Primary Outcome Variable(s): Adults 18-49 years old:

Occurrence of solicited local and general AEs (Days 0-6 following vaccination), including the symptoms of ORS (Days 0-2 following vaccination), unsolicited AEs (Days 0-20 following vaccination) and medically attended events (MAEs) and serious adverse events (SAEs) in subjects aged 18-49 years during the entire study period.

‒ Percentage, intensity and duration of solicited local AEs during a 7-day follow-up period after vaccination (Day 0 – Day 6). ‒ Percentage, intensity, duration and relationship to vaccination of solicited general AEs during a 7-day follow-up period after

vaccination (Day 0 – Day 6). ‒ Percentage, intensity and relationship to vaccination of symptoms of ORS during a 3-day follow-up period after vaccination

(Day 0 – Day 2). ‒ Percentage, intensity and relationship to vaccination of unsolicited AEs during a 21-day follow-up period after vaccination (Day

0 – Day 20). ‒ Percentage, intensity and relationship to vaccination of MAEs during the entire study period. ‒ Percentage and relationship to vaccination of SAEs during the entire study period.


HI antibody titers for each of the 4 influenza strains in subjects aged 3-17 years to calculate: ‒ HI GMTs and GMT ratio (D-QIV_LP 3-17y/ D-QIV_IP 3-17y) for each of the 4 influenza strains at 28 days after completion of

the vaccination series.

Occurrence of solicited local and general AEs (Days 0-6 following vaccination) in subjects aged 3-4 years and 5-17 years, including symptoms of ORS (Days 0-2 following vaccination), unsolicited AEs (Days 0-27 following vaccination) and MAEs and SAEs during the entire study period in children aged 3-17 years.

‒ Percentage, intensity and duration of solicited local AEs during a 7-days follow-up period after vaccination (Day 0 – Day 6). ‒ Percentage, intensity, duration and relationship to vaccination of solicited general AEs during a 7-day follow-up period after

vaccination (Day 0 – Day 6). ‒ Percentage, intensity and relationship to vaccination of symptoms of ORS during a 3-day follow-up period after vaccination

(Day 0 – Day 2). ‒ Percentage, intensity and relationship to vaccination of unsolicited AEs during a 28-day follow-up period after vaccination (Day

0 – Day 27). ‒ Percentage, intensity and relationship to vaccination of MAEs during the entire study period.

‒ Percentage and relationship to vaccination of SAEs during the entire study period. Children 6-35 months old:

HI antibody titers for each of the 4 influenza strains in subjects 6-35 months to calculate: ‒ HI GMTs and GMT ratio (D-QIV_LP 6-35m/ D-QIV_IP 6-35m) for each of the 4 influenza strains at 28 days after completion of

the vaccination series.

Occurrence of fever ≥38ºC (100.4ºF) after Dose 1 or Dose 2 (across doses) during the 7-day post-vaccination period (Day 0 – Day 6) in subjects aged 6-35 months.

‒ Percentage and relative risk (D-QIV_IP 6-35m/ D-QIV_LP 6-35m) of subjects with fever ≥ 38ºC (100.4ºF) after Dose 1 or Dose 2 (across doses) during the 7-day post-vaccination period (Day 0 - Day 6).

Secondary Outcome Variable(s): Adults 18-49 years old:

Humoral immune response in terms of HI antibodies in subjects aged 18-49 years ‒ Serum anti-HA antibody titers against the 4 vaccine strains at Day 0 and Day 21 to calculate:

o GMTs at Day 0 and Day 21. o Seroconversion rate (SCR)* at Day 21. o Seroprotection rate (SPR)** at Day 0 and Day 21. o Mean geometric increase (MGI)*** at Day 21.


Humoral immune response in terms of HI antibodies in children aged 3-17 years ‒ Serum anti- Haemagglutinin (HA) antibody titers against the 4 vaccine strains at Day 0 and Day 28 to calculate:

o GMTs at Day 0 and Day 28. o Seroconversion rate (SCR)* at Day 28. o Seroprotection rate (SPR)** at Day 0 and Day 28. o Mean geometric increase (MGI)*** at Day 28

Occurrence of myalgia during the 7-day post-vaccination period (Day 0 – Day 6) after Dose 1 or Dose 2 (across doses) in subjects aged 5-17 years

‒ Percentage and relative risk (RR) (D-QIV_IP 3-17y / D-QIV_LP 3-17y) of subjects with myalgia during the 7-day post-vaccination period (Day 0 - Day 6) in subjects aged 5-17 years

Children 6-35 months old:

Occurrence of fever ≥ 38°C (100.4ºF) during the 7-day post-vaccination period (Day 0-Day 6) after Dose 1 and after Dose 2 in subjects aged 6-35 months.

‒ Percentage and relative risk (D-QIV_IP 6-35m/ D-QIV_LP 6-35m) of subjects with fever ≥ 38ºC (100.4ºF) after Dose 1 and after Dose 2 during the 7-day post-vaccination period (Day 0 – Day 6) in subjects aged 6-35 months.

Humoral immune response in terms of HI antibodies in children aged 6-35 months. ‒ Serum anti-HA antibody titers against the 4 vaccine strains at Day 0 and 28 days after completion of the vaccination series to

calculate: o GMTs at Day 0 and Day 28. o Seroconversion rate (SCR)* at Day 28. o Seroprotection rate (SPR)** at Day 0 and Day 28. o Mean geometric increase (MGI)*** at Day 28.

Occurrence of solicited local and general AEs (Days 0-6 following vaccination), including the symptoms of ORS (Days 0-2 following vaccination), unsolicited AEs (Days 0-27 following vaccination), MAEs and SAEs during the entire study period in children aged 6-35 months.

‒ Percentage, intensity and duration of solicited local AEs during a 7-day follow-up period after each vaccine dose (Day 0 – Day 6).

‒ Percentage, intensity, duration and relationship to vaccination of solicited general AEs during a 7-day follow-up period after each vaccine dose (Day 0 – Day 6).

‒ Percentage, intensity and relationship to vaccination of symptoms of ORS during a 3-day follow-up period after vaccination (Day 0 – Day 2).

‒ Percentage, intensity and relationship to vaccination of unsolicited AEs during a 28-day follow-up period after each vaccine dose (Day 0 – Day 27).

‒ Percentage, intensity and relationship to vaccination of MAEs during the entire study period. ‒ Percentage and relationship to vaccination of SAEs during the entire study period.

Occurrence of fever ≥ 38°C (100.4ºF) and > 39ºC (102.2ºF) after Dose 1 or after Dose 2 (across doses) during the 2-days post-vaccination period in subjects aged 6 months to < 5 years of age (pooling of 2 independent cohorts).

‒ Percentage and relative risk (D-QIV IP 6m-

for grade 3 unsolicited AEs and for AEs assessed by the investigator related to vaccination. In addition, solicited and unsolicited symptoms experienced by at least 5 % of subjects, classified by MedDRA during the 21 days (Days 0-20) after vaccination for subjects 18-49 years of age and up to 28 days after each vaccination (Days 0-27) for subjects 3-17 years of age and children 6-35 months of age, including number of events reported and excluding SAEs were also tabulated. The occurrences of SAEs and MAEs reported during the entire study period (approximately 21 days for each subject aged 18 to 49 years, approximately 28 days for subjects aged 9 to 17 years and 28 days or 56 days for each subject aged 6 months to 8 years depending on their vaccine-priming status, were summarized and classified according to MedDRA Preferred Term.

Study Population: Healthy male and female subjects, 6 months to 49 years of age at the time of the first vaccination. Female subjects were to be of non-childbearing potential or if of childbearing potential had to practice adequate contraception for 30 days prior to vaccination, had a negative pregnancy test on the day of vaccination and had agreed to continue adequate contraception for 2 months after vaccination. Written informed consent was obtained from the subjects or from parents/legally acceptable representative (LAR) of the subject. Written informed assent obtained from the subject if/as required by local regulations.

Number of Subjects: D-QIV LP Adult Group D-QIV IP Adult Group Planned, N 60 60

Randomised, N (Total Vaccinated cohort) 60 60

Completed, n (%) 59 (98.3) 60 (100)

Total Number Subjects Withdrawn, n (%) 1 (1.7) 0 (0.0)

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

Withdrawn due to Lack of Efficacy, n (%) 0 (0.0) 0 (0.0)

Withdrawn for other reasons, n (%) 1 (1.7) 0 (0.0)

Demographics D-QIV LP Adult Group D-QIV IP Adult Group

N (Total Vaccinated cohort) 60 60

Gender Females, n (%) 35 (58.3) 41 (68.3)

Males, n (%) 25 (41.7) 19 (31.7)

Mean Age, years (SD) # 31.2 (9.3) 29.8 (8.7)

Median# 29 28

Minimum, Maximum# 18, 49 19, 49

White - Caucasian / European Heritage, n (%) 56 (93.3) 60 (100)

Number of Subjects: D-QIV IP 3-17y Group D-QIV LP 3-17y Group

Planned, N 400 400


Completed - Primed subjects, n (%)* 309 (75.4) 312 (75.9)

Completed - Unprimed subjects, n (%)* 101 (24.6) 98 (23.8)

Total Number Subjects Withdrawn, n (%) 0 (0.0) 1 (0.2)



Withdrawn for other reasons, n (%) 0 (0.0) 1 (0.2)

Demographics D-QIV IP 3-17y Group D-QIV LP 3-17y Group


Gender Females, n (%)

196 (47.8) 187 (45.5)

Males, n (%) 214 (52.2) 224 (54.5)

Mean Age, years (SD) # 9.4 (4.2) 9.4 (4.2)

Median# 9 10

Minimum, Maximum# 3, 18# 3, 18#

White - Caucasian / European Heritage, n (%) 378 (92.2) 370 (90.0)

Number of Subjects: D-QIV IP 6-35m Group D-QIV LP 6-35m Group

Planned, N 470 470


Completed - Primed subjects, n (%)* 40 (8.6) 41 (8.6)

Completed - Unprimed subjects, n (%)* 419 (89.9) 420 (88.6)

Total Number Subjects Withdrawn, n (%) 7 (1.5) 13(2.74)



Withdrawn for other reasons, n (%) 5(1.0) 12(2.5)

Demographics D-QIV IP 6-35m Group D-QIV LP 6-35m Group


Gender Females, n (%) 223 (47.9) 209 (44.1)

Males, n (%) 243 (52.1) 265 (55.9)

Mean Age, months (SD) # 19.7 (8.0) 19.9 (8.3)

Median# 19 19

Minimum, Maximum# 4, 36 5, 35

White - Caucasian / European Heritage, n (%) 329 (70.6) 337 (71.1)

Asian - South East Asian Heritage, n (%) 91 (19.5) 91 (19.2)

White - Arabic / North African Heritage, n (%) 28 (6.0) 23 (4.9)

*The study duration was approximately 28 days for subjects aged 9 to 17 years and 28 days or 56 days for each subject aged 6 months to 8 years depending on their vaccine-priming status #For subjects that reported a partial Date of Birth (DoB), the missing information was replaced by 15th of the month in case only the day was missing, or by 30th of June if day and month were missing. The correct age range was selected by the investigator based on the real DoB. However the mean and median age and the min/max range were calculated based on the replacement DoB. Primary Outcome Results: Number (%) of subjects aged 18-49 years reporting solicited local AEs reported during the 7-day (Days 0-6) post-vaccination period (Adult-Total Vaccinated cohort)

D-QIV LP Adult Group D-QIV IP Adult Group

95 % CI 95 % CI

Symptom Intensity N n % LL UL N n % LL UL

Pain Any 59 32 54.2 40.8 67.3 60 41 68.3 55.0 79.7

Grade 3 59 0 0.0 0.0 6.1 60 1 1.7 0.0 8.9

Redness Any 59 1 1.7 0.0 9.1 60 1 1.7 0.0 8.9

>100 mm 59 0 0.0 0.0 6.1 60 0 0.0 0.0 6.0

Swelling Any 59 4 6.8 1.9 16.5 60 2 3.3 0.4 11.5

>100 mm 59 0 0.0 0.0 6.1 60 0 0.0 0.0 6.0

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 local symptom regardless of intensity grade Grade 3 Pain = Significant pain at rest, which prevented normal every day activities.

Primary Outcome Results: Number (%) of subjects aged 18-49 years reporting solicited general AEs reported during the 7-day (Days 0-6) post-vaccination period (Adult-Total Vaccinated cohort)


95 % CI 95 % CI

Symptom Intensity / Relationship

N n % LL UL N n % LL UL

Fatigue Any 59 20 33.9 22.1 47.4 60 32 53.3 40.0 66.3

Grade 3 59 0 0.0 0.0 6.1 60 0 0.0 0.0 6.0

Related 59 20 33.9 22.1 47.4 60 28 46.7 33.7 60.0

Gastrointestinal symptoms*

Any 59 6 10.2 3.8 20.8 60 6 10.0 3.8 20.5

Grade 3 59 0 0.0 0.0 6.1 60 0 0.0 0.0 6.0

Related 59 4 6.8 1.9 16.5 60 4 6.7 1.8 16.2

Headache Any 59 16 27.1 16.4 40.3 60 30 50.0 36.8 63.2

Grade 3 59 1 1.7 0.0 9.1 60 1 1.7 0.0 8.9

Related 59 14 23.7 13.6 36.6 60 26 43.3 30.6 56.8

Joint Pain Any 59 5 8.5 2.8 18.7 60 8 13.3 5.9 24.6

Grade 3 59 0 0.0 0.0 6.1 60 0 0.0 0.0 6.0

Related 59 5 8.5 2.8 18.7 60 8 13.3 5.9 24.6

Widespread muscle ache (myalgia)

Any 59 13 22.0 12.3 34.7 60 21 35.0 23.1 48.4 Grade 3 59 0 0.0 0.0 6.1 60 1 1.7 0.0 8.9

Related 59 13 22.0 12.3 34.7 60 20 33.3 21.7 46.7

Shivering Any 59 7 11.9 4.9 22.9 60 9 15.0 7.1 26.6

Grade 3 59 0 0.0 0.0 6.1 60 1 1.7 0.0 8.9

Related 59 6 10.2 3.8 20.8 60 8 13.3 5.9 24.6

Fever Any# 59 2 3.4 0.4 11.7 60 2 3.3 0.4 11.5

≥38.0°C 59 1 1.7 0.0 9.1 60 2 3.3 0.4 11.5

>39.0°C 59 0 0.0 0.0 6.1 60 0 0.0 0.0 6.0

Related 59 2 3.4 0.4 11.7 60 2 3.3 0.4 11.5

≥38.0°C Related 59 1 1.7 0.0 9.1 60 2 3.3 0.4 11.5

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 intensity grade or relationship to vaccination. # Any fever = all subjects with a documented temperature of ≥ 38°C/100.4°F by any route and all subjects reporting temperature < 38°C but with missing values (MC) for at least one day during the solicited period. Grade 3 = general symptoms that prevented normal activities. Related = general symptom assessed by the investigator as causally related to the vaccination. *Gastrointestinal symptoms = nausea, vomiting, diarrhoea and/or abdominal pain

Primary Outcome Results: Number of days with solicited local and general AEs during the 7-day (Days 0-6) post-vaccination period in subjects aged 18-49 years (Adult-Total Vaccinated cohort)

Solicited symptom Group N Mean Median

Fatigue D-QIV LP Adult 20 1.9 2.0

D-QIV IP Adult 32 2.1 2.0 Gastrointestinal symptoms* D-QIV LP Adult 6 1.3 1.0

D-QIV IP Adult 6 2.0 1.5

Headache D-QIV LP Adult 16 1.9 1.5


Joint Pain D-QIV LP Adult 5 2.6 3.0


Widespread muscle ache (myalgia) D-QIV LP Adult 13 2.5 2.0


Pain D-QIV LP Adult 32 2.2 2.0


Redness D-QIV LP Adult 1 1.0 1.0


Shivering D-QIV LP Adult 7 3.0 3.0


Swelling D-QIV LP Adult 4 2.8 2.5


Fever D-QIV LP Adult 2 1.5 1.5


N = Number of subjects with the symptom and without the missing confirmed grade *Gastrointestinal symptoms = nausea, vomiting, diarrhoea and/or abdominal pain

Primary Outcome Results: Number (%) of subjects aged 18-49 years reporting solicited ORS like symptoms during the 3-day (Days 0-2) post-vaccination period (Adult-Total Vaccinated cohort)


95 % CI 95 % CI



Chest Tightness Any 59 0 0.0 0.0 6.1 60 0 0.0 0.0 6.0

Grade 3 59 0 0.0 0.0 6.1 60 0 0.0 0.0 6.0

Related 59 0 0.0 0.0 6.1 60 0 0.0 0.0 6.0

Cough Any 59 2 3.4 0.4 11.7 60 3 5.0 1.0 13.9

Grade 3 59 0 0.0 0.0 6.1 60 0 0.0 0.0 6.0

Related 59 1 1.7 0.0 9.1 60 3 5.0 1.0 13.9

Difficulty Breathing Any 59 0 0.0 0.0 6.1 60 0 0.0 0.0 6.0

Grade 3 59 0 0.0 0.0 6.1 60 0 0.0 0.0 6.0

Related 59 0 0.0 0.0 6.1 60 0 0.0 0.0 6.0

Hoarseness Any 59 1 1.7 0.0 9.1 60 1 1.7 0.0 8.9

Grade 3 59 0 0.0 0.0 6.1 60 0 0.0 0.0 6.0

Related 59 1 1.7 0.0 9.1 60 1 1.7 0.0 8.9

Red Eyes Any 59 1 1.7 0.0 9.1 60 1 1.7 0.0 8.9

Grade 3 59 0 0.0 0.0 6.1 60 0 0.0 0.0 6.0

Related 59 0 0.0 0.0 6.1 60 1 1.7 0.0 8.9

Sore Throat Any 59 2 3.4 0.4 11.7 60 4 6.7 1.8 16.2

Grade 3 59 0 0.0 0.0 6.1 60 0 0.0 0.0 6.0

Related 59 1 1.7 0.0 9.1 60 3 5.0 1.0 13.9

Swallowing Difficulty Any 59 1 1.7 0.0 9.1 60 3 5.0 1.0 13.9

Grade 3 59 0 0.0 0.0 6.1 60 0 0.0 0.0 6.0

Related 59 0 0.0 0.0 6.1 60 2 3.3 0.4 11.5

Swelling of the face Any 59 0 0.0 0.0 6.1 60 0 0.0 0.0 6.0

Grade 3 59 0 0.0 0.0 6.1 60 0 0.0 0.0 6.0

Related 59 0 0.0 0.0 6.1 60 0 0.0 0.0 6.0

Wheezing Any 59 0 0.0 0.0 6.1 60 0 0.0 0.0 6.0

Grade 3 59 0 0.0 0.0 6.1 60 0 0.0 0.0 6.0

Related 59 0 0.0 0.0 6.1 60 0 0.0 0.0 6.0

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 ORS symptom regardless of intensity grade or relationship to vaccination. Grade 3 = ORS symptoms that prevented normal activities. Related = ORS symptom assessed by the investigator as causally related to the vaccination. Primary Outcome Results: Number (%) of subjects aged 18-49 years reporting the occurrence of MAEs during the entire study period (Adult-Total Vaccinated cohort)

Most frequent adverse events - On-Therapy (occurring within approximately 21 days following vaccination)

D-QIV LP Adult Group N = 60

D-QIV IP Adult Group N = 60

Subjects with any AE(s), n (%) 8 (13.3) 9 (15.0)

Subjects with grade 3 AE(s), n (%) 1 (1.7) 3 (5.0) Subjects with related AE(s), n (%) 0 (0.0) 0 (0.0)

Gastroenteritis 2 (3.3) 1 (1.7)

Nasopharyngitis 2 (3.3) - Back pain 1 (1.7) 1 (1.7)

Bronchitis 1 (1.7) 1 (1.7)

Allergy to arthropod bite 1 (1.7) -

Arthropod bite 1 (1.7) - Hypersensitivity - 1 (1.7)

Intervertebral disc protrusion - 1 (1.7)

Joint injury - 1 (1.7) Otitis media - 1 (1.7)

Post procedural inflammation 1 (1.7) -

Sinusitis 1 (1.7) - Spinal disorder - 1 (1.7)

Tonsillitis - 1 (1.7)

-: MAE absent Primary Outcome Results: Adjusted GMT ratios of Flu A/H1N1, Flu A/H3N2, Flu B/Yamagata, Flu B/Victoria HI antibodies between groups (D-QIV LP 3-17y/ D-QIV IP 3-17y) 28 days post last vaccination in subjects aged 3-17 years (Pediatric - ATP cohort for immunogenicity)

Adjusted GMT ratio (D-QIV LP 3-17y Group / D-QIV IP 3-17y Group)

D-QIV LP 3-17y Group D-QIV IP 3-17y Group 95% CI

Antibody N Adjusted GMT

N Adjusted GMT

Value LL UL

Flu A/H1N1 402 684.9 403 707.3 0.97 0.85 1.11

Flu A/H3N2 402 168.8 403 160.6 1.05 0.94 1.18 Flu B/Yamagata 402 509.4 403 496.0 1.03 0.91 1.16

Flu B/Victoria 402 250.4 403 240.8 1.04 0.90 1.21

Adjusted GMT = geometric mean antibody titre adjusted for baseline titre 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 baseline titre - pooled variance); LL = lower limit, UL = upper limit

Primary Outcome Results: Number (%) of subjects aged 3-17 years reporting solicited local AEs during the 7-day (Days 0-6) post-vaccination period (Pediatric-Total Vaccinated cohort)

D-QIV IP 3-17y Group D-QIV LP 3-17y Group

95 % CI 95 % CI

Symptom Intensity N n % LL UL N n % LL UL Dose 1

Pain Any 410 243 59.3 54.3 64.1 410 253 61.7 56.8 66.4

Grade 3 410 14 3.4 1.9 5.7 410 20 4.9 3.0 7.4

Redness Any 410 118 28.8 24.4 33.4 410 119 29.0 24.7 33.7

>50 mm 410 8 2.0 0.8 3.8 410 7 1.7 0.7 3.5

Swelling Any 410 102 24.9 20.8 29.4 410 100 24.4 20.3 28.8

>50 mm 410 7 1.7 0.7 3.5 410 7 1.7 0.7 3.5

Dose 2

Pain Any 103 36 35.0 25.8 45.0 99 39 39.4 29.7 49.7

Grade 3 103 0 0.0 0.0 3.5 99 2 2.0 0.2 7.1

Redness Any 103 25 24.3 16.4 33.7 99 21 21.2 13.6 30.6

>50 mm 103 0 0.0 0.0 3.5 99 0 0.0 0.0 3.7

Swelling Any 103 16 15.5 9.1 24.0 99 17 17.2 10.3 26.1

>50 mm 103 1 1.0 0.0 5.3 99 0 0.0 0.0 3.7

Across doses Pain Any 410 252 61.5 56.6 66.2 410 264 64.4 59.5 69.0

Grade 3 410 14 3.4 1.9 5.7 410 21 5.1 3.2 7.7

Redness Any 410 129 31.5 27.0 36.2 410 128 31.2 26.8 36.0

>50 mm 410 8 2.0 0.8 3.8 410 7 1.7 0.7 3.5

Swelling Any 410 109 26.6 22.4 31.1 410 110 26.8 22.6 31.4

>50 mm 410 8 2.0 0.8 3.8 410 7 1.7 0.7 3.5

N = number of subjects with at least one documented dose n/% = number/percentage of subjects reporting the symptom at least once Any = occurrence of any local symptom regardless of intensity grade

Grade 3 Pain = Cried when limb was moved/spontaneously painful (

Grade 3 70 1 1.4 0.0 7.7 72 1 1.4 0.0 7.5

Related 70 6 8.6 3.2 17.7 72 8 11.1 4.9 20.7

Loss Of Appetite Any 70 9 12.9 6.1 23.0 72 14 19.4 11.1 30.5

Grade 3 70 2 2.9 0.3 9.9 72 1 1.4 0.0 7.5

Related 70 6 8.6 3.2 17.7 72 6 8.3 3.1 17.3

Fever Any# 70 5 7.1 2.4 15.9 72 7 9.7 4.0 19.0

≥38.0°C 70 4 5.7 1.6 14.0 72 7 9.7 4.0 19.0 >39.0°C 70 1 1.4 0.0 7.7 72 3 4.2 0.9 11.7

Related 70 1 1.4 0.0 7.7 72 5 6.9 2.3 15.5

≥38.0°C Related 70 1 1.4 0.0 7.7 72 5 6.9 2.3 15.5 Dose 2

Drowsiness Any 40 5 12.5 4.2 26.8 41 6 14.6 5.6 29.2

Grade 3 40 0 0.0 0.0 8.8 41 1 2.4 0.1 12.9

Related 40 3 7.5 1.6 20.4 41 4 9.8 2.7 23.1

Irritability / Fussiness Any 40 2 5.0 0.6 16.9 41 8 19.5 8.8 34.9

Grade 3 40 0 0.0 0.0 8.8 41 0 0.0 0.0 8.6

Related 40 2 5.0 0.6 16.9 41 6 14.6 5.6 29.2


Grade 3 40 0 0.0 0.0 8.8 41 0 0.0 0.0 8.6

Related 40 2 5.0 0.6 16.9 41 3 7.3 1.5 19.9

Fever Any# 40 0 0.0 0.0 8.8 41 4 9.8 2.7 23.1

≥38.0°C 40 0 0.0 0.0 8.8 41 3 7.3 1.5 19.9 >39.0°C 40 0 0.0 0.0 8.8 41 0 0.0 0.0 8.6

Related 40 0 0.0 0.0 8.8 41 2 4.9 0.6 16.5

≥38.0°C Related 40 0 0.0 0.0 8.8 41 1 2.4 0.1 12.9 Across Doses

Drowsiness Any 70 16 22.9 13.7 34.4 72 11 15.3 7.9 25.7

Grade 3 70 0 0.0 0.0 5.1 72 2 2.8 0.3 9.7

Related 70 10 14.3 7.1 24.7 72 8 11.1 4.9 20.7


Grade 3 70 1 1.4 0.0 7.7 72 1 1.4 0.0 7.5

Related 70 7 10.0 4.1 19.5 72 11 15.3 7.9 25.7


Grade 3 70 2 2.9 0.3 9.9 72 1 1.4 0.0 7.5

Related 70 8 11.4 5.1 21.3 72 8 11.1 4.9 20.7

Fever Any# 70 5 7.1 2.4 15.9 72 10 13.9 6.9 24.1

≥38.0°C 70 4 5.7 1.6 14.0 72 9 12.5 5.9 22.4 >39.0°C 70 1 1.4 0.0 7.7 72 3 4.2 0.9 11.7

Related 70 1 1.4 0.0 7.7 72 6 8.3 3.1 17.3

≥38.0°C Related 70 1 1.4 0.0 7.7 72 5 6.9 2.3 15.5

N = number of subjects with at least one documented dose n/% = number/percentage of subjects reporting the symptom at least once Any = occurrence of any general symptom regardless of intensity grade or relationship to vaccination. # Any fever = all subjects with a documented temperature of ≥ 38°C/100.4°F by any route and all subjects reporting temperature < 38°C but with missing values (MC) for at least one day during the solicited period. Grade 3 = general symptoms that prevented normal activities. Related = general symptom assessed by the investigator as causally related to the vaccination.

Primary Outcome Results: Number (%) of subjects aged 5-17 years reporting solicited general AEs reported during the 7-day (Days 0-6) post-vaccination period (Pediatric-Total Vaccinated cohort)


95 % CI 95 % CI



Dose 1 Fatigue Any 340 94 27.6 23.0 32.7 338 99 29.3 24.5 34.5

Grade 3 340 8 2.4 1.0 4.6 338 13 3.8 2.1 6.5

Related 340 65 19.1 15.1 23.7 338 70 20.7 16.5 25.4


Any 340 35 10.3 7.3 14.0 338 32 9.5 6.6 13.1

Grade 3 340 2 0.6 0.1 2.1 338 1 0.3 0.0 1.6

Related 340 18 5.3 3.2 8.2 338 16 4.7 2.7 7.6

Headache Any 340 82 24.1 19.7 29.0 338 76 22.5 18.1 27.3

Grade 3 340 3 0.9 0.2 2.6 338 9 2.7 1.2 5.0

Related 340 46 13.5 10.1 17.6 338 50 14.8 11.2 19.0

Joint Pain Any 340 34 10.0 7.0 13.7 338 38 11.2 8.1 15.1

Grade 3 340 3 0.9 0.2 2.6 338 2 0.6 0.1 2.1

Related 340 25 7.4 4.8 10.7 338 29 8.6 5.8 12.1


Any 340 70 20.6 16.4 25.3 338 84 24.9 20.3 29.8

Grade 3 340 3 0.9 0.2 2.6 338 5 1.5 0.5 3.4 Related 340 55 16.2 12.4 20.5 338 72 21.3 17.1 26.1

Shivering Any 340 20 5.9 3.6 8.9 338 29 8.6 5.8 12.1

Grade 3 340 0 0.0 0.0 1.1 338 3 0.9 0.2 2.6

Related 340 16 4.7 2.7 7.5 338 20 5.9 3.7 9.0

Fever Any# 340 12 3.5 1.8 6.1 338 9 2.7 1.2 5.0 ≥38.0°C 340 11 3.2 1.6 5.7 338 8 2.4 1.0 4.6

>39.0°C 340 0 0.0 0.0 1.1 338 0 0.0 0.0 1.1

Related 340 10 2.9 1.4 5.3 338 7 2.1 0.8 4.2

≥38.0°C Related 340 9 2.6 1.2 5.0 338 6 1.8 0.7 3.8 Dose 2

Fatigue Any 63 8 12.7 5.6 23.5 58 4 6.9 1.9 16.7

Grade 3 63 0 0.0 0.0 5.7 58 0 0.0 0.0 6.2

Related 63 4 6.3 1.8 15.5 58 4 6.9 1.9 16.7


Any 63 3 4.8 1.0 13.3 58 1 1.7 0.0 9.2 Grade 3 63 0 0.0 0.0 5.7 58 0 0.0 0.0 6.2

Related 63 0 0.0 0.0 5.7 58 0 0.0 0.0 6.2

Headache Any 63 2 3.2 0.4 11.0 58 7 12.1 5.0 23.3

Grade 3 63 0 0.0 0.0 5.7 58 0 0.0 0.0 6.2

Related 63 2 3.2 0.4 11.0 58 4 6.9 1.9 16.7

Joint Pain Any 63 2 3.2 0.4 11.0 58 4 6.9 1.9 16.7

Grade 3 63 1 1.6 0.0 8.5 58 0 0.0 0.0 6.2

Related 63 1 1.6 0.0 8.5 58 3 5.2 1.1 14.4


Any 63 3 4.8 1.0 13.3 58 9 15.5 7.3 27.4

Grade 3 63 1 1.6 0.0 8.5 58 0 0.0 0.0 6.2 Related 63 2 3.2 0.4 11.0 58 7 12.1 5.0 23.3

Shivering Any 63 2 3.2 0.4 11.0 58 2 3.4 0.4 11.9

Grade 3 63 0 0.0 0.0 5.7 58 0 0.0 0.0 6.2

Related 63 0 0.0 0.0 5.7 58 1 1.7 0.0 9.2

Fever Any# 63 3 4.8 1.0 13.3 58 0 0.0 0.0 6.2

≥38.0°C 63 2 3.2 0.4 11.0 58 0 0.0 0.0 6.2

>39.0°C 63 1 1.6 0.0 8.5 58 0 0.0 0.0 6.2

Related 63 2 3.2 0.4 11.0 58 0 0.0 0.0 6.2

≥38.0°C Related 63 1 1.6 0.0 8.5 58 0 0.0 0.0 6.2

Across Doses

Fatigue Any 340 97 28.5 23.8 33.6 338 101 29.9 25.0 35.1

Grade 3 340 8 2.4 1.0 4.6 338 13 3.8 2.1 6.5

Related 340 66 19.4 15.3 24.0 338 72 21.3 17.1 26.1


Any 340 38 11.2 8.0 15.0 338 32 9.5 6.6 13.1

Grade 3 340 2 0.6 0.1 2.1 338 1 0.3 0.0 1.6

Related 340 18 5.3 3.2 8.2 338 16 4.7 2.7 7.6

Headache Any 340 83 24.4 19.9 29.3 338 80 23.7 19.2 28.6

Grade 3 340 3 0.9 0.2 2.6 338 9 2.7 1.2 5.0

Related 340 48 14.1 10.6 18.3 338 53 15.7 12.0 20.0

Joint Pain Any 340 35 10.3 7.3 14.0 338 42 12.4 9.1 16.4

Grade 3 340 4 1.2 0.3 3.0 338 2 0.6 0.1 2.1

Related 340 25 7.4 4.8 10.7 338 32 9.5 6.6 13.1


Any 340 71 20.9 16.7 25.6 338 88 26.0 21.4 31.1

Grade 3 340 4 1.2 0.3 3.0 338 5 1.5 0.5 3.4 Related 340 56 16.5 12.7 20.8 338 76 22.5 18.1 27.3

Shivering Any 340 21 6.2 3.9 9.3 338 31 9.2 6.3 12.8

Grade 3 340 0 0.0 0.0 1.1 338 3 0.9 0.2 2.6

Related 340 16 4.7 2.7 7.5 338 21 6.2 3.9 9.3

Fever Any# 340 14 4.1 2.3 6.8 338 9 2.7 1.2 5.0 ≥38.0°C 340 12 3.5 1.8 6.1 338 8 2.4 1.0 4.6

>39.0°C 340 1 0.3 0.0 1.6 338 0 0.0 0.0 1.1

Related 340 12 3.5 1.8 6.1 338 7 2.1 0.8 4.2 ≥38.0°C Related 340 10 2.9 1.4 5.3 338 6 1.8 0.7 3.8

For each dose and overall/subject: N = number of subjects with at least one 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 *Gastrointestinal symptoms = nausea, vomiting, diarrhoea and/or abdominal pain Any = occurrence of any general symptom regardless of intensity grade or relationship to vaccination. # Any fever = all subjects with a documented temperature of ≥ 38°C/100.4°F by any route and all subjects reporting temperature < 38°C but with missing values (MC) for at least one day during the solicited period. Grade 3 = general symptoms that prevented normal activities. Related = general symptom assessed by the investigator as causally related to the vaccination.

Primary Outcome Results: Number of days with solicited local AE during the 7-day (Days 0-6) post-vaccination period in subjects aged 3-17 years (Pediatric-Total Vaccinated cohort)

Solicited symptom Dose Group N Mean Median

Pain Dose 1 D-QIV IP 3-17-y 243 2.1 2.0

D-QIV LP 3-17y 253 2.0 2.0

Dose 2 D-QIV IP 3-17y 36 1.8 1.0

D-QIV LP 3-17y 39 1.7 2.0

Redness Dose 1 D-QIV IP 3-17y 118 2.2 2.0

D-QIV LP 3-17y 119 2.2 2.0

Dose 2 D-QIV IP 3-17y 25 1.8 2.0

D-QIV LP 3-17y 21 2.1 1.0

Swelling Dose 1 D-QIV IP 3-17y 102 2.2 2.0

D-QIV LP 3-17y 100 2.4 2.0

Dose 2 D-QIV IP 3-17y 16 2.6 2.0

D-QIV LP 3-17y 17 2.6 2.0

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

Primary Outcome Results: Number of days with solicited general AE during the 7-day (Days 0-6) post-vaccination period in subjects aged 3-4 years (Pediatric-Total Vaccinated cohort)


Drowsiness Dose 1 D-QIV IP 3-4y 14 1.9 1.0

D-QIV LP 3-4y 7 2.1 1.0

Dose 2 D-QIV IP 3-4y 5 1.2 1.0

D-QIV LP 3-4y 6 2.3 2.0

Irritability / fussiness Dose 1 D-QIV IP 3-4y 9 1.6 2.0

D-QIV LP 3-4y 12 1.6 1.0

Dose 2 D-QIV IP 3-4y 2 1.0 1.0

D-QIV LP 3-4y 8 2.3 1.0

Loss of appetite Dose 1 D-QIV IP 3-4y 9 3.1 3.0

D-QIV LP 3-4y 14 2.6 2.0

Dose 2 D-QIV IP 3-4y 4 1.3 1.0

D-QIV LP 3-4y 6 4.0 4.0

Fever Dose 1 D-QIV IP 3-4y 5 2.4 2.0

D-QIV LP 3-4y 7 1.7 1.0

Dose 2 D-QIV LP 3-4y 4 1.8 1.5


Primary Outcome Results: Number of days with solicited general AE during the 7-day (Days 0-6) post-vaccination period in subjects aged 5-17 years (Pediatric-Total Vaccinated cohort)


Fatigue Dose 1 D-QIV IP 5-17y 94 2.4 2.0

D-QIV LP 5-17y 99 2.1 2.0

Dose 2 D-QIV IP 5-17y 8 1.6 1.0

D-QIV LP 5-17y 4 1.8 1.5

Gastrointestinal symptoms* Dose 1 D-QIV IP 5-17y 35 1.6 1.0

D-QIV LP 5-17y 32 1.7 1.0

Dose 2 D-QIV IP 5-17y 3 1.7 2.0

D-QIV LP 5-17y 1 1.0 1.0

Headache Dose 1 D-QIV IP 5-17y 82 1.8 1.0

D-QIV LP 5-17y 76 2.1 2.0

Dose 2 D-QIV IP 5-17y 2 2.5 2.5

D-QIV LP 5-17y 7 1.7 2.0

Joint Pain Dose 1 D-QIV IP 5-17y 34 2.1 2.0

D-QIV LP 5-17y 38 1.7 1.0

Dose 2 D-QIV IP 5-17y 2 1.0 1.0

D-QIV LP 5-17y 4 1.0 1.0

Widespread muscle ache (myalgia) Dose 1 D-QIV IP 5-17y 70 1.9 2.0

D-QIV LP 5-17y 84 1.8 1.0

Dose 2 D-QIV IP 5-17y 3 1.3 1.0

D-QIV LP 5-17y 9 1.2 1.0

Shivering Dose 1 D-QIV IP 5-17y 20 1.8 1.0

D-QIV LP 5-17y 29 1.9 1.0

Dose 2 D-QIV IP 5-17y 2 1.0 1.0

D-QIV LP 5-17y 2 1.0 1.0

Fever Dose 1 D-QIV IP 5-17y 12 1.3 1.0

D-QIV LP 5-17y 9 1.7 1.0

Dose 2 D-QIV IP 5-17y 3 1.7 2.0

N = Number of subjects with the symptom and without the missing confirmed grade *Gastrointestinal symptoms = nausea, vomiting, diarrhoea and/or abdominal pain

Primary Outcome Results: Number (%) of subjects aged 3-17 years reporting solicited ORS like symptoms reported during the 3-day (Days 0-2) post-vaccination period (Pediatric-Total Vaccinated cohort)


95 % CI 95 % CI

Symptom Intensity / Relationship N n % LL UL N n % LL UL

Dose 1 Chest Tightness Any 410 2 0.5 0.1 1.8 410 6 1.5 0.5 3.2

Grade 3 410 0 0.0 0.0 0.9 410 0 0.0 0.0 0.9

Related 410 0 0.0 0.0 0.9 410 3 0.7 0.2 2.1

Cough Any 410 35 8.5 6.0 11.7 410 31 7.6 5.2 10.6

Grade 3 410 2 0.5 0.1 1.8 410 1 0.2 0.0 1.4

Related 410 12 2.9 1.5 5.1 410 10 2.4 1.2 4.4


Grade 3 410 0 0.0 0.0 0.9 410 0 0.0 0.0 0.9

Related 410 2 0.5 0.1 1.8 410 7 1.7 0.7 3.5

Hoarseness Any 410 10 2.4 1.2 4.4 410 12 2.9 1.5 5.1

Grade 3 410 0 0.0 0.0 0.9 410 0 0.0 0.0 0.9

Related 410 2 0.5 0.1 1.8 410 6 1.5 0.5 3.2

Red Eyes Any 410 14 3.4 1.9 5.7 410 12 2.9 1.5 5.1

Grade 3 410 0 0.0 0.0 0.9 410 0 0.0 0.0 0.9

Related 410 6 1.5 0.5 3.2 410 9 2.2 1.0 4.1

Sore Throat Any 410 14 3.4 1.9 5.7 410 18 4.4 2.6 6.8

Grade 3 410 1 0.2 0.0 1.4 410 0 0.0 0.0 0.9

Related 410 2 0.5 0.1 1.8 410 9 2.2 1.0 4.1


Grade 3 410 0 0.0 0.0 0.9 410 0 0.0 0.0 0.9

Related 410 1 0.2 0.0 1.4 410 3 0.7 0.2 2.1


Grade 3 410 0 0.0 0.0 0.9 410 0 0.0 0.0 0.9

Related 410 3 0.7 0.2 2.1 410 2 0.5 0.1 1.8

Wheezing Any 410 1 0.2 0.0 1.4 410 5 1.2 0.4 2.8

Grade 3 410 0 0.0 0.0 0.9 410 0 0.0 0.0 0.9

Related 410 1 0.2 0.0 1.4 410 4 1.0 0.3 2.5

Dose 2


Grade 3 103 0 0.0 0.0 3.5 99 0 0.0 0.0 3.7

Related 103 0 0.0 0.0 3.5 99 0 0.0 0.0 3.7

Cough Any 103 6 5.8 2.2 12.2 99 13 13.1 7.2 21.4

Grade 3 103 0 0.0 0.0 3.5 99 2 2.0 0.2 7.1

Related 103 1 1.0 0.0 5.3 99 1 1.0 0.0 5.5


Grade 3 103 0 0.0 0.0 3.5 99 0 0.0 0.0 3.7

Related 103 0 0.0 0.0 3.5 99 0 0.0 0.0 3.7

Hoarseness Any 103 2 1.9 0.2 6.8 99 3 3.0 0.6 8.6

Grade 3 103 0 0.0 0.0 3.5 99 0 0.0 0.0 3.7

Related 103 1 1.0 0.0 5.3 99 0 0.0 0.0 3.7

Red Eyes Any 103 0 0.0 0.0 3.5 99 1 1.0 0.0 5.5

Grade 3 103 0 0.0 0.0 3.5 99 1 1.0 0.0 5.5

Related 103 0 0.0 0.0 3.5 99 1 1.0 0.0 5.5

Sore Throat Any 103 2 1.9 0.2 6.8 99 3 3.0 0.6 8.6

Grade 3 103 0 0.0 0.0 3.5 99 1 1.0 0.0 5.5

Related 103 0 0.0 0.0 3.5 99 0 0.0 0.0 3.7


Grade 3 103 0 0.0 0.0 3.5 99 1 1.0 0.0 5.5

Related 103 1 1.0 0.0 5.3 99 0 0.0 0.0 3.7


Grade 3 103 0 0.0 0.0 3.5 99 0 0.0 0.0 3.7

Related 103 0 0.0 0.0 3.5 99 0 0.0 0.0 3.7

Wheezing Any 103 0 0.0 0.0 3.5 99 2 2.0 0.2 7.1

Grade 3 103 0 0.0 0.0 3.5 99 0 0.0 0.0 3.7

Related 103 0 0.0 0.0 3.5 99 0 0.0 0.0 3.7

Across Doses


Grade 3 410 0 0.0 0.0 0.9 410 0 0.0 0.0 0.9

Related 410 0 0.0 0.0 0.9 410 3 0.7 0.2 2.1

Cough Any 410 39 9.5 6.9 12.8 410 39 9.5 6.9 12.8

Grade 3 410 2 0.5 0.1 1.8 410 3 0.7 0.2 2.1

Related 410 13 3.2 1.7 5.4 410 11 2.7 1.3 4.7


Grade 3 410 0 0.0 0.0 0.9 410 0 0.0 0.0 0.9

Related 410 2 0.5 0.1 1.8 410 7 1.7 0.7 3.5

Hoarseness Any 410 11 2.7 1.3 4.7 410 15 3.7 2.1 6.0

Grade 3 410 0 0.0 0.0 0.9 410 0 0.0 0.0 0.9

Related 410 3 0.7 0.2 2.1 410 6 1.5 0.5 3.2

Red Eyes Any 410 14 3.4 1.9 5.7 410 13 3.2 1.7 5.4

Grade 3 410 0 0.0 0.0 0.9 410 1 0.2 0.0 1.4

Related 410 6 1.5 0.5 3.2 410 10 2.4 1.2 4.4

Sore Throat Any 410 15 3.7 2.1 6.0 410 21 5.1 3.2 7.7

Grade 3 410 1 0.2 0.0 1.4 410 1 0.2 0.0 1.4

Related 410 2 0.5 0.1 1.8 410 9 2.2 1.0 4.1


Grade 3 410 0 0.0 0.0 0.9 410 1 0.2 0.0 1.4

Related 410 2 0.5 0.1 1.8 410 3 0.7 0.2 2.1


Grade 3 410 0 0.0 0.0 0.9 410 0 0.0 0.0 0.9

Related 410 3 0.7 0.2 2.1 410 2 0.5 0.1 1.8

Wheezing Any 410 1 0.2 0.0 1.4 410 7 1.7 0.7 3.5

Grade 3 410 0 0.0 0.0 0.9 410 0 0.0 0.0 0.9

Related 410 1 0.2 0.0 1.4 410 4 1.0 0.3 2.5

N = number of subjects with at least one documented dose n/% = number/percentage of subjects reporting the symptom at least once Any = occurrence of any ORS symptom regardless of intensity grade or relationship to vaccination. Grade 3 = ORS symptoms that prevented normal activities. Related = ORS symptom assessed by the investigator as causally related to the vaccination.

Primary Outcome Results: Number (%) of subjects aged 3-17 years reporting the occurrence of all MAEs during the entire study period (Pediatric-Total Vaccinated cohort)

Most frequent adverse events - On-Therapy (occurring within approximately 28/56* days following vaccination)

D-QIV IP 3-17y Group N = 410

D-QIV LP 3-17y Group N = 411

Subjects with any AE(s), n (%) 59 (14.4) 52 (12.7) Subjects with grade 3 AE(s), n (%) 7 (1.7) 6 (1.5)

Subjects with related AE(s), n (%) 2 (0.5) 0 (0.0)

Upper respiratory tract infection 4 (1.0) 8 (1.9) Bronchitis 7 (1.7) 4 (1.0)

Pharyngitis 6 (1.5) 4 (1.0)

Nasopharyngitis 5 (1.2) 4 (1.0) Cough 4 (1.0) 4 (1.0)

Gastroenteritis - 5 (1.2)

Rhinitis - 5 (1.2)

Tonsillitis 3 (0.7) 2 (0.5) Laryngitis 2 (0.5) 2 (0.5)

Pharyngotonsillitis 2 (0.5) 2 (0.5)

Tracheitis 2 (0.5) 2 (0.5) Ear infection - 3 (0.7)

Viral infection 3 (0.7) -

Abdominal pain 2 (0.5) -

Dermatitis - 2 (0.5) Impetigo 2 (0.5) -

Oral herpes - 2 (0.5)

Oropharyngeal pain - 2 (0.5) Otitis media 2 (0.5) -

Otitis media acute 2 (0.5) -

Pharyngitis streptococcal 2 (0.5) - Sinusitis - 2 (0.5)

Vomiting 2 (0.5) -

-: 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. 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 are listed. *Approximately 28 days for subjects aged 9 to 17 years and 28 days or 56 days for each subject aged 6 months to 8 years depending on their vaccine-priming status. Primary Outcome Results: Adjusted GMT ratios of Flu A/H1N1, Flu A/H3N2, Flu B/Yamagata, Flu B/Victoria HI antibodies between groups (D-QIV LP 6-35m/ D-QIV IP 6-35m) 28 days post last vaccination in subjects aged 6-35 months (Pediatric - ATP cohort for immunogenicity)

Adjusted GMT ratio (D-QIV LP 6-35m Group / D-QIV IP 6-35m Group)

D-QIV LP 6-35m Group

D-QIV IP 6-35m Group 95% CI

Antibody N Adjusted GMT

N Adjusted GMT

Value LL UL

Flu A/H1N1 424 105.3 431 98.0 1.07 0.90 1.28 Flu A/H3N2 423 56.3 431 47.7 1.18 1.00 1.39

Flu B/Yamagata 423 106.4 431 99.2 1.07 0.91 1.27

Flu B/Victoria 423 37.7 431 32.2 1.17 0.99 1.38

Adjusted GMT = geometric mean antibody titre adjusted for baseline titre 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 baseline titre - pooled variance); LL = lower limit, UL = upper limit

Primary Outcome Results: Percentage and Relative Risk between groups (D-QIV IP 6-35m/ D-QIV LP 6-35m) of subjects with fever ≥ 38°C (100.4°F) during the 7 days (Day 0-Day 6) post-vaccination period after Dose 1 or after Dose 2 (across doses) in subjects aged 6-35 months (Pediatric-Total Vaccinated cohort)

Relative Risk (D-QIV IP 6-35m Group

over D-QIV LP 6-35m Group)

D-QIV IP 6-35m Group D-QIV LP 6-35m Group 95% CI Symptoms Type N n % N n % RR LL UL P-value

Fever Any 462 76 16.5 470 70 14.9 1.10 0.82 1.49 0.5292

≥38°C 462 72 15.6 470 69 14.7 1.06 0.78 1.44 0.7154

N = Number of subjects with the documented dose n/% = number/percentage of subjects reporting a specified symptom 95% CI = Standardized asymptotic 95% confidence interval , LL = Lower Limit, UL = Upper Limit P-value = 2-sided Fisher Exact Test Any = all subjects with a documented temperature of ≥ 38°C/100.4°F by any route and all subjects reporting temperature < 38°C but with missing values (MC) for at least one day during the solicited period. Secondary Outcome Results: Flu A/H1N1, A/H3N2, B/Yamagata, B/Victoria HI antibody parameters (S+,SPR, GMT, SCR, MGI) at Day 0 and Day 21 in subjects aged 18-49 years (Adult - ATP cohort for immunogenicity)

N S+ SPR GMT N’ SCR MGI

95%CI 95%CI 95%CI 95%CI 95%CI

Antibody Group Timing n’’ % LL UL n % LL UL Value

LL UL n’ % LL UL Value

LL UL

Flu A/H1N1 D-QIV LP Adult

PRE(D0) 58 51 87.9 76.7

95.0 35 60.3 46.6

73.0

53.6 36.8 78.0 - -

PI(D21) 57 57 100 93.7

100 57 100 93.7

100 632.2 498.8

801.3

57 42 73.7 60.3

84.5

11.5 7.7 17.0

D-QIV IP Adult

PRE(D0) 57 51 89.5 78.5

96.0 35 61.4 47.6

74.0

48.3 33.4 69.7 - -

PI(D21) 57 57 100 93.7

100 56 98.2 90.6

100 655.7 493.1

871.9

57 42 73.7 60.3

84.5

13.6 8.9 20.8

Flu A/H3N2 D-QIV LP PRE(D0) 58 41 70.7 57. 81.9 14 24.1 13. 37. 16.0 11.9 21.5 - -

Adult 3 9 2

PI(D21) 57 57 100 93.7

100 49 86.0 74.2

93.7

73.0 59.0 90.5 57 29 50.9 37.3

64.4

4.6 3.6 5.7

D-QIV IP Adult

PRE(D0) 57 44 77.2 64.2

87.3 15 26.3 15.5

39.7

16.7 12.6 22.2 - -

PI(D21) 57 57 100 93.7

100 49 86.0 74.2

93.7

80.5 63.2 102.7

57 30 52.6 39.0

66.0

4.8 3.6 6.5

Flu B/Yamagata

D-QIV LP Adult

PRE(D0) 58 57 98.3 90.8

100 50 86.2 74.6

93.9

101.6 76.2 135.4

- -

PI(D21) 57 57 100 93.7

100 57 100 93.7

100 598.6 480.9

745.0

57 36 63.2 49.3

75.6

6.0 4.3 8.2

D-QIV IP Adult

PRE(D0) 57 55 96.5 87.9

99.6 52 91.2 80.7

97.1

133.3 98.4 180.6

- -

PI(D21) 57 57 100 93.7

100 57 100 93.7

100 591.4 475.1

736.3

57 27 47.4 34.0

61.0

4.4 3.3 6.0

Flu B/Victoria D-QIV LP Adult

PRE(D0) 58 49 84.5 72.6

92.7 32 55.2 41.5

68.3

34.8 25.2 48.1 - -

PI(D21) 57 57 100 93.7

100 57 100 93.7

100 302.9 244.0

376.1

57 40 70.2 56.6

81.6

8.6 6.0 12.3

D-QIV IP Adult

PRE(D0) 57 54 94.7 85.4

98.9 34 59.6 45.8

72.4

38.6 29.5 50.5 - -

PI(D21) 57 57 100 93.7

100 57 100 93.7

100 263.4 209.0

331.9

57 36 63.2 49.3

75.6

6.8 5.0 9.2

Seroconversion defined as: For initially seronegative subjects, antibody titer ≥ 1:40 at post-vaccination For initially seropositive subjects, antibody titer at post-vaccination ≥ 4 fold the pre-vaccination antibody titer GMT=geometric mean antibody titer calculated on all subjects MGI=geometric mean of the within-subject ratios of the post-vaccination reciprocal HI titer to the Day 0 reciprocal HI titer N =Number of subjects with results available (for seropositivity rates, SPR and GMT computation) N’=Number of subjects with both pre and post results available (for SCR and MGI computation) n’’/%= number/percentage of subjects with titre equal to or above specified value n/% = Number/percentage of seroprotected subjects n’/% = Number/percentage of seroconverted subjects 95% CI = 95% confidence interval: LL = Lower Limit UL = Upper Limit PRE(D0) = Pre-vaccination at Day 0 PI(D21) = Day 21 post-vaccination dose 1

Secondary Outcome Results: Percentage and Relative Risk between groups (D-QIV IP 5-17y/ D-QIV LP 5-17y) of subjects with myalgia during the 7 days (Days 0-6) post-vaccination period after Dose 1 or Dose 2 (across doses) in subjects aged 5-17 years (Pediatric-Total Vaccinated cohort)

Relative Risk (D-QIV IP 5-17y Group over

D-QIV LP 5-17y Group)

D-QIV IP 5-17y Group

D-QIV LP 5-17y Group

95% CI

Symptoms Intensity N n % N n % RR LL UL P-value

Widespread muscle ache (myalgia) Any 340 71 20.9 338 88 26.0 0.80 0-.58 1.11 0.1914

N = Number of subjects with the documented dose n/% = number/percentage of subjects reporting a specified symptom 95% CI = Standardized asymptotic 95% confidence interval , LL = Lower Limit, UL = Upper Limit P-value = 2-sided Fisher Exact Test Any = occurrence of any myalgia symptom regardless of intensity grade or relationship to vaccination. Secondary Outcome Results: Flu A/H1N1, A/H3N2, B/Yamagata, B/Victoria HI antibody parameters (S+, SPR, GMT, SCR, MGI) at Day 0 and Day 28 post last vaccination in subjects aged 3-17 years (Pediatric - ATP cohort for immunogenicity)


95%CI 95%CI 95%CI 95%CI 95%CI

Antibody Group Timing n’’ % LL UL n % LL UL Valu

e LL UL n’ % LL UL Valu

e LL UL

Flu A/H1N1 D-QIV IP 3-17 y

PRE(D0)

403 354 87.8

84.2

90.9

308 76.4

72.0

80.5

80.2 69.2 93.0 - -

PII(D28) 403 402 99.8

98.6

100 393 97.5

95.5

98.8

698.0 629.6

773.9

403 274 68.0

63.2

72.5

8.7 7.6 10.0

D-QIV LP 3-17 y

PRE(D0)

402 364 90.5

87.3

93.2

314 78.1

73.7

82.1

87.7 76.1 101.0

- -

PII(D28) 402 401 99.8

98.6

100 395 98.3

96.4

99.3

694.1 625.8

769.7

402 269 66.9

62.1

71.5

7.9 6.9 9.1

Flu A/H3N2 D-QIV IP 3-17 y

PRE(D0)

403 346 85.9

82.1

89.1

245 60.8

55.8

65.6

38.9 34.6 43.8 - -

PII(D28) 403 400 99.3

97.8

99.8

377 93.5

90.7

95.7

158.2 143.7

174.2

403 192 47.6

42.7

52.6

4.1 3.7 4.5

D-QIV LP 3-17 y

PRE(D0)

402 345 85.8

82.0

89.1

252 62.7

57.8

67.4

41.9 37.1 47.3 - -

PII(D28) 402 401 99.8

98.6

100 378 94.0

91.2

96.1

171.4 156.3

188.0

402 183 45.5

40.6

50.5

4.1 3.7 4.6

Flu B/Yamagata

D-QIV IP 3-17 y

PRE(D0)

403 325 80.6

76.4

84.4

266 66.0

61.2

70.6

58.1 49.7 68.0 - -

PII(D28) 403 403 100 99.1

100 396 98.3

96.5

99.3

479.0 434.1

528.5

403 273 67.7

62.9

72.3

8.2 7.2 9.4

D-QIV LP 3-17 y

PRE(D0)

402 333 82.8

78.8

86.4

281 69.9

65.2

74.3

70.8 60.4 83.0 - -

PII(D28) 402 401 99.8

98.6

100 395 98.3

96.4

99.3

527.6 475.5

585.3

402 268 66.7

61.8

71.3

7.4 6.5 8.5

Flu B/Victoria D-QIV IP 3-17 y

PRE(D0)

403 285 70.7

66.0

75.1

192 47.6

42.7

52.6

27.3 23.8 31.3 - -

PII(D28) 403 398 98.8

97.1

99.6

375 93.1

90.1

95.3

237.6 210.4

268.3

403 285 70.7

66.0

75.1

8.7 7.7 9.8

D-QIV LP 3-17 y

PRE(D0)

402 287 71.4

66.7

75.8

195 48.5

43.5

53.5

28.8 25.0 33.1 - -

PII(D28) 402 394 98.0

96.1

99.1

374 93.0

90.1

95.3

253.7 222.7

289.1

402 287 71.4

66.7

75.8

8.8 7.7 10.0

Seroconversion defined as: For initially seronegative subjects, antibody titer ≥ 40 1/DIL at post-vaccination For initially seropositive subjects, antibody titer at post-vaccination ≥ 4 fold the pre-vaccination antibody titer GMT=geometric mean antibody titer calculated on all subjects MGI=geometric mean of the within-subject ratios of the post-vaccination reciprocal HI titer to the Day 0 reciprocal HI titer N =Number of subjects with results available (for seropositivity rates, SPR and GMT computation) N’=Number of subjects with both pre and post results available (for SCR and MGI computation) n’’/%= number/percentage of subjects with titre equal to or above specified value n/% = Number/percentage of seroprotected subjects n’/% = Number/percentage of seroconverted subjects 95% CI = 95% confidence interval: LL = Lower Limit UL = Upper Limit PRE(D0) = Pre-vaccination at Day 0 PII(D28) = Day 28 post-vaccination (Day 28 for primed subjects and Day 56 for unprimed subjects)

Secondary Outcome Results: Flu A/H1N1, A/H3N2, B/Yamagata, B/Victoria HI antibody parameters (S+, SPR, GMT, SCR, MGI) 28 days post last vaccination in subjects aged 6-35 months (Pediatric - ATP cohort for immunogenicity)


95%CI 95%CI 95%CI 95%CI 95%CI

Antibody Group Timing n’’ % LL UL n % LL UL Value

LL UL n’ % LL UL Value

LL UL

Flu A/H1N1 D-QIV IP 6-35m

PRE(D0)

431 109 25.3 21.3

29.7

84 19.5

15.9

23.5

11.1 9.6 12.8 - -

PII(D28) 432 406 94.0 91.3

96.0

303

70.1

65.6

74.4

97.5 82.1

115.7

431

287

66.6

61.9

71.0

8.8 7.8 10.0

D-QIV LP 6-35 m

PRE(D0)

424 111 26.2 22.1

30.6

83 19.6

15.9

23.7

11.2 9.7 12.9 - -

PII(D28) 427 408 95.6 93.1

97.3

289

67.7

63.0

72.1

105.5

88.2

126.1

424

275

64.9

60.1

69.4

9.5 8.3 10.8

Flu A/H3N2 D-QIV IP 6-35 m

PRE(D0)

431 79 18.3 14.8

22.3

55 12.8

9.8 16.3

7.5 6.8 8.2 - -

PII(D28) 432 388 89.8 86.6

92.5

232

53.7

48.9

58.5

45.2 39.0

52.3 431

217

50.3

45.5

55.2

6.0 5.4 6.8

D-QIV LP 6-35 m

PRE(D0)

423 91 21.5 17.7

25.7

67 15.8

12.5

19.7

8.4 7.5 9.3 - -

PII(D28) 427 403 94.4 91.8

96.4

259

60.7

55.8

65.3

59.9 51.7

69.4 423

236

55.8

50.9

60.6

7.1 6.3 7.9

Flu B/Yamagata

D-QIV IP 6-35 m

PRE(D0)

431 105 24.4 20.4

28.7

53 12.3

9.3 15.8

8.3 7.5 9.1 - -

PII(D28) 432 415 96.1 93.8

97.7

329

76.2

71.9

80.1

100.8

87.8

115.8

431

318

73.8

69.4

77.9

12.2 10.8

13.8

D-QIV LP 6-35 m

PRE(D0)

423 99 23.4 19.4

27.7

49 11.6

8.7 15.0

7.9 7.2 8.6 - -

PII(D28) 427 409 95.8 93.4

97.5

331

77.5

73.3

81.4

105.4

91.8

121.0

423

321

75.9

71.5

79.9

13.3 11.8

15.0

Flu B/Victoria

D-QIV IP 6-35 m

PRE(D0)

431 30 7.0 4.7 9.8 17 3.9 2.3 6.2 5.7 5.4 6.1 - -

PII(D28) 432 359 83.1 79.2

86.5

214

49.5

44.7

54.4

32.1 28.1

36.7 431

213

49.4

44.6

54.2

5.6 5.0 6.3

D-QIV LP 6-35 m

PRE(D0)

423 30 7.1 4.8 10.0

16 3.8 2.2 6.1 5.7 5.4 6.1 - -

PII(D28) 427 366 85.7 82.0

88.9

217

50.8

46.0

55.7

38.0 33.2

43.5 423

211

49.9

45.0

54.8

6.6 5.8 7.4

Seroconversion defined as: For initially seronegative subjects, antibody titer ≥ 1:40 at post-vaccination For initially seropositive subjects, antibody titer at post-vaccination ≥ 4 fold the pre-vaccination antibody titer GMT=geometric mean antibody titer calculated on all subjects MGI=geometric mean of the within-subject ratios of the post-vaccination reciprocal HI titer to the Day 0 reciprocal HI titer N =Number of subjects with results available (for seropositivity rates, SPR and GMT computation) N’=Number of subjects with both pre and post results available (for SCR and MGI computation) n’’/%= number/percentage of subjects with titre equal to or above specified value n/% = Number/percentage of seroprotected subjects n’/% = Number/percentage of seroconverted subjects 95% CI = 95% confidence interval: LL = Lower Limit UL = Upper Limit PRE(D0) = activity 10 VISIT D0 PII(D28) = VISIT at Day 28 post-vaccination (Day 28 for primed subjects and Day 56 for unprimed subjects)

Secondary Outcome Results: Percentage and Relative Risk between groups (FLU D-QIV IP/FLU D-QIV LP) of subjects with fever ≥ 38°C (100.4°F) during the 7 days (Day 0-Day 6) post-vaccination period after Dose 1 and after Dose 2 in subjects aged 6-35 months (Pediatric-Total Vaccinated cohort)

Relative Risk (D-QIV IP 6-35m Group over

D-QIV LP 6-35m Group)

D-QIV IP 6-35m Group

D-QIV LP 6-35m Group

95% CI

Symptoms Intensity N n % N n % RR LL UL P-value

Dose 1

Fever Any 462 42 9.1 470 44 9.4 0.97 0.62 1.52 0.9777

≥38.0 °C 462 39 8.4 470 42 8.9 0.94 0.59 1.50 0.8851

Dose 2

Fever Any 420 41 9.8 421 40 9.5 1.03 0.65 1.63 0.9914

≥38.0 °C 420 40 9.5 421 40 9.5 1.00 0.63 1.59 1.0000

N = Number of subjects with at least one documented dose n/% = number/percentage of subjects reporting a specified symptom 95% CI = Standardized asymptotic 95% confidence interval , LL = Lower Limit, UL = Upper Limit P-value = 2-sided Fisher Exact Test Any = all subjects with a documented temperature of ≥ 38°C/100.4°F by any route and all subjects reporting temperature < 38°C but with missing values (MC) for at least one day during the solicited period.

Secondary Outcome Results:: Percentage and Relative Risk between groups (D-QIV IP 6m-50 mm 462 0 0.0 0.0 0.8 470 0 0.0 0.0 0.8

Swelling Any 462 50 10.8 8.1 14.0 470 51 10.9 8.2 14.0

>50 mm 462 0 0.0 0.0 0.8 470 1 0.2 0.0 1.2

N = number of subjects with at least one documented dose n/% = number/percentage of subjects reporting the symptom at least once

Any = occurrence of any local symptom regardless of intensity grade Grade 3 Pain = Cried when limb was moved/spontaneously painful

Secondary Outcome Results: Number (%) of subjects aged 6-35 months reporting solicited general AEs reported during the 7-day (Days 0-6) post-vaccination period (Pediatric-Total Vaccinated cohort)

D-QIV IP 6-35m Group D-QIV LP 6-35m Group

95 % CI 95 % CI



Dose 1

Drowsiness Any 462 87 18.8 15.4 22.7 470 77 16.4 13.2 20.0

Grade 3 462 3 0.6 0.1 1.9 470 7 1.5 0.6 3.0

Related 462 54 11.7 8.9 15.0 470 50 10.6 8.0 13.8


Grade 3 462 10 2.2 1.0 3.9 470 10 2.1 1.0 3.9

Related 462 75 16.2 13.0 19.9 470 58 12.3 9.5 15.7


Grade 3 462 9 1.9 0.9 3.7 470 8 1.7 0.7 3.3

Related 462 47 10.2 7.6 13.3 470 40 8.5 6.1 11.4

Fever Any# 462 42 9.1 6.6 12.1 470 44 9.4 6.9 12.4

≥38.0°C 462 39 8.4 6.1 11.4 470 42 8.9 6.5 11.9 >39.0°C 462 8 1.7 0.8 3.4 470 5 1.1 0.3 2.5

Related 462 16 3.5 2.0 5.6 470 23 4.9 3.1 7.3

≥38.0°C Related 462 14 3.0 1.7 5.0 470 22 4.7 3.0 7.0

Dose 2

Drowsiness Any 420 63 15.0 11.7 18.8 421 58 13.8 10.6 17.4

Grade 3 420 6 1.4 0.5 3.1 421 7 1.7 0.7 3.4

Related 420 46 11.0 8.1 14.3 421 35 8.3 5.9 11.4


Grade 3 420 5 1.2 0.4 2.8 421 8 1.9 0.8 3.7

Related 420 59 14.0 10.9 17.7 421 50 11.9 8.9 15.4


Grade 3 420 4 1.0 0.3 2.4 421 10 2.4 1.1 4.3

Related 420 39 9.3 6.7 12.5 421 37 8.8 6.3 11.9

Fever Any# 420 41 9.8 7.1 13.0 421 40 9.5 6.9 12.7

≥38.0°C 420 40 9.5 6.9 12.7 421 40 9.5 6.9 12.7 >39.0°C 420 10 2.4 1.1 4.3 421 9 2.1 1.0 4.0

Related 420 19 4.5 2.7 7.0 421 17 4.0 2.4 6.4

≥38.0°C Related 420 19 4.5 2.7 7.0 421 17 4.0 2.4 6.4

Across Doses Drowsiness Any 462 115 24.9 21.0 29.1 470 103 21.9 18.3 25.9

Grade 3 462 8 1.7 0.8 3.4 470 13 2.8 1.5 4.7

Related 462 78 16.9 13.6 20.6 470 66 14.0 11.0 17.5


Grade 3 462 15 3.2 1.8 5.3 470 17 3.6 2.1 5.7

Related 462 98 21.2 17.6 25.2 470 87 18.5 15.1 22.3


Grade 3 462 13 2.8 1.5 4.8 470 17 3.6 2.1 5.7

Related 462 69 14.9 11.8 18.5 470 61 13.0 10.1 16.4

Fever Any# 462 76 16.5 13.2 20.2 470 70 14.9 11.8 18.4

≥38.0°C 462 72 15.6 12.4 19.2 470 69 14.7 11.6 18.2

>39.0°C 462 18 3.9 2.3 6.1 470 14 3.0 1.6 4.9 Related 462 32 6.9 4.8 9.6 470 35 7.4 5.2 10.2

≥38.0°C Related 462 30 6.5 4.4 9.1 470 34 7.2 5.1 10.0

N = number of subjects with at least one documented dose

n/% = number/percentage of subjects reporting the symptom at least once Any = occurrence of any general symptom regardless of intensity grade or relationship to vaccination. # Any fever = all subjects with a documented temperature of ≥ 38°C/100.4°F by any route and all subjects reporting temperature < 38°C but with missing values (MC) for at least one day during the solicited period. Grade 3 = general symptoms that prevented normal activities. Related = general symptom assessed by the investigator as causally related to the vaccination. Secondary Outcome Results: Number of days with solicited local AE during the 7-day (Days 0-6) post-vaccination period in subjects aged 6-35 months (Pediatric-Total Vaccinated cohort) Solicited symptom Dose Group N Mean Median Pain Dose 1 D-QIV IP 6-35m 69 1.6 1.0

D-QIV LP 6-35m 77 1.5 1.0

Dose 2 D-QIV IP 6-35m 47 1.8 2.0

D-QIV LP 6-35m 48 1.8 2.0

Redness Dose 1 D-QIV IP 6-35m 88 2.2 2.0

D-QIV LP 6-35m 86 2.1 2.0 Dose 2 D-QIV IP 6-35m 61 1.9 2.0

D-QIV LP 6-35m 66 2.0 2.0

Swelling Dose 1 D-QIV IP 6-35m 33 1.8 1.0

D-QIV LP 6-35m 42 1.9 1.0 Dose 2 D-QIV IP 6-35m 32 2.0 2.0

D-QIV LP 6-35m 27 2.1 2.0


Secondary Outcome Results: Number of days with solicited general AE during the 7-day (Days 0-6) post-vaccination period in subjects aged 6-35 months (Pediatric-Total Vaccinated cohort) Solicited symptom Dose Group N Mean Median

Drowsiness Dose 1 D-QIV IP 6-35-m 87 2.5 2.0

D-QIV LP 6-35m 77 2.2 2.0

Dose 2 D-QIV IP 6-35m 63 2.5 2.0

D-QIV LP 6-35m 58 2.7 2.0

Irritability / fussiness Dose 1 D-QIV IP 6-35m 124 2.4 2.0

D-QIV LP 6-35m 96 2.6 2.0

Dose 2 D-QIV IP 6-35m 87 2.5 2.0

D-QIV LP 6-35m 87 2.8 2.0

Loss of appetite Dose 1 D-QIV IP 6-35m 94 2.5 2.0

D-QIV LP 6-35m 76 2.6 2.0

Dose 2 D-QIV IP 6-35m 64 2.9 2.0

D-QIV LP 6-35m 69 2.9 2.0

Temperature Dose 1 D-QIV IP 6-35m 42 1.9 2.0

D-QIV LP 6-35 m 44 1.6 1.0

Dose 2 D-QIV IP 6-35 m 41 1.9 1.0

D-QIV LP 6-35 m 40 2.1 2.0


Secondary Outcome Results: Incidence of solicited ORS like symptoms reported during the 3-day (Days 0-2) post-vaccination period in subjects aged 6-35 months (Pediatric-Total Vaccinated cohort)

D-QIV IP 6-35m Group D-QIV LP 6-35m Group

95 % CI 95 % CI

Symptom Intensity / Relationship N n % LL UL N n % LL UL Dose 1


Grade 3 462 0 0.0 0.0 0.8 470 0 0.0 0.0 0.8

Related 462 0 0.0 0.0 0.8 470 0 0.0 0.0 0.8

Cough Any 462 47 10.2 7.6 13.3 470 50 10.6 8.0 13.8

Grade 3 462 3 0.6 0.1 1.9 470 3 0.6 0.1 1.9

Related 462 16 3.5 2.0 5.6 470 13 2.8 1.5 4.7


Grade 3 462 1 0.2 0.0 1.2 470 1 0.2 0.0 1.2

Related 462 4 0.9 0.2 2.2 470 2 0.4 0.1 1.5

Hoarseness Any 462 13 2.8 1.5 4.8 470 11 2.3 1.2 4.1

Grade 3 462 0 0.0 0.0 0.8 470 0 0.0 0.0 0.8

Related 462 1 0.2 0.0 1.2 470 4 0.9 0.2 2.2

Red Eyes Any 462 10 2.2 1.0 3.9 470 11 2.3 1.2 4.1

Grade 3 462 0 0.0 0.0 0.8 470 0 0.0 0.0 0.8

Related 462 6 1.3 0.5 2.8 470 5 1.1 0.3 2.5

Sore Throat Any 462 6 1.3 0.5 2.8 470 7 1.5 0.6 3.0

Grade 3 462 0 0.0 0.0 0.8 470 0 0.0 0.0 0.8

Related 462 1 0.2 0.0 1.2 470 3 0.6 0.1 1.9


Grade 3 462 0 0.0 0.0 0.8 470 0 0.0 0.0 0.8

Related 462 0 0.0 0.0 0.8 470 2 0.4 0.1 1.5


Grade 3 462 0 0.0 0.0 0.8 470 0 0.0 0.0 0.8

Related 462 1 0.2 0.0 1.2 470 1 0.2 0.0 1.2

Wheezing Any 462 9 1.9 0.9 3.7 470 12 2.6 1.3 4.4

Grade 3 462 1 0.2 0.0 1.2 470 1 0.2 0.0 1.2

Related 462 3 0.6 0.1 1.9 470 3 0.6 0.1 1.9

Dose 2 Chest Tightness Any 420 9 2.1 1.0 4.0 421 4 1.0 0.3 2.4

Grade 3 420 0 0.0 0.0 0.9 421 2 0.5 0.1 1.7

Related 420 0 0.0 0.0 0.9 421 1 0.2 0.0 1.3

Cough Any 420 37 8.8 6.3 11.9 421 53 12.6 9.6 16.1

Grade 3 420 5 1.2 0.4 2.8 421 3 0.7 0.1 2.1

Related 420 8 1.9 0.8 3.7 421 8 1.9 0.8 3.7


Grade 3 420 1 0.2 0.0 1.3 421 2 0.5 0.1 1.7

Related 420 5 1.2 0.4 2.8 421 3 0.7 0.1 2.1

Hoarseness Any 420 13 3.1 1.7 5.2 421 9 2.1 1.0 4.0

Grade 3 420 0 0.0 0.0 0.9 421 1 0.2 0.0 1.3

Related 420 1 0.2 0.0 1.3 421 1 0.2 0.0 1.3

Red Eyes Any 420 10 2.4 1.1 4.3 421 11 2.6 1.3 4.6

Grade 3 420 0 0.0 0.0 0.9 421 0 0.0 0.0 0.9

Related 420 6 1.4 0.5 3.1 421 1 0.2 0.0 1.3

Sore Throat Any 420 7 1.7 0.7 3.4 421 11 2.6 1.3 4.6

Grade 3 420 1 0.2 0.0 1.3 421 1 0.2 0.0 1.3

Related 420 0 0.0 0.0 0.9 421 2 0.5 0.1 1.7


Grade 3 420 2 0.5 0.1 1.7 421 1 0.2 0.0 1.3

Related 420 0 0.0 0.0 0.9 421 1 0.2 0.0 1.3


Grade 3 420 0 0.0 0.0 0.9 421 0 0.0 0.0 0.9

Related 420 1 0.2 0.0 1.3 421 1 0.2 0.0 1.3

Wheezing Any 420 11 2.6 1.3 4.6 421 16 3.8 2.2 6.1

Grade 3 420 3 0.7 0.1 2.1 421 1 0.2 0.0 1.3

Related 420 4 1.0 0.3 2.4 421 3 0.7 0.1 2.1

Across Doses Chest Tightness Any 462 10 2.2 1.0 3.9 470 5 1.1 0.3 2.5

Grade 3 462 0 0.0 0.0 0.8 470 2 0.4 0.1 1.5

Related 462 0 0.0 0.0 0.8 470 1 0.2 0.0 1.2

Cough Any 462 73 15.8 12.6 19.5 470 85 18.1 14.7 21.9

Grade 3 462 8 1.7 0.8 3.4 470 6 1.3 0.5 2.8

Related 462 22 4.8 3.0 7.1 470 18 3.8 2.3 6.0


Grade 3 462 2 0.4 0.1 1.6 470 3 0.6 0.1 1.9

Related 462 8 1.7 0.8 3.4 470 4 0.9 0.2 2.2

Hoarseness Any 462 23 5.0 3.2 7.4 470 17 3.6 2.1 5.7

Grade 3 462 0 0.0 0.0 0.8 470 1 0.2 0.0 1.2

Related 462 2 0.4 0.1 1.6 470 5 1.1 0.3 2.5

Red Eyes Any 462 18 3.9 2.3 6.1 470 19 4.0 2.5 6.2

Grade 3 462 0 0.0 0.0 0.8 470 0 0.0 0.0 0.8

Related 462 10 2.2 1.0 3.9 470 5 1.1 0.3 2.5

Sore Throat Any 462 12 2.6 1.3 4.5 470 17 3.6 2.1 5.7

Grade 3 462 1 0.2 0.0 1.2 470 1 0.2 0.0 1.2

Related 462 1 0.2 0.0 1.2 470 5 1.1 0.3 2.5


Grade 3 462 2 0.4 0.1 1.6 470 1 0.2 0.0 1.2

Related 462 0 0.0 0.0 0.8 470 3 0.6 0.1 1.9


Grade 3 462 0 0.0 0.0 0.8 470 0 0.0 0.0 0.8

Related 462 2 0.4 0.1 1.6 470 2 0.4 0.1 1.5

Wheezing Any 462 19 4.1 2.5 6.3 470 26 5.5 3.6 8.0

Grade 3 462 4 0.9 0.2 2.2 470 2 0.4 0.1 1.5

Related 462 7 1.5 0.6 3.1 470 5 1.1 0.3 2.5

N = number of subjects with at least one documented dose n/% = number/percentage of subjects reporting the symptom at least once Any = occurrence of any ORS symptom regardless of intensity grade or relationship to vaccination. Grade 3 = ORS symptoms that prevented normal activities. Related = ORS symptom assessed by the investigator as causally related to the vaccination.

Secondary Outcome Results: Number (%) of subjects reporting the occurrence of all MAEs during the entire study period in subjects aged 6-35 months (Pediatric-Total Vaccinated cohort)

Most frequent adverse events - On-Therapy (occurring within approximately 28/56* days following vaccination)

D-QIV IP 6-35m Group N = 466

D-QIV LP 6-35m Group N = 474


Subjects with any grade3 AE(s), n (%) 35 (7.5) 29 (6.1) Subjects with any related AE(s), n (%) 2 (0.4) -

Upper respiratory tract infection 60 (12.9) 66 (13.9)

Bronchitis 46 (9.9) 57 (12.0)

Gastroenteritis 29 (6.2) 34 (7.2) Nasopharyngitis 27 (5.8) 30 (6.3)

Pyrexia 21 (4.5) 20 (4.2)

Conjunctivitis 17 (3.6) 16 (3.4) Otitis media acute 19 (4.1) 14 (3.0)

Ear infection 11 (2.4) 15 (3.2)

Cough 11 (2.4) 14 (3.0)

Viral infection - 15 (3.2) Pharyngitis 13 (2.8) -

Bronchospasm 11 (2.4) -

-: 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. 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 are listed. *Approximately 28 days or 56 days following vaccination for each subject aged 6-35 months depending on their vaccine-priming status.

Secondary Outcome Results: Number(%)of subjects reporting the occurrence of unsolicited AEs classified by MedDRA Preferred Term within the 21-day (Days 0-20) post-vaccination period in subjects aged 18-49 years (Adult-Total Vaccinated cohort)

Most frequent adverse events - On-Therapy (occurring within days 0-20 following vaccination)

D-QIV LP Adult Group N = 60

D-QIV IP Adult Group N = 60


Subjects with grade 3 AE(s), n (%) 2(3.3) 3(5.0)

Subjects with related AE(s), n (%) 1 (1.7) 2 (3.3) Nasopharyngitis 4 (6.7) 1 (1.7)

Back pain 2 (3.3) 1 (1.7)

Gastroenteritis 2 (3.3) 1 (1.7) Headache 1 (1.7) 2 (3.3)

Bronchitis 1 (1.7) 1 (1.7)

Toothache 1 (1.7) 1 (1.7) Allergy to arthropod bite 1 (1.7) -

Arthropod bite 1 (1.7) -

Dysmenorrhoea 1 (1.7) -

Hypersensitivity - 1 (1.7) Injection site hypoaesthesia - 1 (1.7)

Injection site warmth - 1 (1.7)

Intervertebral disc protrusion - 1 (1.7) Joint injury - 1 (1.7)

Oropharyngeal pain 1 (1.7) -

Otitis media - 1 (1.7)

Post procedural inflammation 1 (1.7) - Rhinitis 1 (1.7) -

Sinusitis 1 (1.7) -

Spinal disorder - 1 (1.7) Tonsillitis - 1 (1.7)

- : Adverse event absent Secondary Outcome Results: Number(%) of subjects reporting the occurrence of unsolicited AEs classified by MedDRA Preferred Term within the 28-day (Days 0-27) post-vaccination period in subjects aged 3-17 years (Pediatric-Total Vaccinated cohort)


D-QIV IP 3-17y Group N = 410

D-QIV LP 3-17y Group N = 411

Subjects with any AE(s), n (%) 83(20.2) 86(20.9)


Subjects with related AE(s), n (%) 10(2.4) 7(1.7) Upper respiratory tract infection 13(3.2) 17(14.1)

Bronchitis 5(1.2) 4(1.0)

Pharyngitis 5(1.2) 4(1.0) Cough 5(1.2) 7(1.7)

Laryngitis 4(1.0) 2(0.5)

Nasopharyngitis 4(1.0) 6(1.5) Tonsillitis 4(1.0) - Viral infection 4(1.0) - Headache 4(1.0) 4(1.0)

Abdominal pain 3(0.7) - Rhinitis 3(0.7) 9(2.2)

Diarrhoea 2(0.5) 1(0.2) Vomiting 2(0.5) 3(0.7)

Pyrexia 2(0.5) 5(1.2)

Enterobiasis 2(0.5) - Gastroenteritis 2(0.5) 4(1.0)

Impetigo 2(0.5) -

Otitis media 2(0.5) 1(0.2)

Otitis media acute 2(0.5) 1(0.2)

Pharyngotonsillitis 2(0.5) 2(0.5)

Neck pain 2(0.5) - Erythema 2(0.5) -

Lymphadenitis 1(0.2) -

Lymphadenopathy 1(0.2) -

Eye pain 1(0.2) - Orbital oedema 1(0.2) -

Gastritis 1(0.2) -

Axillary pain 1(0.2) 1(0.2) Injection site bruising 1(0.2) -

Vaccination site lymphadenopathy 1(0.2) -

Acute tonsillitis 1(0.2) 1(0.2) Bronchopneumonia 1(0.2) -

Conjunctivitis 1(0.2) -

Enterovirus infection 1(0.2) -

Herpes simplex 1(0.2) 1(0.2) Infection 1(0.2) -

Meningitis viral 1(0.2) -

Molluscum contagiosum 1(0.2) - Oral herpes 1(0.2) 2(0.5)

Otitis externa 1(0.2) -

Paronychia 1(0.2) -

Periporitis staphylogenes 1(0.2) - Pertussis 1(0.2) -

Pharyngitis streptococcal 1(0.2) -

Pseudocroup 1(0.2) - Tooth abscess 1(0.2) -

Tracheitis 1(0.2) 2(0.5)

Viral upper respiratory tract infection 1(0.2) - Vulvitis 1(0.2) -

Arthropod bite 1(0.2) 3(0.7)

Contusion 1(0.2) 1(0.2)

Injury 1(0.2) - Joint injury 1(0.2) -

Laceration 1(0.2) 1(0.2)

Muscle strain 1(0.2) 1(0.2) Skin abrasion 1(0.2) -

Wound 1(0.2) -

Myalgia 1(0.2) 3(0.7)

Pain in extremity 1(0.2) - Skin papilloma 1(0.2) -

Dizziness 1(0.2) 1(0.2)

Syncope 1(0.2) - Enuresis 1(0.2) -

Dysmenorrhoea 1(0.2) -

Bronchial hyperreactivity 1(0.2) 1(0.2) Dyspnoea 1(0.2) -

Oropharyngeal pain 1(0.2) 2(0.5)

Dermatitis 1(0.2) 2(0.5)

Rhinorrhoea - 2(0.5) Ligament sprain - 2(0.5)

Pain - 2(0.5)

Eczema 1(0.2) - Urticaria 1(0.2) 1(0.2)

Otorrhoea - 1(0.2)

Vertigo - 1(0.2)

Dry eye - 1(0.2) Constipation - 1(0.2)

Enteritis - 1(0.2)

Inguinal hernia - 1(0.2)

Oral pain - 1(0.2) Stomatitis - 1(0.2)

Chest pain - 1(0.2)

Feeling hot - 1(0.2) Injection site hypersensitivity - 1(0.2)

Local swelling - 1(0.2)

Food allergy - 1(0.2) Milk allergy - 1(0.2)

Cellulitis - 1(0.2)

Cystitis - 1(0.2)

Ear infection - 3(0.7) Herpangina - 1(0.2)

Injection site pustule - 1(0.2)

Respiratory tract infection - 1(0.2) Scarlet fever - 1(0.2)

Sinusitis - 1(0.2)

Viral diarrhoea - 1(0.2)

Hand fracture - 1(0.2) Procedural pain - 1(0.2)

Hyperglycaemia - 1(0.2)

Arthralgia - 1(0.2) Asthma - 1(0.2)

Epistaxis - 1(0.2)

- : Adverse event absent Secondary Outcome Results: Number (%) of subjects reporting the occurrence of unsolicited AEs classified by MedDRA Primary System Organ Class and Preferred Term within the 28-day (Days 0-27) post-vaccination period in subjects aged 6-35 months (Pediatric-Total vaccinated cohort)


D-QIV IP 6-35m Group N = 466

D-QIV LP 6-35m Group N = 474

Subjects with any AE(s), n (%) 243(52.1) 262(55.3)


Subjects with related AE(s), n (%) 6(1.3) 3(0.6)

Upper respiratory tract infection 62(13.3) 73(15.4) Bronchitis 40(8.6) 58(12.2)

Gastroenteritis 34(7.3) 37(7.8)

Pyrexia 28(6.0) 26(5.5) Nasopharyngitis 26(5.6) 29(6.1)

Rhinitis 17(3.6) 12(2.5)

Conjunctivitis 16(3.4) 17(3.6)

Otitis media acute 16(3.4) 12(2.5) Cough 15(3.2) 19(4.0)

Pharyngitis 12(2.6) 9(1.9)

Viral infection 10(2.1) 14(3.0) Bronchospasm 10(2.1) 8(1.7)

Otitis media 8(1.7) 7(1.5)

Ear infection 7(1.5) 11(2.3)

Dermatitis diaper 7(1.5) 3(0.6)

Bronchopneumonia 6(1.3) -

Respiratory tract infection 6(1.3) 8(1.7)

Tonsillitis 6(1.3) 6(1.3)

Tracheitis 6(1.3) 6(1.3)

Diarrhoea 5(1.1) 11(2.3)

Teething 5(1.1) 2(0.4)

Vomiting 5(1.1) 8(1.7)

Bronchial hyperreactivity 5(1.1) 7(1.5)

Bronchiolitis 4(0.9) 8(1.7)

Herpangina 4(0.9) 2(0.4)

Lower respiratory tract infection 4(0.9) 1(0.2)

Asthma 4(0.9) 2(0.4)

Dermatitis 4(0.9) 2(0.4)

Constipation 3(0.6) 1(0.2)

Enteritis 3(0.6) 4(0.9)

Hand-foot-and-mouth disease 3(0.6) 5(1.1)

Laryngitis 3(0.6) 6(1.3)

Pharyngotonsillitis 3(0.6) 2(0.4)

Pneumonia 3(0.6) 4(0.9)

Respiratory tract infection viral 3(0.6) 5(1.1)

Arthropod bite 3(0.6) 1(0.2)

Toothache 2(0.4) 7(1.5)

Candida infection 2(0.4) -

Croup infectious 2(0.4) -

Fungal infection 2(0.4) -

Fungal skin infection 2(0.4) 1(0.2)

Impetigo 2(0.4) -

Rhinotracheitis 2(0.4) 3(0.6)

Roseola 2(0.4) 3(0.6)

Sinusitis 2(0.4) -

Urinary tract infection 2(0.4) 2(0.4)

Varicella 2(0.4) 3(0.6)

Thermal burn 2(0.4) -

Rhinorrhoea 2(0.4) -

Dermatitis allergic 2(0.4) 1(0.2)

Dry skin 2(0.4) -

Eczema 2(0.4) -

Rash 2(0.4) 5(1.1)

Urticaria 2(0.4) -

Lymphadenitis 1(0.2) -

Ear pain 1(0.2) 1(0.2)

Middle ear inflammation 1(0.2) -

Conjunctivitis allergic 1(0.2) -

Abdominal pain 1(0.2) 1(0.2)

Dyspepsia 1(0.2) 1(0.2)

Odynophagia 1(0.2) -

Stomatitis 1(0.2) 1(0.2)

Tooth disorder 1(0.2) 5(1.1)

Umbilical hernia 1(0.2) -

Chills 1(0.2) -

Inflammation 1(0.2) -

Pain 1(0.2) -

Vaccination site erythema 1(0.2) -

Acarodermatitis 1(0.2) -

Exanthema subitum 1(0.2) -

Gastroenteritis viral 1(0.2) -

Giardiasis 1(0.2) -

Herpes virus infection 1(0.2) -

Hordeolum 1(0.2) 1(0.2)

Lice infestation 1(0.2) -

Oral candidiasis 1(0.2) 2(0.4)

Oral herpes 1(0.2) -

Pneumonia respiratory syncytial viral 1(0.2) -

Pseudocroup 1(0.2) 1(0.2)

Rash pustular 1(0.2) -

Viral rash 1(0.2) -

Foreign body 1(0.2) -

Head injury 1(0.2) 1(0.2)

Lip injury 1(0.2) -

Traumatic haematoma 1(0.2) -

Dehydration 1(0.2) -

Iron deficiency 1(0.2) -

Lactose intolerance 1(0.2) -

Synovitis 1(0.2) 1(0.2)

Anxiety 1(0.2) -

Middle insomnia 1(0.2) -

Balanoposthitis 1(0.2) -

Allergic bronchitis 1(0.2) -

Asthmatic crisis 1(0.2) -

Oropharyngeal pain 1(0.2) 2(0.4)

Skin fissures 1(0.2) -

Pallor 1(0.2) -

Cryptorchism - 1(0.2)

Anal fissure - 1(0.2)

Inguinal hernia - 1(0.2)

Oral pain - 1(0.2)

Food allergy - 1(0.2)

Hypersensitivity - 2(0.4)

Acute tonsillitis - 1(0.2)

Candida nappy rash - 1(0.2)

Dysentery - 2(0.4)

Enterobiasis - 1(0.2)

Epstein-barr virus infection - 1(0.2)

Gianotti-crosti syndrome - 1(0.2)

Gingivitis - 1(0.2)

Haemophilus infection - 1(0.2)

Molluscum contagiosum - 1(0.2)

Myringitis - 1(0.2)

Oral fungal infection - 1(0.2)

Otitis externa - 1(0.2)

Respiratory syncytial virus bronchiolitis - 1(0.2)

Scarlet fever - 1(0.2)

Sinobronchitis - 1(0.2)

Viral tonsillitis - 1(0.2)

Bite - 1(0.2)

Contusion - 1(0.2)

Hair injury - 1(0.2)

Injury - 1(0.2)

Skeletal injury - 1(0.2)

Skin abrasion - 1(0.2)

Wound dehiscence - 1(0.2)

Weight gain poor - 1(0.2)

Melanocytic naevus - 1(0.2)

Headache - 1(0.2)

Insomnia - 1(0.2)

Allergic cough - 2(0.4)

Epistaxis - 2(0.4)

Nasal obstruction - 1(0.2)

Rhinitis allergic - 1(0.2)

Dermatitis atopic - 2(0.4)

Dermatosis - 1(0.2)

Erythema - 1(0.2)

Idiopathic urticaria - 1(0.2)

Skin hyperpigmentation - 1(0.2)

- : Adverse event absent

Secondary Outcome Results: Please refer to the ’Safety results’ section of this CTRS for the SAE table.

Safety Results: Solicited and Unsolicited AEs experienced by at least 5 % of subjects classified by MedDRA Primary System Organ Class and Preferred Term within the 21-day (Days 0-20) post-vaccination period including number of events reported - SAE excluded (Adult-Total Vaccinated cohort)

D-QIV LP adults N = 60

D-QIV IP adults N = 60

95% CI 95% CI

Primary System Organ Class (CODE) Preferred Term (CODE) n* n % LL UL n* n % LL UL

At least one symptom 114 42 70.0 56.8 81.2 162 51 85.0 73.4 92.9

Gastrointestinal disorders (10017947) Dysphagia (10013950) 1 1 1.7 0.0 8.9 3 3 5.0 1.0 13.9

Gastrointestinal disorder (10017944) 6 6 10.0 3.8 20.5 6 6 10.0 3.8 20.5

General disorders and administration site conditions (10018065)

Chills (10008531) 7 7 11.7 4.8 22.6 9 9 15.0 7.1 26.6

Fatigue (10016256) 20 20 33.3 21.7 46.7 32 32 53.3 40.0 66.3

Pain (10033371) 32 32 53.3 40.0 66.3 41 41 68.3 55.0 79.7 Swelling (10042674) 4 4 6.7 1.8 16.2 2 2 3.3 0.4 11.5

Infections and infestations (10021881) Nasopharyngitis (10028810) 4 4 6.7 1.8 16.2 1 1 1.7 0.0 8.9

Musculoskeletal and connective tissue disorders (10028395)

Arthralgia (10003239) 5 5 8.3 2.8 18.4 8 8 13.3 5.9 24.6 Myalgia (10028411) 13 13 21.7 12.1 34.2 21 21 35.0 23.1 48.4

Nervous system disorders (10029205) Headache (10019211) 17 16 26.7 16.1 39.7 32 31 51.7 38.4 64.8

Respiratory, thoracic and mediastinal disorders (10038738)

Cough (10011224) 2 2 3.3 0.4 11.5 3 3 5.0 1.0 13.9 Oropharyngeal pain (10068319) 3 3 5.0 1.0 13.9 4 4 6.7 1.8 16.2

At least one symptom = at least one symptom experienced (regardless of the MedDRA Preferred Term) N = number of subjects with the administered dose n* = number of events reported n/% = number/percentage of subjects reporting the symptom at least once 95% CI = exact 95% confidence interval; LL = Lower Limit, UL = Upper Limit

Safety Results: Solicited and Unsolicited AEs experienced by at least 5 % of subjects classified by MedDRA Primary System Organ Class and Preferred Term within the 28-day (Days 0-27) post-vaccination period including number of events reported - SAE excluded (Pediatric-Total Vaccinated cohort)

D-QIV IP 3-17 y N = 410

D-QIV LP 3-17 y N = 411

D-QIV IP 6-35 m N = 466

D-QIV LP 6-35 m N = 474

95% CI 95% CI 95% CI 95% CI

Primary System Organ Class (CODE)

Preferred Term (CODE)

n* n % LL UL n* n % LL UL n* n % LL UL n* n % LL UL

At least one symptom

1063 327 79.8 75.5 83.5 1149 324 78.8 74.6 82.7 1319 315 67.6 63.1 71.8 1344 319 67.3 62.9 71.5

Gastrointestinal disorders (10017947)

Gastrointestinal disorder (10017944)

38 38 9.3 6.6 12.5 33 32 7.8 5.4 10.8 0 0 0.0 0.0 0.8 0 0 0.0 0.0 0.8

General disorders and administration site conditions (10018065)

Chills (10008531)

22 21 5.1 3.2 7.7 31 31 7.5 5.2 10.5 1 1 0.2 0.0 1.2 0 0 0.0 0.0 0.8

Fatigue (10016256)

102 97 23.7 19.6 28.1 103 101 24.6 20.5 29.0 0 0 0.0 0.0 0.8 0 0 0.0 0.0 0.8

Pain (10033371) 279 252 61.5 56.6

(flu d-qiv) · occurrence of myalgia during the 7-day post-vaccination period (day 0 – day 6)...

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