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

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1 The study listed may include approved and non-approved uses, formulations or treatment regimens. The results reported in any single study may not reflect the overall results obtained on studies of a product. Before prescribing any product mentioned in this Register, healthcare professionals should consult prescribing information for the product approved in their country. GSK Medicine: GlaxoSmithKline (GSK) Biologicals Quadrivalent Inactivated Split Virion Influenza Vaccine 2/2, GSK22A (FLU D-QIV) Study Number: 22 (FLU D-QIV-) Title: Safety and immunogenicity study of GSK Biologicals Quadrivalent Influenza Vaccine (GSK22A) 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: August 2 to April 2 Study Design: Double-blind, controlled, multi-country, self-contained study with staggered enrolment of adult (- years) and pediatric treatment groups ( months to years). Centres: centers [ center in Bangladesh, centers in C zech Republic, centers in France, centers in Germany, centers in Poland, centers in Spain and 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 - years received dose of D-QIV_IP vaccine at Day. D-QIV_LP Adult Group: Subjects aged - years received dose of D-QIV_LP vaccine at Day. D-QIV_IP -y Group: Subjects aged - years received or 2 doses of D-QIV_IP vaccine depending on vaccine-priming status*. D-QIV_LP -y Group: Subjects aged - years received or 2 doses of D-QIV_LP vaccine depending on vaccine-priming status*. D-QIV_IP -m Group: Subjects aged - months received or 2 doses of D-QIV_IP vaccine depending on vaccine-priming status*. D-QIV_LP -m Group: Subjects aged - months received or 2 doses of D-QIV_IP vaccine depending on vaccine-priming status*. Dose of all vaccines were administered intramuscularly (IM) in the anterolateral region of left thigh for subjects below 2 months of age and in the deltoid region of left or non-dominant arm in subjects 2 months of age. Dose 2 of all vaccines were administered IM in the anterolateral region of right thigh for subjects below 2 months of age and in the deltoid region of right or dominant arm in subjects 2 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 -day post-vaccination period of the adults, enrolment of the pediatric cohort aged - years commenced. Enrolment of the - months old cohort started only after the first subjects - years old were vaccinated and no life-threatening related SAE(s) were reported within 2 days post-dose vaccination in these first pediatric subjects. *Vaccine-primed subjects are subjects aged months to years (inclusive), who had received at least dose of the seasonal influenza vaccine 2-2 or a total of 2 or more doses of seasonal influenza vaccine since July 2 or a total of 2 or more doses of seasonal influenza vaccine before July, 2 and or more doses of monovalent 2 (HN) vaccine or a total of or more doses of seasonal influenza vaccine before July, 2 and or more doses of seasonal influenza since July, 2. All subjects aged years of age are considered vaccine-primed and received only dose of seasonal influenza vaccine in this study. Subjects months to years of age, inclusive, who did not meet these criteria were considered as vaccine-unprimed subjects. Objectives: Adults - years old: To describe the safety of dose of D-QIV_IP vaccine and dose of D-QIV_LP vaccine in terms of solicited adverse events

2 (AEs) days after vaccination, including the symptoms of Oculorespiratory Syndrome (ORS) # over days post-vaccination, and in terms of unsolicited AEs 2 days after vaccination in subjects aged - years. Children - 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 2 days after completion of the vaccination series in subjects aged - years. Non-inferiority criterion (for each of the strains): upper limit (UL) of the % confidence interval (CI) of the GMT ratio (D- QIV_LP/D-QIV_IP) is.. To describe the safety of D-QIV_IP vaccine and D-QIV_LP vaccine in terms of solicited AEs days after vaccination, including the symptoms of ORS over days post-vaccination, and in terms of unsolicited AEs 2 days after vaccination in subjects aged - years. Children - 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 2 days after completion of the vaccination series in subjects aged - months. Non-inferiority criterion (for each of the strains): UL of the % CI for the GMT ratio (D-QIV_LP/ D-QIV_IP) is.. To demonstrate there is no significant increase of fever in subjects who reported fever ºC (.ºF) after Dose or Dose 2 (overall per subject) with D-QIV_IP compared to D-QIV_LP within days post-vaccination in subjects aged - months. Success criterion: UL of the % CI for relative risk (RR) of fever ºC (.ºF) (FLU D-QIV IP/FLU D-QIV LP) is 2.. # Oculorespiratory syndrome (ORS) was defined as the occurrence within 2 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 - years old: Occurrence of solicited local and general AEs (Days - following vaccination), including the symptoms of ORS (Days -2 following vaccination), unsolicited AEs (Days -2 following vaccination) and medically attended events (MAEs) and serious adverse events (SAEs) in subjects aged - years during the entire study period. Percentage, intensity and duration of solicited local AEs during a -day follow-up period after vaccination (Day Day ). Percentage, intensity, duration and relationship to vaccination of solicited general AEs during a -day follow-up period after vaccination (Day Day ). Percentage, intensity and relationship to vaccination of symptoms of ORS during a -day follow-up period after vaccination (Day Day 2). Percentage, intensity and relationship to vaccination of unsolicited AEs during a 2-day follow-up period after vaccination (Day Day 2). 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 - years old: HI antibody titers for each of the influenza strains in subjects aged - years to calculate: HI GMTs and GMT ratio (D-QIV_LP -y/ D-QIV_IP -y) for each of the influenza strains at 2 days after completion of the vaccination series. Occurrence of solicited local and general AEs (Days - following vaccination) in subjects aged - years and - years, including symptoms of ORS (Days -2 following vaccination), unsolicited AEs (Days -2 following vaccination) and MAEs and SAEs during the entire study period in children aged - years. Percentage, intensity and duration of solicited local AEs during a -days follow-up period after vaccination (Day Day ). Percentage, intensity, duration and relationship to vaccination of solicited general AEs during a -day follow-up period after vaccination (Day Day ). Percentage, intensity and relationship to vaccination of symptoms of ORS during a -day follow-up period after vaccination (Day Day 2). Percentage, intensity and relationship to vaccination of unsolicited AEs during a 2-day follow-up period after vaccination (Day Day 2). Percentage, intensity and relationship to vaccination of MAEs during the entire study period.

3 Percentage and relationship to vaccination of SAEs during the entire study period. Children - months old: HI antibody titers for each of the influenza strains in subjects - months to calculate: HI GMTs and GMT ratio (D-QIV_LP -m/ D-QIV_IP -m) for each of the influenza strains at 2 days after completion of the vaccination series. Occurrence of fever ºC (.ºF) after Dose or Dose 2 (across doses) during the -day post-vaccination period (Day Day ) in subjects aged - months. Percentage and relative risk (D-QIV_IP -m/ D-QIV_LP -m) of subjects with fever ºC (.ºF) after Dose or Dose 2 (across doses) during the -day post-vaccination period (Day - Day ). Secondary Outcome Variable(s): Adults - years old: Humoral immune response in terms of HI antibodies in subjects aged - years Serum anti-ha antibody titers against the vaccine strains at Day and Day 2 to calculate: o GMTs at Day and Day 2. o Seroconversion rate (SCR)* at Day 2. o Seroprotection rate (SPR)** at Day and Day 2. o Mean geometric increase (MGI)*** at Day 2. Children - years old: Humoral immune response in terms of HI antibodies in children aged - years Serum anti- Haemagglutinin (HA) antibody titers against the vaccine strains at Day and Day 2 to calculate: o GMTs at Day and Day 2. o Seroconversion rate (SCR)* at Day 2. o Seroprotection rate (SPR)** at Day and Day 2. o Mean geometric increase (MGI)*** at Day 2 Occurrence of myalgia during the -day post-vaccination period (Day Day ) after Dose or Dose 2 (across doses) in subjects aged - years Percentage and relative risk (RR) (D-QIV_IP -y / D-QIV_LP -y) of subjects with myalgia during the -day postvaccination period (Day - Day ) in subjects aged - years Children - months old: Occurrence of fever C (.ºF) during the -day post-vaccination period (Day -Day ) after Dose and after Dose 2 in subjects aged - months. Percentage and relative risk (D-QIV_IP -m/ D-QIV_LP -m) of subjects with fever ºC (.ºF) after Dose and after Dose 2 during the -day post-vaccination period (Day Day ) in subjects aged - months. Humoral immune response in terms of HI antibodies in children aged - months. Serum anti-ha antibody titers against the vaccine strains at Day and 2 days after completion of the vaccination series to calculate: o GMTs at Day and Day 2. o Seroconversion rate (SCR)* at Day 2. o Seroprotection rate (SPR)** at Day and Day 2. o Mean geometric increase (MGI)*** at Day 2. Occurrence of solicited local and general AEs (Days - following vaccination), including the symptoms of ORS (Days -2 following vaccination), unsolicited AEs (Days -2 following vaccination), MAEs and SAEs during the entire study period in children aged - months. Percentage, intensity and duration of solicited local AEs during a -day follow-up period after each vaccine dose (Day Day ). Percentage, intensity, duration and relationship to vaccination of solicited general AEs during a -day follow-up period after each vaccine dose (Day Day ). Percentage, intensity and relationship to vaccination of symptoms of ORS during a -day follow-up period after vaccination (Day Day 2). Percentage, intensity and relationship to vaccination of unsolicited AEs during a 2-day follow-up period after each vaccine dose (Day Day 2).

4 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 C (.ºF) and > ºC (2.2ºF) after Dose or after Dose 2 (across doses) during the 2-days post-vaccination period in subjects aged months to < years of age (pooling of 2 independent cohorts). Percentage and relative risk (D-QIV IP m-<y/ D-QIV LP m-<y) of subjects with fever ºC (.ºF) and > ºC (2.2ºF) during the 2-days post-vaccination period in subjects aged months to < years (Day and Day ). * Seroconversion rate (SCR) is defined as the percentage of vaccinees that have either a pre-vaccination HI titer < : and a postvaccination HI titer : or pre-vaccination HI titer : and at least a -fold increase in post-vaccination HI titer. ** Seroprotection rate (SPR) is defined as the percentage of vaccinees with serum HI titer : usually accepted as indication protection in at least % of vaccinees. *** Mean geometric increase (MGI) is defined as the fold increase in serum HI GMTs post-vaccination compared to Day. Statistical Methods: The Analyses were performed on the Adult-Total Vaccinated cohort, Pediatric-Total Vaccinated cohort, the Adult According-to-Protocol (ATP) cohort for immunogenicity and the Pediatric ATP cohort for immunogenicity. The Adult-Total Vaccinated cohort and Pediatric-Total Vaccinated cohort included all subjects with at least one vaccine administration documented. The Adult ATP cohort for immunogenicity and the Pediatric ATP cohort for immunogenicity included all evaluable subjects (i.e., those meeting all eligibility criteria, complying with the procedures defined in the protocol, with no elimination criteria) who received the study vaccine according to their treatment assignment and for whom the assay results for antibodies against at least one study vaccine strain after vaccination were available. Analysis of Immunogenicity The analyses were performed on the Adult ATP cohort for immunogenicity and Pediatric ATP cohort for immunogenicity. Descriptive analysis: For each of the vaccine influenza strains the following parameters (with % CIs) were calculated for each vaccine group in Adults aged - years and Children aged - years by the previous year influenza vaccination (Yes/No), in Children aged - years and Children aged - months by priming status if applicable (primed and unprimed): GMTs of anti-ha antibody titers at Day and 2 days (adult population) or 2 days after completion of the vaccination series (pediatric populations). SCRs at 2 days (adult population) or 2 days after completion of the vaccination series (pediatric populations). SPRs at Day and day 2 (adult population) or 2 days after completion of the vaccination series (pediatric populations). MGI at 2 days (adult population) or 2 days after completion of the vaccination series (pediatric populations). Inferential analysis: For the humoral response in terms of HI antibodies for all vaccine strains, the following parameters were calculated with % CI between D-QIV_IP and D-QIV_LP groups at 2 days after completion of the vaccination series in subjects aged - months and subjects aged - years: Adjusted GMT ratio of D-QIV LP/ D-QIV IP. Analysis of Safety The analyses were performed on the Adult-Total Vaccinated Cohort and Pediatric-Total Vaccinated cohort. The percentages of subjects reporting each individual solicited local and general symptom during the days (Day Day ) follow-up after vaccination were tabulated with exact % CI. The same tabulation was performed for grade solicited symptoms and for general symptoms assessed by the investigator as related to the study vaccination. The duration statistics (in terms of number of days) of each solicited local and general AE during the -day (Day to Day ) post-vaccination follow-up period were also tabulated. The percentage of subjects reporting symptoms of ORS (any, grade, related, grade related) during a -day (Day to Day 2) post-vaccination follow-up period were tabulated with exact % CI. The percentage of subjects reporting fever and it s RR were tabulated at % CI, during the -day (Days -) and 2-day (Day Day ) follow-up period following each vaccine dose were tabulated for groups to months and months to < years, respectively. The percentage of subjects reporting myalgia and it s RR were tabulated at % CI, during the -day (Days -) follow-up period following each vaccine dose in subjects aged - years were tabulated. The percentages of subjects with at least one report of an unsolicited AE classified by Medical Dictionary for Regulatory Activities (MedDRA) Preferred Term up to 2 days (Days -2) after vaccination for subjects - years of age and up to 2 days after each vaccination (Days -2) for subjects - years of age and children - months of age were tabulated. The same tabulation was done

5 for grade unsolicited AEs and for AEs assessed by the investigator related to vaccination. The occurrences of SAEs and MAEs reported during the entire study period (approximately 2 days for each subject aged to years, approximately 2 days for subjects aged to years and 2 days or days for each subject aged months to years depending on their vaccine-priming status, were summarized and classified according to MedDRA Preferred Term. Study Population: Healthy male and female subjects, months to 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 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 Randomised, N (Total Vaccinated cohort) Completed, n (%) (.) () Total Number Subjects Withdrawn, n (%) (.) (.) Withdrawn due to Adverse Events, n (%) (.) (.) Withdrawn due to Lack of Efficacy, n (%) (.) (.) Withdrawn for other reasons, n (%) (.) (.) Demographics D-QIV LP Adult Group D-QIV IP Adult Group N (Total Vaccinated cohort) Gender Females, n (%) (.) (.) Males, n (%) 2 (.) (.) Mean Age, years (SD) #.2 (.) 2. (.) Median # 2 2 Minimum, Maximum #,, White - Caucasian / European Heritage, n (%) (.) () Number of Subjects: D-QIV IP -y Group D-QIV LP -y Group Planned, N Randomised, N (Total Vaccinated cohort) Completed - Primed subjects, n (%)* (.) 2 (.) Completed - Unprimed subjects, n (%)* (2.) (2.) Total Number Subjects Withdrawn, n (%) (.) (.2) Withdrawn due to Adverse Events, n (%) (.) (.) Withdrawn due to Lack of Efficacy, n (%) (.) (.) Withdrawn for other reasons, n (%) (.) (.2) Demographics D-QIV IP -y Group D-QIV LP -y Group N (Total Vaccinated cohort) Gender (.) (.) Females, n (%) Males, n (%) 2 (2.2) 22 (.) Mean Age, years (SD) #. (.2). (.2) Median # Minimum, Maximum #, #, # White - Caucasian / European Heritage, n (%) (2.2) (.) Number of Subjects: D-QIV IP -m Group D-QIV LP -m Group Planned, N Randomised, N (Total Vaccinated cohort) Completed - Primed subjects, n (%)* (.) (.) Completed - Unprimed subjects, n (%)* (.) 2 (.) Total Number Subjects Withdrawn, n (%) (.) (2.) Withdrawn due to Adverse Events, n (%) 2 (.) (.2) Withdrawn due to Lack of Efficacy, n (%) (.) (.) Withdrawn for other reasons, n (%) (.) 2(2.) Demographics D-QIV IP -m Group D-QIV LP -m Group

6 N (Total Vaccinated cohort) Gender Females, n (%) 22 (.) 2 (.) Males, n (%) 2 (2.) 2 (.) Mean Age, months (SD) #. (.). (.) Median # Minimum, Maximum #,, White - Caucasian / European Heritage, n (%) 2 (.) (.) Asian - South East Asian Heritage, n (%) (.) (.2) White - Arabic / North African Heritage, n (%) 2 (.) 2 (.) *The study duration was approximately 2 days for subjects aged to years and 2 days or days for each subject aged months to years depending on their vaccine-priming status # For subjects that reported a partial Date of Birth (DoB), the missing information was replaced by th of the month in case only the day was missing, or by th 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 - years reporting solicited local AEs reported during the -day (Days -) post-vaccination period (Adult-Total Vaccinated cohort) D-QIV LP Adult Group D-QIV IP Adult Group % CI % CI Symptom Intensity N n % LL UL N n % LL UL Pain Any Grade Redness Any > mm Swelling Any > mm N = number of subjects with the documented dose n/% = number/percentage of subjects reporting the symptom at least once %CI = Exact % confidence interval; LL = lower limit, UL = upper limit Any = occurrence of any local symptom regardless of intensity grade Grade Pain = Significant pain at rest, which prevented normal every day activities. Primary Outcome Results: Number (%) of subjects aged - years reporting solicited general AEs reported during the -day (Days -) post-vaccination period (Adult-Total Vaccinated cohort) D-QIV LP Adult Group D-QIV IP Adult Group % CI % CI Symptom Intensity / N n % LL UL N n % LL UL Relationship Fatigue Any Grade Related Gastrointestinal symptoms* Any Grade Related Headache Any Grade Related Joint Pain Any Grade Related Widespread muscle ache (myalgia) Any Grade Related Shivering Any Grade......

7 Related Fever Any # C >. C Related C Related N = number of subjects with the documented dose n/% = number/percentage of subjects reporting the symptom at least once %CI = Exact % 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 C/. F by any route and all subjects reporting temperature < C but with missing values (MC) for at least one day during the solicited period. Grade = 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 -day (Days -) post-vaccination period in subjects aged - years (Adult-Total Vaccinated cohort) Solicited symptom Group N Mean Median Fatigue D-QIV LP Adult D-QIV IP Adult Gastrointestinal symptoms* D-QIV LP Adult.. D-QIV IP Adult 2.. Headache D-QIV LP Adult.. D-QIV IP Adult 2.. Joint Pain D-QIV LP Adult 2.. D-QIV IP Adult.. Widespread muscle ache (myalgia) D-QIV LP Adult D-QIV IP Adult Pain D-QIV LP Adult D-QIV IP Adult. 2. Redness D-QIV LP Adult.. D-QIV IP Adult Shivering D-QIV LP Adult.. D-QIV IP Adult. 2. Swelling D-QIV LP Adult D-QIV IP Adult 2.. Fever D-QIV LP Adult 2.. D-QIV IP Adult 2.. 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 - years reporting solicited ORS like symptoms during the -day (Days -2) post-vaccination period (Adult-Total Vaccinated cohort) D-QIV LP Adult Group D-QIV IP Adult Group % CI % CI Symptom Intensity / N n % LL UL N n % LL UL Relationship Chest Tightness Any Grade Related Cough Any Grade Related Difficulty Breathing Any Grade Related......

8 Hoarseness Any Grade Related Red Eyes Any Grade Related Sore Throat Any Grade Related Swallowing Difficulty Any Grade Related Swelling of the face Any Grade Related Wheezing Any Grade Related N = number of subjects with the documented dose n/% = number/percentage of subjects reporting the symptom at least once %CI = Exact % confidence interval; LL = lower limit, UL = upper limit Any = occurrence of any ORS symptom regardless of intensity grade or relationship to vaccination. Grade = 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 - years reporting the occurrence of MAEs during the entire study period (Adult-Total Vaccinated cohort) Most frequent adverse events - On-Therapy (occurring within approximately 2 days following vaccination) D-QIV LP Adult Group N = D-QIV IP Adult Group N = Subjects with any AE(s), n (%) (.) (.) Subjects with grade AE(s), n (%) (.) (.) Subjects with related AE(s), n (%) (.) (.) Gastroenteritis 2 (.) (.) Nasopharyngitis 2 (.) - Back pain (.) (.) Bronchitis (.) (.) Allergy to arthropod bite (.) - Arthropod bite (.) - Hypersensitivity - (.) Intervertebral disc protrusion - (.) Joint injury - (.) Otitis media - (.) Post procedural inflammation (.) - Sinusitis (.) - Spinal disorder - (.) Tonsillitis - (.) -: MAE absent Primary Outcome Results: Adjusted GMT ratios of Flu A/HN, Flu A/HN2, Flu B/Yamagata, Flu B/Victoria HI antibodies between groups (D-QIV LP -y/ D-QIV IP -y) 2 days post last vaccination in subjects aged - years (Pediatric - ATP cohort for immunogenicity) Adjusted GMT ratio (D-QIV LP -y Group / D-QIV IP -y Group) D-QIV LP -y Group D-QIV IP -y Group % CI

9 Antibody N Adjusted N Adjusted Value LL UL GMT GMT Flu A/HN Flu A/HN Flu B/Yamagata Flu B/Victoria Adjusted GMT = geometric mean antibody titre adjusted for baseline titre N = Number of subjects with both pre- and post-vaccination results available % CI = % 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 - years reporting solicited local AEs during the -day (Days -) postvaccination period (Pediatric-Total Vaccinated cohort) D-QIV IP -y Group D-QIV LP -y Group % CI % CI Symptom Intensity N n % LL UL N n % LL UL Dose Pain Any Grade Redness Any > mm Swelling Any > mm Dose 2 Pain Any Grade Redness Any > mm Swelling Any > mm Across doses Pain Any Grade Redness Any > mm Swelling Any > mm 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 Pain = Cried when limb was moved/spontaneously painful Primary Outcome Results: Number (%) of subjects aged - years reporting solicited general AEs reported during the -day (Days -) post-vaccination period (Pediatric-Total Vaccinated cohort) D-QIV IP -y Group D-QIV LP -y Group % CI % CI Symptom Intensity / Relationship N n % LL UL N n % LL UL Dose Drowsiness Any Grade Related Irritability / Fussiness Any Grade Related Loss Of Appetite Any Grade

10 Related Fever Any # C >. C Related C Related Dose 2 Drowsiness Any Grade Related Irritability / Fussiness Any Grade Related Loss Of Appetite Any Grade Related Fever Any # C >. C Related C Related Across Doses Drowsiness Any Grade Related Irritability / Fussiness Any Grade Related Loss Of Appetite Any Grade Related Fever Any # C >. C Related C Related 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 C/. F by any route and all subjects reporting temperature < C but with missing values (MC) for at least one day during the solicited period. Grade = 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 - years reporting solicited general AEs reported during the -day (Days -) post-vaccination period (Pediatric-Total Vaccinated cohort) D-QIV IP -y Group D-QIV LP -y Group % CI % CI Symptom Intensity / Relationship N n % LL UL N n % LL UL Dose Fatigue Any Grade Related

11 Gastrointestinal symptoms* Any Grade Related Headache Any Grade Related Joint Pain Any Grade Related Widespread muscle ache (myalgia) Any Grade Related Shivering Any Grade Related Fever Any # C >. C Related C Related Dose 2 Fatigue Any Grade Related Gastrointestinal symptoms* Any Grade Related Headache Any Grade Related Joint Pain Any Grade Related Widespread muscle ache (myalgia) Any Grade Related Shivering Any Grade Related Fever Any # C >. C Related C Related Across Doses Fatigue Any Grade Related Gastrointestinal symptoms* Any Grade Related Headache Any Grade Related

12 Joint Pain Any Grade Related Widespread muscle ache (myalgia) Any Grade Related Shivering Any Grade Related Fever Any # C >. C Related C Related 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 %CI = Exact % 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 C/. F by any route and all subjects reporting temperature < C but with missing values (MC) for at least one day during the solicited period. Grade = 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 -day (Days -) post-vaccination period in subjects aged - years (Pediatric-Total Vaccinated cohort) Solicited symptom Dose Group N Mean Median Pain Dose D-QIV IP --y D-QIV LP -y Dose 2 D-QIV IP -y.. D-QIV LP -y. 2. Redness Dose D-QIV IP -y D-QIV LP -y.. Dose 2 D-QIV IP -y 2.. D-QIV LP -y 2.. Swelling Dose D-QIV IP -y D-QIV LP -y Dose 2 D-QIV IP -y.. 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 -day (Days -) post-vaccination period in subjects aged - years (Pediatric-Total Vaccinated cohort) Solicited symptom Dose Group N Mean Median Drowsiness Dose D-QIV IP -y.. D-QIV LP -y 2.. Dose 2 D-QIV IP -y.2. D-QIV LP -y Irritability / fussiness Dose D-QIV IP -y. 2. D-QIV LP -y 2.. Dose 2 D-QIV IP -y 2.. D-QIV LP -y 2.. Loss of appetite Dose D-QIV IP -y.. D-QIV LP -y Dose 2 D-QIV IP -y..

13 D-QIV LP -y.. Fever Dose D-QIV IP -y D-QIV LP -y.. Dose 2 D-QIV LP -y.. 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 -day (Days -) post-vaccination period in subjects aged - years (Pediatric-Total Vaccinated cohort) Solicited symptom Dose Group N Mean Median Fatigue Dose D-QIV IP -y D-QIV LP -y Dose 2 D-QIV IP -y.. D-QIV LP -y.. Gastrointestinal symptoms* Dose D-QIV IP -y.. D-QIV LP -y 2.. Dose 2 D-QIV IP -y. 2. D-QIV LP -y.. Headache Dose D-QIV IP -y 2.. D-QIV LP -y Dose 2 D-QIV IP -y D-QIV LP -y. 2. Joint Pain Dose D-QIV IP -y D-QIV LP -y.. Dose 2 D-QIV IP -y 2.. D-QIV LP -y.. Widespread muscle ache (myalgia) Dose D-QIV IP -y. 2. D-QIV LP -y.. Dose 2 D-QIV IP -y.. D-QIV LP -y.2. Shivering Dose D-QIV IP -y 2.. D-QIV LP -y 2.. Dose 2 D-QIV IP -y 2.. D-QIV LP -y 2.. Fever Dose D-QIV IP -y 2.. D-QIV LP -y.. Dose 2 D-QIV IP -y. 2. 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 - years reporting solicited ORS like symptoms reported during the -day (Days -2) post-vaccination period (Pediatric-Total Vaccinated cohort) D-QIV IP -y Group D-QIV LP -y Group % CI % CI Symptom Intensity / Relationship N n % LL UL N n % LL UL Dose Chest Tightness Any Grade Related Cough Any Grade Related Difficulty Breathing Any Grade Related Hoarseness Any Grade......

14 Related Red Eyes Any Grade Related Sore Throat Any Grade Related Swallowing Difficulty Any Grade Related Swelling of the face Any Grade Related Wheezing Any Grade Related Dose 2 Chest Tightness Any Grade Related Cough Any Grade Related Difficulty Breathing Any Grade Related Hoarseness Any Grade Related Red Eyes Any Grade Related Sore Throat Any Grade Related Swallowing Difficulty Any Grade Related Swelling of the face Any Grade Related Wheezing Any Grade Related Across Doses Chest Tightness Any Grade Related Cough Any Grade Related Difficulty Breathing Any Grade Related

15 Hoarseness Any Grade Related Red Eyes Any Grade Related Sore Throat Any Grade Related Swallowing Difficulty Any Grade Related Swelling of the face Any Grade Related Wheezing Any Grade Related 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 = 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 - 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 2/* days following vaccination) D-QIV IP -y Group N = D-QIV LP -y Group N = Subjects with any AE(s), n (%) (.) 2 (2.) Subjects with grade AE(s), n (%) (.) (.) Subjects with related AE(s), n (%) 2 (.) (.) Upper respiratory tract infection (.) (.) Bronchitis (.) (.) Pharyngitis (.) (.) Nasopharyngitis (.2) (.) Cough (.) (.) Gastroenteritis - (.2) Rhinitis - (.2) Tonsillitis (.) 2 (.) Laryngitis 2 (.) 2 (.) Pharyngotonsillitis 2 (.) 2 (.) Tracheitis 2 (.) 2 (.) Ear infection - (.) Viral infection (.) - Abdominal pain 2 (.) - Dermatitis - 2 (.) Impetigo 2 (.) - Oral herpes - 2 (.) Oropharyngeal pain - 2 (.) Otitis media 2 (.) - Otitis media acute 2 (.) - Pharyngitis streptococcal 2 (.) - Sinusitis - 2 (.) Vomiting 2 (.) -

16 -: 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 most frequent events for that group. Counting rule applied: As there were more than subjects per treatment group and groups, only the most frequent events in each treatment group are listed. *Approximately 2 days for subjects aged to years and 2 days or days for each subject aged months to years depending on their vaccine-priming status. Primary Outcome Results: Adjusted GMT ratios of Flu A/HN, Flu A/HN2, Flu B/Yamagata, Flu B/Victoria HI antibodies between groups (D-QIV LP -m/ D-QIV IP -m) 2 days post last vaccination in subjects aged - months (Pediatric - ATP cohort for immunogenicity) Adjusted GMT ratio (D-QIV LP -m Group / D-QIV IP -m Group) D-QIV LP -m D-QIV IP -m Group % CI Group Antibody N Adjusted N Adjusted Value LL UL GMT GMT Flu A/HN Flu A/HN Flu B/Yamagata Flu B/Victoria Adjusted GMT = geometric mean antibody titre adjusted for baseline titre N = Number of subjects with both pre- and post-vaccination results available % CI = % 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 -m/ D-QIV LP -m) of subjects with fever C (. F) during the days (Day -Day ) post-vaccination period after Dose or after Dose 2 (across doses) in subjects aged - months (Pediatric-Total Vaccinated cohort) Relative Risk (D-QIV IP -m Group over D-QIV LP -m Group) D-QIV IP -m Group D-QIV LP -m Group % CI Symptoms Type N n % N n % RR LL UL P-value Fever Any C N = Number of subjects with the documented dose n/% = number/percentage of subjects reporting a specified symptom % CI = Standardized asymptotic % confidence interval, LL = Lower Limit, UL = Upper Limit P-value = 2-sided Fisher Exact Test Any = all subjects with a documented temperature of C/. F by any route and all subjects reporting temperature < C but with missing values (MC) for at least one day during the solicited period. Secondary Outcome Results: Flu A/HN, A/HN2, B/Yamagata, B/Victoria HI antibody parameters (S+,SPR, GMT, SCR, MGI) at Day and Day 2 in subjects aged - years (Adult - ATP cohort for immunogenicity) N S+ SPR GMT N SCR MGI %CI %CI %CI %CI %CI Antibody Group Timing n % LL UL n % LL UL Valu LL UL n % LL UL Valu LL UL e Flu A/HN D-QIV LP PRE(D) Adult PI(D2) D-QIV IP PRE(D) Adult PI(D2) Flu A/HN2 D-QIV LP PRE(D) e

17 Flu B/Yamagata Flu B/Victoria Adult 2 PI(D2) D-QIV IP PRE(D) Adult 2 PI(D2) D-QIV LP PRE(D) Adult PI(D2) D-QIV IP PRE(D) Adult PI(D2) D-QIV LP PRE(D) Adult PI(D2) D-QIV IP PRE(D) Adult PI(D2) Seroconversion defined as: For initially seronegative subjects, antibody titer /DIL at post-vaccination For initially seropositive subjects, antibody titer at post-vaccination 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 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 % CI = % confidence interval: LL = Lower Limit UL = Upper Limit PRE(D) = Pre-vaccination at Day PI(D2) = Day 2 post-vaccination dose Secondary Outcome Results: Percentage and Relative Risk between groups (D-QIV IP -y/ D-QIV LP -y) of subjects with myalgia during the days (Days -) post-vaccination period after Dose or Dose 2 (across doses) in subjects aged - years (Pediatric-Total Vaccinated cohort) Relative Risk (D-QIV IP -y Group over D-QIV LP -y Group) D-QIV IP -y Group D-QIV LP -y Group % CI Symptoms Intensity N n % N n % RR LL UL P-value Widespread muscle ache (myalgia) Any N = Number of subjects with the documented dose n/% = number/percentage of subjects reporting a specified symptom % CI = Standardized asymptotic % 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/HN, A/HN2, B/Yamagata, B/Victoria HI antibody parameters (S+, SPR, GMT, SCR, MGI) at Day and Day 2 post last vaccination in subjects aged - years (Pediatric - ATP cohort for immunogenicity) N S+ SPR GMT N SCR MGI %CI %CI %CI %CI %CI

18 Antibody Group Timing n % LL UL n % LL UL Valu e LL UL n % LL UL Valu e LL UL Flu A/HN D-QIV IP - y PRE(D ) PII(D2) D-QIV LP PRE(D y ) 2 PII(D2) Flu A/HN2 D-QIV IP - y PRE(D ) PII(D2) D-QIV LP PRE(D y ) PII(D2) Flu B/Yamagata D-QIV IP - y PRE(D ) PII(D2) D-QIV LP PRE(D y ) 2 PII(D2) Flu B/Victoria D-QIV IP - y PRE(D ) PII(D2) D-QIV LP PRE(D y ) PII(D2) Seroconversion defined as: For initially seronegative subjects, antibody titer /DIL at post-vaccination For initially seropositive subjects, antibody titer at post-vaccination 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 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 % CI = % confidence interval: LL = Lower Limit UL = Upper Limit PRE(D) = Pre-vaccination at Day PII(D2) = Day 2 post-vaccination (Day 2 for primed subjects and Day for unprimed subjects) Secondary Outcome Results: Flu A/HN, A/HN2, B/Yamagata, B/Victoria HI antibody parameters (S+, SPR, GMT, SCR, MGI) 2 days post last vaccination in subjects aged - months (Pediatric - ATP cohort for immunogenicity) N S+ SPR GMT N SCR MGI %CI %CI %CI %CI %CI Antibody Group Timing n % LL UL n % LL UL Valu LL UL n % LL UL Valu LL UL Flu A/HN D-QIV IP -m PRE(D ) e e

19 PII(D2) D-QIV LP - m PRE(D ) PII(D2) Flu A/HN2 D-QIV IP - m PRE(D ) PII(D2) D-QIV LP - m PRE(D ) PII(D2) Flu B/Yamagat D-QIV IP - m PRE(D ) a PII(D2) D-QIV LP - m PRE(D ) PII(D2) Flu B/Victoria D-QIV IP - m PRE(D ) PII(D2) D-QIV LP - m PRE(D ) PII(D2) Seroconversion defined as: For initially seronegative subjects, antibody titer /DIL at post-vaccination For initially seropositive subjects, antibody titer at post-vaccination 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 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 % CI = % confidence interval: LL = Lower Limit UL = Upper Limit PRE(D) = activity VISIT D PII(D2) = VISIT at Day 2 post-vaccination (Day 2 for primed subjects and Day for unprimed subjects) Secondary Outcome Results: Percentage and Relative Risk between groups (FLU D-QIV IP/FLU D-QIV LP) of subjects with fever C (. F) during the days (Day -Day ) post-vaccination period after Dose and after Dose 2 in subjects aged - months (Pediatric- Total Vaccinated cohort) Relative Risk (D-QIV IP -m Group over D-QIV LP -m Group) D-QIV IP -m Group D-QIV LP -m Group % CI Symptoms Intensity N n % N n % RR LL UL P-value Dose Fever Any C

20 Dose 2 Fever Any C N = Number of subjects with at least one documented dose n/% = number/percentage of subjects reporting a specified symptom % CI = Standardized asymptotic % confidence interval, LL = Lower Limit, UL = Upper Limit P-value = 2-sided Fisher Exact Test Any = all subjects with a documented temperature of C/. F by any route and all subjects reporting temperature < 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 m-<y/ D-QIV LP m-<y) of subjects with fever C (. F) and >. C (2.2ºF) during the 2 days (Day -Day ) post-vaccination period (across doses) in subjects aged months to <years (Pediatric-Total Vaccinated cohort) Relative Risk (D-QIV IP m-<y Group over D-QIV LP m-<y Group) D-QIV IP m-<y Group D-QIV LP m-<y Group % CI Symptoms Intensity N n % N n % RR LL UL P-value Temperature Any C >. C N = Number of subjects with the documented dose n/% = number/percentage of subjects reporting a specified symptom % CI = Standardized asymptotic % confidence interval, LL = Lower Limit, UL = Upper Limit P-value = 2-sided Fisher Exact Test Any = all subjects with a documented temperature of C/. F by any route and all subjects reporting temperature < C but with missing values (MC) for at least one day during the solicited period. Secondary Outcome Results: Number (%) of subjects aged - months reporting solicited local AEs reported during the -day (Days - ) post-vaccination period (Pediatric-Total Vaccinated cohort) D-QIV IP -m Group D-QIV LP -m Group % CI % CI Symptom Intensity N n % LL UL N n % LL UL Dose Pain Any Grade Redness Any > mm Swelling Any > mm Dose 2 Pain Any Grade Redness Any > mm Swelling Any > mm Across Doses Pain Any Grade Redness Any > mm Swelling Any > mm N = number of subjects with at least one documented dose n/% = number/percentage of subjects reporting the symptom at least once

21 Any = occurrence of any local symptom regardless of intensity grade Grade Pain = Cried when limb was moved/spontaneously painful Secondary Outcome Results: Number (%) of subjects aged - months reporting solicited general AEs reported during the -day (Days -) post-vaccination period (Pediatric-Total Vaccinated cohort) D-QIV IP -m Group D-QIV LP -m Group Symptom Intensity / Relationship % CI % CI N n % LL UL N n % LL UL Dose Drowsiness Any Grade Related Irritability / Fussiness Any Grade Related Loss Of Appetite Any Grade Related Fever Any # C >. C Related C Related Dose 2 Drowsiness Any Grade Related Irritability / Fussiness Any Grade Related Loss Of Appetite Any Grade Related Fever Any # C >. C Related C Related Across Doses Drowsiness Any Grade Related Irritability / Fussiness Any Grade Related Loss Of Appetite Any Grade Related Fever Any # C >. C Related C Related N = number of subjects with at least one documented dose

22 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 C/. F by any route and all subjects reporting temperature < C but with missing values (MC) for at least one day during the solicited period. Grade = 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 -day (Days -) post-vaccination period in subjects aged - months (Pediatric-Total Vaccinated cohort) Solicited symptom Dose Group N Mean Median Pain Dose D-QIV IP -m.. D-QIV LP -m.. Dose 2 D-QIV IP -m. 2. D-QIV LP -m. 2. Redness Dose 2 D-QIV IP -m 2.. D-QIV LP -m.. Swelling Dose 2 D-QIV LP -m.. N = Number of subjects with the symptom and without the missing confirmed grade Secondary Outcome Results: Number of days with solicited general AE during the -day (Days -) post-vaccination period in subjects aged - months (Pediatric-Total Vaccinated cohort) Solicited symptom Dose Group N Mean Median Drowsiness Dose D-QIV IP --m D-QIV LP -m Dose 2 D-QIV IP -m D-QIV LP -m Irritability / fussiness Dose D-QIV IP -m D-QIV LP -m Dose 2 D-QIV IP -m D-QIV LP -m Loss of appetite Dose D-QIV IP -m D-QIV LP -m Dose 2 D-QIV IP -m D-QIV LP -m Temperature Dose D-QIV IP -m D-QIV LP - m.. Dose 2 D-QIV IP - m.. D-QIV LP - m N = Number of subjects with the symptom and without the missing confirmed grade Secondary Outcome Results: Incidence of solicited ORS like symptoms reported during the -day (Days -2) post-vaccination period in subjects aged - months (Pediatric-Total Vaccinated cohort) D-QIV IP -m Group D-QIV LP -m Group % CI % CI Symptom Intensity / Relationship N n % LL UL N n % LL UL Dose Chest Tightness Any Grade Related Cough Any Grade Related Difficulty Breathing Any Grade Related Hoarseness Any