Safety and Immunogenicity of Different Dosages of High-Dose Quadrivalent Influenza Vaccine in Children 6 Months to 17 Years of Age

Study Overview
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Brief Summary
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The objectives of this study were: To describe the safety of each dosage of high-dose quadrivalent influenza vaccine (QIV-HD) used in the study during the 28 days following each vaccination, and serious adverse events (including adverse events of special interest throughout the study). To describe the antibody response induced by each dosage of QIV-HD used in the study compared with unadjuvanted standard-dose quadrivalent influenza vaccine (QIV-SD) by hemagglutination inhibition (HAI) measurement method. To describe the antibody response induced by each dosage of QIV-HD used in the study compared with unadjuvanted QIV-SD by virus seroneutralization (SN) measurement method. To describe the antibody response induced by the highest acceptable dosage of QIV-HD compared with adjuvanted trivalent influenza vaccine (TIV) by HAI and virus SN measurement methods.

Detailed Description
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Study duration per participant was approximately 180 days for participants who received one dose of vaccine and 208 days for participants who received two doses of vaccine.

Official Title
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Safety and Immunogenicity of Different Dosages of High-Dose Quadrivalent Influenza Vaccine in Children 6 Months to 17 Years of Age

Conditions
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Influenza

Intervention / Treatment
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* Biological: High-Dose Quadrivalent Influenza Vaccine (QIV-HD) 30 μg (split-virion, inactivated)
* Biological: High-Dose Quadrivalent Influenza Vaccine (QIV-HD) 45 μg, (split-virion, inactivated)
* Biological: High-Dose Quadrivalent Influenza Vaccine (QIV-HD) 60 µg (split-virion, inactivated)
* Biological: Fluarix Quadrivalent Influenza vaccine (Unadjuvanted QIV-SD) (Inactivated)
* Biological: FLUAD Pediatric (adjuvanted TIV) (Surface Antigen, Inactivated)


Participation Criteria
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Eligibility Criteria
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Inclusion criteria : Aged 6 months to 17 years on the day of inclusion. Assent form was signed and dated by the participant (7 to 17 years of age) and informed consent form was signed and dated by the parent(s) or guardian(s) and by an independent witness, if required by local regulations. Participant and parent/guardian were able to attend all scheduled visits and complied with all study procedures. For participants aged <24 months: Born at full term of pregnancy (greater than or equal to [>=] 37 weeks) and/or with a birth weight >=2.5 kilogram. Exclusion criteria: Participant was pregnant, or lactating, or of childbearing potential and not using an effective method of contraception or abstinence from at least 4 weeks prior to vaccination until at least 4 weeks after vaccination. To be considered of non-childbearing potential, a female must be pre-menarche. Participation at the time of study enrollment (or in the 4 weeks preceding the first study vaccination) or planned participation during the present study period in another clinical study investigating a vaccine, drug, medical device, or medical procedure. Receipt of any vaccine in the 30 days preceding the first study vaccination, or planned receipt of any vaccine before Visit 3 for participants receiving 1 dose of influenza vaccine or Visit 5 for participants receiving 2 doses of influenza vaccine. For previously influenza vaccinated participants: Previous vaccination against influenza in the preceding 6 months with either the study vaccine or another vaccine. For previously influenza unvaccinated participants: Any influenza vaccination (from birth to the day of inclusion) with either the study vaccine or another influenza vaccine. For previously influenza unvaccinated participants: Any previous laboratory confirmed influenza infection (from birth to the day of inclusion) Receipt of immune globulins, blood or blood-derived products in the past 3 months. Known or suspected congenital or acquired immunodeficiency; or receipt of immunosuppressive therapy, such as anti-cancer chemotherapy or radiation therapy, within the preceding 6 months; or long-term systemic corticosteroid therapy (prednisone or equivalent for more than 2 consecutive weeks within the past 3 months). Known systemic hypersensitivity to any of the vaccine components, or history of a life-threatening reaction to the vaccines used in the study or to a vaccine containing any of the same substances. Thrombocytopenia or bleeding disorder, contraindicating IM vaccination based on Investigator's judgement. Deprived of freedom by an administrative or court order, or in an emergency setting, or hospitalized involuntarily. Current alcohol abuse or drug addiction. Chronic illness that, in the opinion of the investigator, was at a stage where it might interfere with study conduct or completion. Moderate or severe acute illness/infection (according to investigator judgment) on the day of vaccination or febrile illness (temperature >=38.0°Celsius [>=100.4°Fahrenheit]). A prospective participant should not be included in the study until the condition had resolved or the febrile event had subsided. Identified as an immediate family member (i.e., spouse, natural or adopted child, grandchild, nephew, or niece) of the Investigator or employee with direct involvement in the proposed study. Personal history of Guillain-Barré syndrome. Any condition that in the opinion of the Investigator would pose a health risk to the participant if enrolled or could interfere with the evaluation of the vaccine Personal history of clinically significant development delay (at the discretion of the Investigator), neurologic disorder, or seizure disorder. Known seropositivity for hepatitis B or hepatitis C. The above information was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

Ages Eligible for Study
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Minimum Age: 6 Months
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: The study was divided into 13 groups and enrolled participants in 4 stages. The study used a stepwise age de-escalation and dose ascension design for children 6 months to less than (<) 5 years of age.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1: QIV-HD 30 μg (US: 6 months to 17 years)<br>Participants from United States (US) (aged 6 months to 17 years) received single injection of 30 microgram (μg) QIV-HD, intramuscularly (IM) at Day 0. Participants for whom 2 doses of influenza vaccine were recommended, a second dose was administered at Day 28. | Biological: High-Dose Quadrivalent Influenza Vaccine (QIV-HD) 30 μg (split-virion, inactivated)<br>* Pharmaceutical form: Suspension for injection in pre-filled syringe Route of administration: IM<br>|
| Experimental: Group 2: QIV-HD 45 μg (US: 6 months to 17 years)<br>Participants from US (aged 6 months to 17 years) received single injection of 45 μg QIV-HD, IM at Day 0. Participants for whom 2 doses of influenza vaccine were recommended, a second dose was administered at Day 28. | Biological: High-Dose Quadrivalent Influenza Vaccine (QIV-HD) 45 μg, (split-virion, inactivated)<br>* Pharmaceutical form: Suspension for injection in pre-filled syringe Route of administration: IM<br>|
| Experimental: Group 3: QIV-HD, 60 μg (US: 6 months to 17 years)<br>Participants from US (aged 6 months to 17 years) received single injection of 60 μg QIV-HD, IM at Day 0. Participants for whom 2 doses of influenza vaccine were recommended, a second dose was administered at Day 28. | Biological: High-Dose Quadrivalent Influenza Vaccine (QIV-HD) 60 µg (split-virion, inactivated)<br>* Pharmaceutical form: Suspension for injection in pre-filled syringe Route of administration: IM<br>|
| Active Comparator: Group 4: Pooled QIV-SD, 15 μg (US: 6 months to 17 years)<br>Pooled arm consisted of participants who were from US aged 6 months to 17 years, randomized to Groups 1, 2 and 3 and received single injection of 15 μg QIV-SD, IM at Day 0. Participants for whom 2 doses of influenza vaccine were recommended, a second dose was administered at Day 28. | Biological: Fluarix Quadrivalent Influenza vaccine (Unadjuvanted QIV-SD) (Inactivated)<br>* Pharmaceutical form: Solution for injection Route of administration: IM<br>|
| Experimental: Group 5: QIV-HD, 60 μg (Canada: 6 to <24 months)<br>Participants from Canada (aged 6 to less than [<] 24 months) received single injection of 60 μg QIV-HD, IM at Day 0. Participants for whom 2 doses of influenza vaccine were recommended, a second dose was administered at Day 28. | Biological: High-Dose Quadrivalent Influenza Vaccine (QIV-HD) 60 µg (split-virion, inactivated)<br>* Pharmaceutical form: Suspension for injection in pre-filled syringe Route of administration: IM<br>|
| Active Comparator: Group 6: Adjuvanted TIV (Canada: 6 to <24 months)<br>Participants from Canada (aged 6 to <24 months) received single injection of 7.5 μg adjuvanted TIV, IM at Day 0. Participants for whom 2 doses of influenza vaccine were recommended, a second dose was administered at Day 28. | Biological: FLUAD Pediatric (adjuvanted TIV) (Surface Antigen, Inactivated)<br>* Pharmaceutical form: Solution for injection Route of administration: IM<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Immediate Unsolicited Adverse Events (AEs) After Any Vaccination | An unsolicited AE was an observed AE that did not fulfill the conditions prelisted in the case report book (CRB) in terms of diagnosis and/or onset window post-vaccination. Unsolicited AEs includes both serious (SAEs) and non-serious unsolicited AEs. An SAE was any untoward medical occurrence that at any dose resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, or was an important medical event. All participants were observed for 30 minutes after vaccination, and any unsolicited systemic AEs occurred during that time were recorded as immediate unsolicited AEs in the CRB. | Within 30 minutes after any vaccination | 
| Number of Participants With Unsolicited Adverse Events After Any Vaccination | An unsolicited AE was an observed AE that does not fulfill the conditions prelisted in the CRB in terms of diagnosis and/or onset window post-vaccination. Unsolicited AEs included both serious and non-serious unsolicited AEs. An SAE was any untoward medical occurrence that at any dose resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, or was an important medical event. Adverse reactions (ARs) were AEs related to vaccination. An injection site reaction was an AR at and around the injection site. Systemic AEs were all AEs that were not injection or administration site reactions. | Within 28 days after any vaccination | 
| Number of Participants With Serious Adverse Events (SAEs) After Any Vaccination | An SAE was any untoward medical occurrence that at any dose resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, or was an important medical event. An SAE which caused death of the participant was considered as fatal SAE. Adverse events of special interest (AESIs) were defined as SAEs which included new onset of Guillain-Barré syndrome, encephalitis/myelitis (including transverse myelitis), Bell's palsy, convulsions, optic neuritis, and brachial neuritis. | From Day 0 up to 6 months (i.e. 180 days) post last vaccination | 
| Number of Participants Achieving Seroconversion Against Antigens Following Vaccination With Either a High-Dose Quadrivalent Influenza Vaccine or Standard-Dose Quadrivalent Influenza Vaccine or Adjuvanted Trivalent Influenza Vaccine | Anti-influenza antibodies were measured by hemagglutination inhibition (HAI) assay for strains A/H1N1, A/H3N2, B/Victoria and B/Yamagata lineage. Seroconversion: defined as either HAI titer <10(1/dilution) at Day 0 and post-vaccination titer greater than or equal to (>=)40(1/dilution) at Day 28, or HAI titer >=10(1/dilution) at Day 0 and >=4-fold increase in HAI titer (1/dilution) at Day 28. Data for this Outcome Measure (OM) was planned to be collected and reported for dose level (QIV-HD 30μg and 45μg) matched separate groups for QIV-SD (Groups 4a, 4b and 4c), instead of pooled QIV-SD arm. Due to complex study design and analysis of doses and age groups, QIV-SD group participants, who matched to participants in QIV-HD 30μg and 45μg dose formulations groups (who were 9 through 17 years old and shared matching age group with QIV-SD control group), included in Groups 4a, 4b and 4c in this OM might be counted in more than once in QIV-SD arms for different dose levels, as applicable. | Day 28 post any vaccination | 
| Geometric Mean Titers (GMTs) of Influenza Antibodies Following Vaccination With Either a High-Dose Quadrivalent Influenza Vaccine or Standard-Dose Quadrivalent Influenza Vaccine or Adjuvanted Trivalent Influenza Vaccine | GMTs of anti-influenza antibodies were measured using an HAI assay for 4 strains: A/H1N1, A/H3N2, B Victoria lineage, and B Yamagata lineage. Data for this OM was planned to be collected and reported for dose level (QIV-HD 30 μg and QIV-HD 45 μg) matched separate groups for QIV-SD (Groups 4a, 4b and 4c), instead of pooled QIV-SD arm. Due to the complex study design and analysis of the dose formulation and age groups in the study, QIV-SD group participants, who matched to participants in the QIV-HD 30 μg and QIV-HD 45 μg dose formulations groups (who were 9 through 17 years old and shared a matching age group with QIV-SD control group), included in Groups 4a, 4b and 4c in this OM might be counted in more than once in QIV-SD arms for different dose levels, as applicable. | Day 28 post any vaccination | 
| Geometric Mean Titer Ratios (GMTRs) of Influenza Antibodies Following Vaccination With Either a High-Dose Quadrivalent Influenza Vaccine or Standard-Dose Quadrivalent Influenza Vaccine or Adjuvanted Trivalent Influenza Vaccine | GMTs of anti-influenza antibodies were measured using an HAI assay for 4 strains: A/H1N1, A/H3N2, B Victoria lineage, and B Yamagata lineage. GMTRs were calculated as the ratio of GMTs post-vaccination and pre-vaccination. | Day 0 (pre-vaccination), Day 28 (post any vaccination) | 
| Number of Participants With Neutralization Antibody Titers >= 40 (1/Dilution) Following Vaccination With Either a High-Dose Quadrivalent Influenza Vaccine or Standard-Dose Quadrivalent Influenza Vaccine or Adjuvanted Trivalent Influenza Vaccine | GMT was measured for each influenza strain using HAI assay method for 4 strains: A/H1N1, A/H3N2, B/Victoria lineage, and B/Yamagata lineage. | Day 28 post any vaccination | 
| Geometric Mean Titers of Influenza Antibodies (Measured by Seroneutralization [SN] Assay) Following Vaccination With Either High-Dose Quadrivalent Influenza Vaccine or Standard-Dose Quadrivalent Influenza Vaccine or Adjuvanted Trivalent Influenza Vaccine | GMT was measured for each influenza strain using SN assay method for 4 strains: A/H1N1, A/H3N2, B/Victoria lineage, and B/Yamagata lineage. | Day 28 post any vaccination | 
| Geometric Mean Titers Ratio of Influenza Antibodies (Measured by Seroneutralization Assay) Following Vaccination With Either High-Dose Quadrivalent Influenza Vaccine or Standard-Dose Quadrivalent Influenza Vaccine or Adjuvanted Trivalent Influenza Vaccine | GMTRs of anti-influenza antibodies were measured using SN assay method for 4 strains: A/H1N1, A/H3N2, B/Victoria lineage and B/Yamagata lineage. GMTRs were calculated as the ratio of GMTs post vaccination and pre-vaccination. | Day 0 (pre-vaccination), Day 28 (post any vaccination) | 
| Number of Participants With Neutralization Antibody Titers Above Pre-Defined Thresholds | Neutralizing Antibody titer was measured for each influenza strain with SN assay method for 4 strains: A/H1N1, A/H3N2, B/Victoria lineage, and B/Yamagata lineage at pre-defined thresholds of >=20, >=40 and >=80 (1/dilution). | Day 28 post any vaccination | 
| Number of Participants With Two-Fold and Four-Fold Increase in Neutralization Antibody Titer | Neutralizing Antibody titer was measured for each influenza strain with SN method for 4 strains: A/H1N1, A/H3N2, B/Victoria lineage, and B/Yamagata lineage. 2-fold and 4-fold rise was defined as the computed value = post-vaccination computed value / pre-vaccination computed value. | Day 28 post any vaccination | 
| Number of Participants With Solicited Injection Site Reactions | A solicited reaction was an expected adverse reaction (sign or symptom) observed and reported under the conditions (nature and onset) prelisted (i.e., solicited) in the CRB and considered as related to the administered vaccination. Solicited injection site reactions included tenderness/pain, erythema, swelling, induration and bruising. | Within 7 days after any vaccination | 
| Number of Participants With Solicited Systemic Reactions After Any Vaccination | A solicited reaction was an expected adverse reaction (sign or symptom) observed and reported under the conditions (nature and onset) prelisted (i.e., solicited) in the CRB and considered as related to the administered vaccination. Solicited systemic reactions included fever, vomiting, crying abnormal, drowsiness, appetite loss and irritability. Fever was planned to be evaluated for the whole population where as, the other events (vomiting, crying abnormal, drowsiness, appetite lost, and irritability) were planned to be evaluated only in the participants aged 6 months to <36 months. | Within 7 days after any vaccination | 
| Number of Participants With Solicited Systemic Reactions After Any Vaccination: Participants Aged >36 Months | A solicited reaction was an expected adverse reaction (sign or symptom) observed and reported under the conditions (nature and onset) prelisted (i.e., solicited) in the CRB and considered as related to the administered vaccination. Solicited systemic reactions included: headache, malaise, myalgia and shivering. | Within 7 days after any vaccination |