Pediatric Safety and Immunogenicity Study of Cell-Culture Derived and Egg-based Subunit Influenza Vaccines in Healthy Children and Adolescents

Study Overview
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Brief Summary
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The present study is the first study designed to evaluate safety, tolerability and immunogenicity of the cell culture-derived influenza vaccine in healthy children and adolescents aged 3 to 17 years. A step-down approach is utilized in which reactogenicity and safety will be assessed in children and adolescents 9 to 17 years of age (Cohort 1) prior to enrolling additional children and adolescents 9 to 17 years of age (Cohort 2) and children 3 to 8 years of age (Cohort 3).

Official Title
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A Combined Phase II/III, Observer-Blind, Randomized, Multi-center Study to Evaluate Safety, Tolerability and Immunogenicity of Trivalent Subunit Influenza Vaccines, Produced Either in Mammalian Cell Culture or in Embryonated Hen Eggs, in Healthy Children and Adolescents

Conditions
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Influenza

Intervention / Treatment
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* Biological: Cell culture-derived influenza subunit vaccine (cTIV)
* Biological: Egg derived influenza subunit vaccine (eTIV)
* Biological: Cell culture-derived influenza subunit vaccine (cTIV)
* Biological: Egg derived influenza subunit vaccine (eTIV)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects aged 9 to 17 years (Cohorts 1 and 2) and 3 to 8 years (Cohort 3), whose parents/legal guardians have given written informed consent prior to study entry. Assent will be obtained from subjects according to age requirements of the ECs/IRBs; In good health as determined by: medical history, physical examination, clinical judgment of the Investigator; Able to comply with all study procedures and available for all clinic visits and telephone calls scheduled in the study. Exclusion Criteria: Any serious disease, such as: cancer, autoimmune disease (including rheumatoid arthritis), diabetes mellitus, chronic pulmonary disease, acute or progressive hepatic disease, acute or progressive renal disease; History of any anaphylaxis or serious reaction following administration of vaccine, or hypersensitivity to eggs, egg protein, chicken feathers, influenza viral protein, neomycin, polymyxin, or any other vaccine component, chemically related substance, or component of the potential packaging materials; Known or suspected impairment/alteration of immune function, including: use of immunosuppressive therapy such as systemic corticosteroids known to be associated with the suppression of hypothalamic-pituitary-adrenal (HPA) axis or chronic use of inhaled high-potency corticosteroids within 60 days prior to Visit 1, cancer chemotherapy, receipt of immunostimulants within 60 days prior to Visit 1, receipt of parenteral immunoglobulin preparation, blood products, and/or plasma derivatives within 3 months prior to Visit 1 or planned during the full length of the study, known HIV infection or HIV-related disease; History of Guillain-Barré syndrome; Bleeding diathesis; Surgery planned during the study period; Receipt of another investigational agent within 90 days, or before completion of the safety follow-up period in another study, whichever is longer, prior to enrollment and unwilling to refuse participation in another clinical study through the end of the study; Receipt of another vaccine within 2 weeks (for inactivated vaccines) or 4 weeks (for live vaccines) prior to Visit 1; Laboratory-confirmed influenza disease within 6 months prior to Visit 1; For subjects aged 3 to 8 years old, ever received two doses of an influenza vaccine in one influenza season; Receipt of an influenza vaccine within 6 months prior to Visit 1; Experienced a temperature 38.0°C [100.4°F]) and/or any acute illness within 3 days prior to Visit 1; Pregnant or nursing mother; Female of childbearing potential who is sexually active and has not used acceptable birth control measures for at least 2 months prior to study entry and who does not plan to use acceptable birth control measures during the 3 weeks following vaccination or refuses to have a urine pregnancy test prior to enrollment. Oral, injected, inserted or implanted hormonal contraceptive, diaphragm or condom with spermicidal agent or intrauterine device are considered acceptable forms of birth control; Children of research staff or those living with research staff directly involved with the clinical study. Research staff are individuals with direct study subject contact, indirect contact with study subjects, or study site personnel who have access to any study documents containing subject information. This would include receptionists, persons scheduling appointments or making screening calls, regulatory specialists, laboratory technicians, etc.; Any condition, which in the opinion of the Investigator, might interfere with the evaluation of the study objectives.

Ages Eligible for Study
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Minimum Age: 3 Years
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: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohorts 1 + Cohort 2 (9-17 Yrs) cTIV<br>All subjects received one 0.5 mL IM injection, of cell culture-derived trivalent influenza vaccine containing 15μg of HA for each strain (A/Solomon Islands/3/2006 [H1N1]-like, A/Wisconsin/67/2005 [H3N2]-like, and B/Malaysia/ 2506/2004-like), recommended for the 2007-2008 influenza season in the Northern Hemisphere | Biological: Cell culture-derived influenza subunit vaccine (cTIV)<br>* One 0.5 ml injection of the cell culture-derived influenza vaccine in the deltoid muscle, preferably of the nondominant arm.<br>|
| Active Comparator: Cohorts 1 + Cohort 2 (9-17 Yrs) eTIV<br>All subjects received one 0.5 mL injection, of egg -derived trivalent influenza vaccine containing 15μg of HA for each strain (A/Solomon Islands/3/2006 [H1N1]-like, A/Wisconsin/67/2005 [H3N2]-like and B/Malaysia/ 2506/2004-like), recommended for the 2007-2008 influenza season in the Northern Hemisphere. | Biological: Egg derived influenza subunit vaccine (eTIV)<br>* One 0.5 ml injection of the conventional egg-derived influenza vaccine in the deltoid muscle, preferably of the nondominant arm.<br>|
| Experimental: Cohort 3 (3-8 Yrs) cTIV<br>All subjects received two 0.5 mL injections, administered four weeks apart, of cell culture-derived trivalent influenza vaccine containing 15μg of HA for each strain (A/Solomon Islands/3/2006 [H1N1]-like, A/Wisconsin/67/2005 [H3N2]-like and B/Malaysia/ 2506/2004-like), recommended for the 2007-2008 influenza season in the Northern Hemisphere | Biological: Cell culture-derived influenza subunit vaccine (cTIV)<br>* Two 0.5 mL injections,of the cell culture-derived influenza vaccine in the deltoid muscle, preferably of the nondominant arm, administered four weeks apart.<br>|
| Active Comparator: Cohort 3 (3-8 Yrs) eTIV<br>All subjects received two 0.5 mL injections, administered four weeks apart of egg -derived trivalent influenza vaccine containing 15μg of HA for each strain (A/Solomon Islands/3/2006 [H1N1]-like, A/Wisconsin/67/2005 [H3N2]-like and B/Malaysia/ 2506/2004-like), recommended for the 2007-2008 influenza season in the Northern Hemisphere | Biological: Egg derived influenza subunit vaccine (eTIV)<br>* Two 0.5 mL injections of the conventional egg-derived influenza vaccine in the deltoid muscle, preferably of the nondominant arm,administered four weeks apart.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Geometric Mean Titers of the Cell Culture-derived Vaccine Compared With the Egg-derived Vaccine in 3 to 8 Year-old Children | To demonstrate non-inferiority of the post vaccination hemagglutination inhibition (HI) geometric mean titer (GMT) of the cell culture-derived influenza (cTIV) vaccine to the corresponding GMT of the egg-derived (eTIV) influenza vaccine, for all three strains, after two injections administered four weeks apart to a subset of children 3 to 8 years of age. GMTs were evaluated using two assays, HI egg derived antigen assay and HI cell derived antigen assay. | Day 50 post vaccination | 
| Percentages of Subjects Who Attained Seroconversion or Significant Increase in Antibody Titers in the Cell Culture-derived Vaccine Compared With the Egg-derived Vaccine in 3 to 8 Year-old Children | To demonstrate non-inferiority of the cell culture-derived influenza (cTIV) vaccine to the egg-derived (eTIV) influenza vaccine in the percentage of subjects achieving seroconversion or significant increase in antibody titer post vaccination, for all three strains, after two injections administered four weeks apart in children 3 to 8 years of age. Seroconversion rate was evaluated using two assays- HI egg derived antigen assay and HI cell derived antigen assay. | Day 50 post vaccination | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Geometric Mean Titers After 1 Dose of the Cell Culture-derived or the Egg-derived Influenza Vaccine in 9 to 17 Year-old Children and Adolescents | To evaluate immunogenicity in terms of Geometric Mean Titers (GMTs) in children 9 to 17 years of age after one injection of either cTIV vaccine or eTIV. GMTs were evaluated using two assays, HI egg derived antigen assay and HI cell derived antigen assay. | Day 29 post vaccination | 
| Geometric Mean Ratio After 1 Dose of the Cell Culture-derived or the Egg-derived Influenza Vaccine in 9 to 17 Year-old Children and Adolescents. | Immunogenicity was evaluated in terms of Geometric Mean Ratio (GMRs) in 9 to 17 year-old children and adolescents after one injection of either cTIV vaccine or eTIV. The criterion is met according to European (CHMP) guideline if the mean geometric increase GMR (day29/day1) in HI antibody titer is >2.5. | Day 29 post vaccination | 
| Percentages of Subjects Who Achieved HI Titers ≥40 After 1 Dose of the Cell Culture-derived Vaccine or the Egg-derived Influenza Vaccine in 9 to 17 Year-old Children and Adolescents | To evaluate immunogenicity in terms of percentage of 9 to 17 year-old children and adolescents achieving HI titers ≥40, after one injection of either the cTIV vaccine or the eTIV vaccine. This criterion is met according to European (CHMP) guideline if the percentage of subjects achieving HI titers ≥40 is >70% and according to the US (CBER) guideline is met if the lower bound of the two sided 95%CI for percentage of subjects achieving HI titers ≥40 is ≥70%. | Day 29 post vaccination | 
| Percentages of Subjects Who Attained Seroconversion or Significant Increase After 1 Dose of the Cell Culture-derived Vaccine or the Egg-derived Influenza Vaccine in 9 to 17 Year-old Children and Adolescents | Seroconversion or significant increase as per CHMP criteria is defined as percentage of subjects with a pre vaccination HI titer <10 to a post vaccination titer ≥40 or a pre vaccination HI titer ≥10 and a ≥4-fold increase in post vaccination HI antibody titer. According to the CHMP criteria, the percentage of subjects achieving seroconversion or significant increase should be >40%. According to the CBER criteria, the lower bound of the two-sided 95% CI for the percentage of subjects achieving seroconversion/significant increase should be ≥40%. | Day 29 post vaccination | 
| Geometric Mean Titers After Two Doses of the Cell Derived or the Egg Derived Vaccine in 3 to 8 Year-old Children | To evaluate immunogenicity in terms of Geometric Mean Titers (GMTs) in children 3 to 8 years of age after two doses of either cTIV vaccine or eTIV,administered 4 weeks apart. | Day 29 and Day 50 post vaccination | 
| Geometric Mean Ratio After Two Doses of the Cell-derived or the Egg-derived Vaccine in 3 to 8 Year-old Children | To evaluate immunogenicity in terms of Geometric Mean Ratio (GMR) in children 3 to 8 years of age after two doses of either the cTIV vaccine or the eTIV vaccine, administered 4 weeks apart according to the CHMP criteria. The criterion is met according to the European (CHMP) guideline if the mean geometric increase (GMR day 29/day 1 and GMR day 50/day 1) in HI antibody titer is >2.5 | Day 29 and Day 50 post vaccination | 
| Percentages of Subjects Who Achieved HI Titers ≥40 After Two Doses of the Cell Culture Derived or the Egg Derived Influenza Vaccine in 3 to 8 Year-old Children | To evaluate immunogenicity in terms of HI titers ≥40, in children 3-8 years of age after two doses of either cTIV vaccine or eTIV vaccine, administered 4 weeks apart. The criterion is met according to European (CHMP) guideline if the percentage of subjects achieving HI titers ≥40 is >70% and according to the US (CBER) guideline if the lower bound of the two sided 95%CI for percentage of subjects achieving HI titers ≥40 is ≥70%. | Day 29 and Day 50 post vaccination | 
| Percentages of Subjects Who Achieved Seroconversion or Significant Increase in HI Titers After Two Doses of the Cell Culture-derived Vaccine or the Egg-derived Influenza Vaccine in 3 to 8 Year-old Children | Seroconversion or significant increase as per CHMP criteria is defined as percentage of subjects with a pre vaccination HI titer <10 to a post vaccination titer ≥40 or a pre vaccination HI titer ≥10 and a ≥4-fold increase in post vaccination HI antibody titer. According to the CHMP criteria, the percentage of subjects achieving seroconversion or significant increase should be >40%. According to the CBER criteria, the lower bound of the two-sided 95% CI for the percentage of subjects achieving seroconversion/significant increase should be ≥40%. | Day 29 and Day 50 post vaccination | 
| Number of Subjects Reporting Local and Systemic Reactions After 1 Dose of the Cell Culture-derived or the Egg-derived Influenza Vaccine in 9 to 17 Year-old Children and Adolescents. | To evaluate safety and tolerability in terms of number of 9 to 17 year-old children and adolescents (cohorts 1 and 2) reporting local and systemic reactions following of one injection of the cTIV or the eTIV vaccine . | up to 7 days after vaccination | 
| Number of Subjects Reporting Local and Systemic Reactions After One and Two Doses of the Cell Culture-derived Vaccine or Egg-derived Influenza Vaccine in 3 to 8 Year-old Children. | To evaluate the safety and tolerability of the cTIV and the eTIV influenza vaccines in 3 to 8 year-old children terms of number of participants reporting local and systemic reactions after each vaccination. | up to 7 days after each vaccination | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Influenza, Flu, Cell Culture-Derived, Egg-Derived, Healthy Children, Healthy Adolescents, Safety, Immunogenicity, Trivalent, Inactivated, Vaccination