Evaluate Safety & Immunogenicity of a Pandemic Influenza Vaccine (GSK1562902A) in Children

Phase 2

Completed

Conditions: Influenza

Interventions: Biological: Fluarix™
Biological: Pandemic Influenza Vaccine (GSK1562902A)

Registration Number: NCT00502593

Lead Sponsor: GlaxoSmithKline

Brief Summary: The present study is designed to evaluate in children (aged between 3 and 9 years) the immunogenicity and safety of different antigen doses of the candidate vaccine (GSK1562902A) administered following a two-administration schedule (21 days apart). Subjects in the control group will receive Fluarix. The Protocol Posting has been updated in order to comply with the FDA Amendment Act, Sep 2007.

Detailed Description: This 107066 study is a participating study to the broader NCT00502593 study, which included 2 other studies, the 108498 and 108500 studies. The NCT00502593 study had a staggered design (subjects from each group being enrolled sequentially into 2 age strata, '6-9 years' 1st, and '3-5 years' next) and was run in 3 phases, phases A (Study 107066), B (Study 108498) and C (Study 108500). In each phase, the decision to vaccinate subjects aged 3-5 years and to administer a 2nd injection to subjects aged 6-9 years was made based on safety data collected on Days 0-6 after the 1st injection for the subjects aged 6-9 years. Decision to start Phase B was made on complete safety data including those collected on Day 28 of Phase A (7 days after the 2nd injection) for each age group. A similar approach was to be used to start Phase C. As safety data in Phase A did not raise any safety concerns, Phases B and C were run in parallel.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 138

Inclusion Criteria

Children who the investigator believes that their parents/guardians can and will comply with the requirements of the protocol.
Children aged between and including 3 and 9 years of age at the time of first vaccination.
Written informed consent obtained from the parent(s) or guardian of the subject.
Healthy children as established by medical history and clinical examination before entering the study.
Subjects who are likely to reside in the vicinity of the study center for the duration of the study.

Exclusion criteria:

Use of any investigational or non-registered product (drug or vaccine) other than the investigational vaccine within 30 days prior to the enrolment in this study, or planned use during the study period.
Administration of licensed vaccines within 2 weeks (for inactivated vaccines) or 4 weeks (for live vaccines) prior to enrolment in this study. Planned administration of a vaccine not foreseen by the study protocol up to 30 days after the second vaccination, with the exception of routine childhood inoculations which cannot be delayed, but which must not be administered on the same day as the investigational vaccine candidate.
Administration of the interpandemic influenza vaccine 21 days prior to Day 0 or up to Day 51.
Chronic administration (defined as more than 14 days) of immunosuppressants or other immune-modifying drugs within six months prior to the enrolment in this study.
Any chronic drug therapy to be continued during the study period, with the exception of inhalative treatment for seasonal allergies or asthma.
Any confirmed or suspected immunosuppressive or immunodeficient condition, based on medical history and physical examination.
Acute or chronic clinically significant pulmonary, cardiovascular, hepatic or renal functional abnormality, as determined by medical history and physical examination.
History of hypersensitivity to vaccines.
History of allergic disease or reactions likely to be exacerbated by any component of the vaccines used in this study.
History of any neurological disorders or seizures.
Acute disease at the time of enrolment.
Administration of immunoglobulins and/or any blood products within the three months prior to the enrolment in this study or planned during the study.
Any condition which, in the opinion of the investigator, renders the subject unfit for participation in the study

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Fluarix-A 3-5Y Group	Fluarix™	Subjects aged 3-5 years received 2 doses of Fluarix™ vaccine. These subjects were enrolled in the Phase A of this NCT00502593 study (or study 107066). The Fluarix™ vaccine was administered intramuscularly in the deltoid region of the non-dominant arm on Days 0 and 21.
GSK1562902A-A Lot 1 6-9Y Group	Pandemic Influenza Vaccine (GSK1562902A)	Subjects aged 6-9 years received 2 doses of GSK1562902A vaccine, lot 1. These subjects were enrolled in the Phase A of this NCT00502593 study (or study 107066). The GSK1562902A vaccine was administered intramuscularly in the deltoid region of the non-dominant arm on Days 0 and 21.
Fluarix-A 6-9Y Group	Fluarix™	Subjects aged 6-9 years received 2 doses of Fluarix™ vaccine. These subjects were enrolled in the Phase A of this NCT00502593 study (or study 107066). The Fluarix™ vaccine was administered intramuscularly in the deltoid region of the non-dominant arm on Days 0 and 21.
GSK1562902A-A Lot 1 3-5Y Group	Pandemic Influenza Vaccine (GSK1562902A)	Subjects aged 3-5 years received 2 doses of GSK1562902A vaccine, lot 1. These subjects were enrolled in the Phase A of this NCT00502593 study (or study 107066). The GSK1562902A vaccine was administered intramuscularly in the deltoid region of the non-dominant arm on Days 0 and 21.
Fluarix-B 6-9Y Group	Fluarix™	Subjects aged 6-9 years received 2 doses of Fluarix™ vaccine. These subjects were enrolled in the Phase B of this NCT00502593 study (or study 108498). The Fluarix™ vaccine was administered intramuscularly in the deltoid region of the non-dominant arm on Days 0 and 21.
GSK1562902A-B Lot 2 6-9Y Group	Pandemic Influenza Vaccine (GSK1562902A)	Subjects aged 6-9 years received 2 doses of GSK1562902A vaccine, lot 2. These subjects were enrolled in the Phase B of this NCT00502593 study (or study 108498). The GSK1562902A vaccine was administered intramuscularly in the deltoid region of the non-dominant arm on Days 0 and 21.
GSK1562902A-C Lot 3 3-5Y Group	Pandemic Influenza Vaccine (GSK1562902A)	Subjects aged 3-5 years received 2 doses of GSK1562902A vaccine, lot 3. These subjects were enrolled in the Phase C of this NCT00502593 study (or study 108500). The GSK1562902A vaccine was administered intramuscularly in the deltoid region of the non-dominant arm on Days 0 and 21.
Fluarix-B 3-5Y Group	Fluarix™	Subjects aged 3-5 years received 2 doses of Fluarix™ vaccine. These subjects were enrolled in the Phase B of this NCT00502593 study (or study 108498). The Fluarix™ vaccine was administered intramuscularly in the deltoid region of the non-dominant arm on Days 0 and 21.
GSK1562902A-B Lot 2 3-5Y Group	Pandemic Influenza Vaccine (GSK1562902A)	Subjects aged 3-5 years received 2 doses of GSK1562902A vaccine, lot 2. These subjects were enrolled in the Phase B of this NCT00502593 study (or study 108498). The GSK1562902A vaccine was administered intramuscularly in the deltoid region of the non-dominant arm on Days 0 and 21.
Fluarix-C 6-9Y Group	Fluarix™	Subjects aged 6-9 years received 2 doses of Fluarix™ vaccine. These subjects were enrolled in the Phase C of this NCT00502593 study (or study 108500). The Fluarix™ vaccine was administered intramuscularly in the deltoid region of the non-dominant arm on Days 0 and 21.
Fluarix-C 3-5Y Group	Fluarix™	Subjects aged 3-5 years received 2 doses of Fluarix™ vaccine. These subjects were enrolled in the Phase C of this NCT00502593 study (or study 108500). The Fluarix™ vaccine was administered intramuscularly in the deltoid region of the non-dominant arm on Days 0 and 21.
GSK1562902A-C Lot 3 6-9Y Group	Pandemic Influenza Vaccine (GSK1562902A)	Subjects aged 6-9 years received 2 doses of GSK1562902A vaccine, lot 3. These subjects were enrolled in the Phase C of this NCT00502593 study (or study 108500). The GSK1562902A vaccine was administered intramuscularly in the deltoid region of the non-dominant arm on Days 0 and 21.

Primary Outcome Measures

Name	Time	Method
Number of Seroconverted Subjects Against 2 Strains of Influenza Disease	At Month 24	A seroconverted subject was a subject with a pre-vaccination serum haemagglutination-inhibition (HI) antibody titer \< 1:10 and a post-vaccination HI antibody titer ≥1:40 or a pre-vaccination HI antibody titer ≥ 1:10 and at least four-fold increase in post-vaccination HI antibody titer. The 2 strains assessed were A/Vietnam/1194/04 (A/VIET) and A/Indonesia/05/2005 (A/INDO).
Seroconversion Factor for Hemagglutination Inhibition (HI) Antibodies Against 2 Strains of Influenza Disease	At Month 24	The seroconversion factor (SCF) was defined as the fold increase in serum Hemagglutination Inhibition (HI) geometric mean titers (GMTs) post vaccination compared to Day 0. The 2 flu strains assessed were A/Vietnam/1194/2004 (A/VIET) and A/Indonesia/5/2005 (A/INDO).
Number of Subjects With Any, Grade 3 and Related Unsolicited Adverse Events	During a 21 day follow-up period after the first vaccination, during a 30-day follow-up period after the second vaccination	An unsolicited adverse event is any adverse event (i.e. any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product) reported in addition to those solicited during the clinical study. Also any "solicited" symptom with onset outside the specified period of follow-up for solicited symptoms will be reported as an unsolicited adverse event. Grade 3 AE = AE that prevented normal activity, everyday activities, or required intervention of a physician/healthcare provider. Related = symptom assessed as causally related to study vaccination.
Number of Seroprotected Subjects Against the 2 Strains of Influenza Disease	At Month 24	A seroprotected subject was defined as a vaccinated subject with a serum HI antibody titer ≥ 1:40, a level of HI antibody that has been viewed as correlating with protection against influenza. The 2 influenza strains assessed were A/Vietnam/1194/04 (A/VIET) and A/Indonesia/5/2005 (A/INDO).
Number of Subjects With Any, Grade 3 and Related Solicited General Symptoms	During the 7-day (Days 0-6) follow-up period after any vaccination	Solicited general symptoms were arthralgia, fatigue, headache, muscle aches, shivering and fever, assessed as oral temperature above or equal (≥) 37.0 degrees Celsius (°C). Any = occurrence of a symptom regardless of intensity or relationship to vaccination. Grade 3 = general symptom that prevented normal activity, everyday activities, or required intervention of a physician/healthcare provider. Grade 3 fever= oral temperature ≥ 39.0°C. Related = symptom assessed as causally related to study vaccination. This outcome presents results related to subjects aged 6 to 9 years participating in the study phases A, B and C.
Number of Subjects With Changed Status as Regards to the Biochemical Parameter Creatine Phosphokinase (CPK) in Study Phase A	At Days 21 and 42 and Months 6, 12 and 24	Changes from baseline are categorised as below, within, or above the normal ranges at each scheduled post-vaccination time point versus the category of the laboratory values at baseline. Assessed parameters were alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine (CREA), blood urea nitrogen (BUN), lactate dehydrogenase (LDH), and creatine phosphokinase (CPK) Per parameter and range, it was assessed according to baseline values whether laboratory values of the subjects were below normal, normal or above the normal range. This outcome presents results for CPK for subjects participating in Phase A of the study.
Number of Subjects With Serious Adverse Events (SAEs)	During the entire study (Day 0 to Month 24)	Serious adverse events (SAEs) assessed include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization, result in disability/incapacity or are a congenital anomaly/birth defect in the offspring of a study subject. Any SAE = any SAE regardless of intensity or relationship to vaccination.
Number of Subjects With Changed Status as Regards to the Biochemical Parameter Alanine Aminotransferase (ALT) for Subjects in Study Phase A	At Days 21 and 42 and Months 6, 12 and 24	Changes from baseline are categorised as below, within(normal), or above the normal ranges at each scheduled post-vaccination time point versus the category of the laboratory values at baseline. Assessed parameters were alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine (CREA), blood urea nitrogen (BUN), lactate dehydrogenase (LDH), and creatine phosphokinase (CPK) Per parameter and range, it was assessed according to baseline values whether laboratory values of the subjects were below normal, normal or above the normal range. This outcome presents results for ALT for subjects participating in Phase A of the study.
Number of Subjects With Changed Status as Regards to the Biochemical Parameter Alanine Aminotransferase (ALT) for Subjects in Study Phase C	At Days 21, and 42, and at Months 6, 12 and 24	Changes from baseline are categorised as below, within, or above the normal ranges at each scheduled post-vaccination time point versus the category of the laboratory values at baseline. Assessed parameters were alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine (CREA), blood urea nitrogen (BUN), lactate dehydrogenase (LDH), and creatine phosphokinase (CPK) Per parameter and range, it was assessed according to baseline values whether laboratory values of the subjects were below normal, normal or above the normal range. This outcome presents results for ALT for subjects participating in Phase C of the study.
Number of Subjects With Changed Status as Regards to the Biochemical Parameter Aspartate Aminotransferase (AST) in Study Phase C	At Days 21, and 42, and at Months 6, 12 and 24	Changes from baseline are categorised as below, within, or above the normal ranges at each scheduled post-vaccination time point versus the category of the laboratory values at baseline. Assessed parameters were alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine (CREA), blood urea nitrogen (BUN), lactate dehydrogenase (LDH), and creatine phosphokinase (CPK) Per parameter and range, it was assessed according to baseline values whether laboratory values of the subjects were below normal, normal or above the normal range. This outcome presents results for AST for subjects participating in Phase C of the study.
Titers for Serum Hemagglutination Inhibition (HI) Antibodies Against 2 Strains of Influenza Disease	At Month 24	Titers of serum HI antibodies are presented as geometric mean titers (GMTs). The 2 influenza strains assessed were A/Vietnam/1194/04 (A/VIET) and A/Indonesia/05/2005 (A/INDO). The cut-off of the assay was the seropositivity cut-off value of 1:10
Number of Subjects With Any, Grade 3 and Related Solicited Local Symptoms	During the 7-day follow-up period after each vaccination	Assessed solicited local symptoms were ecchymosis, induration, pain, redness and swelling at the injection site. Any = occurrence of a symptom regardless of intensity. Grade 3 pain = significant pain at rest/ that prevented normal activities. Grade 3 ecchymosis/induration/redness/swelling = ecchymosis/induration/redness/swelling larger than (\>) 100 millimeters (mm). All solicited local symptoms were considered to be related to study vaccination. This outcome presents results from subjects participating to Phase B of the study.
Number of Subjects With Changed Status as Regards to the Biochemical Parameter Blood Urea Nitrogen (BUN) in Study Phase A	At Days 21 and 42 and Months 6, 12 and 24	Changes from baseline are categorised as below, within, or above the normal ranges at each scheduled post-vaccination time point versus the category of the laboratory values at baseline. Assessed parameters were alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine (CREA), blood urea nitrogen (BUN), lactate dehydrogenase (LDH), and creatine phosphokinase (CPK) Per parameter and range, it was assessed according to baseline values whether laboratory values of the subjects were below normal, normal or above the normal range. This outcome presents results for BUN for subjects participating in Phase A of the study.
Number of Subjects With Changed Status as Regards to the Biochemical Parameter Lactate Dehydrogenase (LDH) in Study Phase A	At Days 21 and 42 and Months 6, 12 and 24	Changes from baseline are categorised as below, within, or above the normal ranges at each scheduled post-vaccination time point versus the category of the laboratory values at baseline. Assessed parameters were alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine (CREA), blood urea nitrogen (BUN), lactate dehydrogenase (LDH), and creatine phosphokinase (CPK) Per parameter and range, it was assessed according to baseline values whether laboratory values of the subjects were below normal, normal or above the normal range. This outcome presents results for LDH for subjects participating in Phase A of the study
Number of Subjects With Changed Status as Regards to the Biochemical Parameter Alanine Aminotransferase (ALT) for Subjects in Study Phase B	At Days 21 and 42 and Months 6, 12 and 24	Changes from baseline are categorised as below, within, or above the normal ranges at each scheduled post-vaccination time point versus the category of the laboratory values at baseline. Assessed parameters were alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine (CREA), blood urea nitrogen (BUN), lactate dehydrogenase (LDH), and creatine phosphokinase (CPK) Per parameter and range, it was assessed according to baseline values whether laboratory values of the subjects were below normal, normal or above the normal range. This outcome presents results for ALT for subjects participating in Phase B of the study.
Number of Subjects With Changed Status as Regards to the Biochemical Parameter Blood Urea Nitrogen (BUN) in Study Phase B	At Days 21, and 42, and at Months 6, 12 and 24	Changes from baseline are categorised as below, within, or above the normal ranges at each scheduled post-vaccination time point versus the category of the laboratory values at baseline. Assessed parameters were alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine (CREA), blood urea nitrogen (BUN), lactate dehydrogenase (LDH), and creatine phosphokinase (CPK) Per parameter and range, it was assessed according to baseline values whether laboratory values of the subjects were below normal, normal or above the normal range. This outcome presents results for BUN for subjects participating in Phase B of the study.
Number of Subjects With Changed Status as Regards to the Biochemical Parameter Aspartate Aminotransferase (AST) in Study Phase A	At Days 21 and 42 and Months 6, 12 and 24	Changes from baseline are categorised as below, within, or above the normal ranges at each scheduled post-vaccination time point versus the category of the laboratory values at baseline. Assessed parameters were alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine (CREA), blood urea nitrogen (BUN), lactate dehydrogenase (LDH), and creatine phosphokinase (CPK) Per parameter and range, it was assessed according to baseline values whether laboratory values of the subjects were below normal, normal or above the normal range. This outcome presents results for AST for subjects participating in Phase A of the study.
Number of Subjects With Changed Status as Regards to the Biochemical Parameter Blood Creatinine (CREA) in Study Phase B	At Days 21, and 42, and at Months 6, 12 and 24	Changes from baseline are categorised as below, within, or above the normal ranges at each scheduled post-vaccination time point versus the category of the laboratory values at baseline. Assessed parameters were alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine (CREA), blood urea nitrogen (BUN), lactate dehydrogenase (LDH), and creatine phosphokinase (CPK) Per parameter and range, it was assessed according to baseline values whether laboratory values of the subjects were below normal, normal or above the normal range. This outcome presents results for CREA for subjects participating in Phase B of the study.
Number of Subjects With Normal and Abnormal Biochemical Parameters Assessed With Regards to Creatine Phosphokinase (CPK) in Study Phase A	At Days 0, 21, and 42, and at Months 6, 12 and 24	Assessed biochemical parameters were alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine (CREA), blood urea nitrogen (BUN), lactate dehydrogenase (LDH), and creatine phosphokinase (CPK). Per parameter , it was assessed whether subjects had laboratory values below normal, normal, or above normal range. This outcome presents CPK results for subjects participating in Phase A of the study.
Number of Subjects With Normal and Abnormal Biochemical Parameters Assessed With Regards to Blood Urea Nitrogen (BUN) in Study Phase C	At Days 0, 21 and 42 and at Months 6, 12 and 24	Assessed biochemical parameters were alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine (CREA), blood urea nitrogen (BUN), lactate dehydrogenase (LDH), and creatine phosphokinase (CPK). Per parameter , it was assessed whether subjects had laboratory values below normal, normal, or above normal range. This outcome presents BUN results, for subjects participating to Phase C of the study.
Number of Subjects With Normal and Abnormal Biochemical Parameters Assessed With Respect to Aspartate Aminotransferase (AST) in Study Phase C	At Days 0, 21, and 42, and at Months 6, 12 and 24	Assessed biochemical parameters were alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine (CREA), blood urea nitrogen (BUN), lactate dehydrogenase (LDH), and creatine phosphokinase (CPK). Per parameter , it was assessed whether subjects had laboratory values below normal, normal, or above normal range. This outcome presents AST results, for subjects participating to Phase C of the study.
Number of Subjects With Changed Status as Regards to the Biochemical Parameter Blood Creatinine (CREA) in Study Phase A	At Days 21 and 42 and Months 6, 12 and 24	Changes from baseline are categorised as below, within, or above the normal ranges at each scheduled post-vaccination time point versus the category of the laboratory values at baseline. Assessed parameters were alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine (CREA), blood urea nitrogen (BUN), lactate dehydrogenase (LDH), and creatine phosphokinase (CPK) Per parameter and range, it was assessed according to baseline values whether laboratory values of the subjects were below normal, normal or above the normal range. This outcome presents results for CREA for subjects participating in Phase A of the study.
Number of Subjects With Changed Status as Regards to the Biochemical Parameter Aspartate Aminotransferase (AST) in Study Phase B	At Days 21, and 42, and at Months 6, 12 and 24	Changes from baseline are categorised as below, within, or above the normal ranges at each scheduled post-vaccination time point versus the category of the laboratory values at baseline. Assessed parameters were alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine (CREA), blood urea nitrogen (BUN), lactate dehydrogenase (LDH), and creatine phosphokinase (CPK) Per parameter and range, it was assessed according to baseline values whether laboratory values of the subjects were below normal, normal or above the normal range. This outcome presents results for AST for subjects participating in Phase B of the study.
Number of Subjects With Changed Status as Regards to the Biochemical Parameter Blood Creatinine (CREA) in Study Phase C	At Days 21, and 42, and at Months 6, 12 and 24	Changes from baseline are categorised as below, within, or above the normal ranges at each scheduled post-vaccination time point versus the category of the laboratory values at baseline. Assessed parameters were alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine (CREA), blood urea nitrogen (BUN), lactate dehydrogenase (LDH), and creatine phosphokinase (CPK) Per parameter and range, it was assessed according to baseline values whether laboratory values of the subjects were below normal, normal or above the normal range. This outcome presents results for CREA for subjects participating in Phase C of the study.
Number of Subjects With Changed Status With Regards to Creatine Phosphokinase (CPK) in Study Phase C	At Days 21, and 42, and at Months 6, 12 and 24	Changes from baseline are categorised as below, within, or above the normal ranges at each scheduled post-vaccination time point versus the category of the laboratory values at baseline. Assessed parameters were alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine (CREA), blood urea nitrogen (BUN), lactate dehydrogenase (LDH), and creatine phosphokinase (CPK) Per parameter and range, it was assessed according to baseline values whether laboratory values of the subjects were below normal, normal or above the normal range. This outcome presents results for CPK for subjects participating in Phase C of the study.
Number of Subjects With Normal and Abnormal Biochemical Parameters Assessed With Respect to Aspartate Aminotransferase (AST) in Study Phase A	At Days 0, 21, and 42, and at Months 6, 12 and 24	Assessed biochemical parameters were alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine (CREA), blood urea nitrogen (BUN), lactate dehydrogenase (LDH), and creatine phosphokinase (CPK). Per parameter , it was assessed whether subjects had laboratory values below normal, normal, or above normal range. This outcome presents AST results for subjects participating in Phase A of the study.
Number of Subjects With Normal and Abnormal Biochemical Parameters Assessed With Regards to Blood Urea Nitrogen (BUN) in Study Phase A	At Days 0, 21, and 42, and at Months 6, 12 and 24	Assessed biochemical parameters were alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine (CREA), blood urea nitrogen (BUN), lactate dehydrogenase (LDH), and creatine phosphokinase (CPK). Per parameter , it was assessed whether subjects had laboratory values below normal, normal, or above normal range. This outcome presents BUN results for subjects participating in Phase A of the study.
Number of Subjects With Normal and Abnormal Biochemical Parameters Assessed With Regards to Creatine Phosphokinase (CPK) in Study Phase B	At Days 0, 21, and 42, and at Months 6, 12 and 24	Assessed biochemical parameters were alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine (CREA), blood urea nitrogen (BUN), lactate dehydrogenase (LDH), and creatine phosphokinase (CPK). Per parameter , it was assessed whether subjects had laboratory values below normal, normal, or above normal range. This outcome presents CPK results, for subjects participating to Phase B of the study.
Number of Subjects With Changed Status as Regards to the Biochemical Parameter Creatine Phosphokinase (CPK) in Study Phase B	At Days 21, and 42, and at Months 6, 12 and 24	Changes from baseline are categorised as below, within, or above the normal ranges at each scheduled post-vaccination time point versus the category of the laboratory values at baseline. Assessed parameters were alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine (CREA), blood urea nitrogen (BUN), lactate dehydrogenase (LDH), and creatine phosphokinase (CPK) Per parameter and range, it was assessed according to baseline values whether laboratory values of the subjects were below normal, normal or above the normal range. This outcome presents results for CPK for subjects participating in Phase B of the study.
Number of Subjects With Changed Status as Regards to the Biochemical Parameter Lactate Dehydrogenase (LDH) in Study Phase B	At Days 21, and 42, and at Months 6, 12 and 24	Changes from baseline are categorised as below, within, or above the normal ranges at each scheduled post-vaccination time point versus the category of the laboratory values at baseline. Assessed parameters were alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine (CREA), blood urea nitrogen (BUN), lactate dehydrogenase (LDH), and creatine phosphokinase (CPK) Per parameter and range, it was assessed according to baseline values whether laboratory values of the subjects were below normal, normal or above the normal range. This outcome presents results for LDH for subjects participating in Phase B of the study.
Number of Subjects With Normal and Abnormal Biochemical Parameters Assessed With Regards to Aspartate Aminotransferase (AST) in Study Phase B	At Days 0, 21, and 42, and at Months 6, 12 and 24	Assessed biochemical parameters were alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine (CREA), blood urea nitrogen (BUN), lactate dehydrogenase (LDH), and creatine phosphokinase (CPK). Per parameter , it was assessed whether subjects had laboratory values below normal, normal, or above normal range. This outcome presents AST results, for subjects participating to Phase B of the study.
Number of Subjects With Normal and Abnormal Biochemical Parameters Assessed With Regards to Lactate Dehydrogenase (LDH) in Study Phase B	At Days 0, 21, and 42, and at Months 6, 12 and 24	Assessed biochemical parameters were alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine (CREA), blood urea nitrogen (BUN), lactate dehydrogenase (LDH), and creatine phosphokinase (CPK). Per parameter , it was assessed whether subjects had laboratory values below normal, normal, or above normal range. This outcome presents LDH results, for subjects participating to Phase B of the study.
Number of Subjects With Normal and Abnormal Biochemical Parameters Assessed With Respect to Alanine Aminotransferase (ALT) in Study Phase C	At Days 0, 21, and 42, and at Months 6, 12 and 24	Assessed biochemical parameters were alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine (CREA), blood urea nitrogen (BUN), lactate dehydrogenase (LDH), and creatine phosphokinase (CPK). Per parameter , it was assessed whether subjects had laboratory values below normal, normal, or above normal range. This outcome presents ALT results, for subjects participating to Phase C of the study.
Number of Subjects With Normal and Abnormal Biochemical Parameters Assessed With Regards to Creatine Phosphokinase (CPK) in Study Phase C	At Days 0, 21, and 42, and at Months 6, 12 and 24	Assessed biochemical parameters were alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine (CREA), blood urea nitrogen (BUN), lactate dehydrogenase (LDH), and creatine phosphokinase (CPK). Per parameter , it was assessed whether subjects had laboratory values below normal, normal, or above normal range. This outcome presents CPK results, for subjects participating to Phase C of the study.
Number of Subjects With Normal and Abnormal Biochemical Parameters Assessed With Regards to Lactate Dehydrogenase (LDH) in Study Phase C	At Days 0, 21 and 42 and at Months 6, 12 and 24	Assessed biochemical parameters were alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine (CREA), blood urea nitrogen (BUN), lactate dehydrogenase (LDH), and creatine phosphokinase (CPK). Per parameter , it was assessed whether subjects had laboratory values below normal, normal, or above normal range. This outcome presents LDH results, for subjects participating to Phase C of the study.
Number of Subjects With Changed Status as Regards to the Biochemical Parameter Blood Urea Nitrogen (BUN) in Study Phase C	At Days 21, and 42, and at Months 6, 12 and 24	Changes from baseline are categorised as below, within(normal), or above the normal ranges at each scheduled post-vaccination time point versus the category of the laboratory values at baseline. Assessed parameters were alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine (CREA), blood urea nitrogen (BUN), lactate dehydrogenase (LDH), and creatine phosphokinase (CPK) Per parameter and range, it was assessed according to baseline values whether laboratory values of the subjects were below normal, normal or above the normal range. This outcome presents results for BUN for subjects participating in Phase C of the study.
Number of Subjects With Normal and Abnormal Biochemical Parameters Assessed With Regards to Lactate Dehydrogenase (LDH) in Study Phase A	At Days 0, 21, and 42, and at Months 6, 12 and 24	Assessed biochemical parameters were alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine (CREA), blood urea nitrogen (BUN), lactate dehydrogenase (LDH), and creatine phosphokinase (CPK). Per parameter , it was assessed whether subjects had laboratory values below normal, normal, or above normal range. This outcome presents LDH results for subjects participating in Phase A of the study.
Number of Subjects With Normal and Abnormal Biochemical Parameters Assessed With Respect to Alanine Aminotransferase (ALT) in Study Phase B	At Days 0, 21, and 42, and at Months 6, 12 and 24	Assessed biochemical parameters were alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine (CREA), blood urea nitrogen (BUN), lactate dehydrogenase (LDH), and creatine phosphokinase (CPK). Per parameter , it was assessed whether subjects had laboratory values below normal, normal, or above normal range. This outcome presents AST results, for subjects participating to Phase B of the study.
Number of Subjects With Normal and Abnormal Biochemical Parameters Assessed With Regards to Creatinine (CREA) in Study Phase B	At Days 0, 21 and 42 and at Month 6, 12 and 24	Assessed biochemical parameters were alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine (CREA), blood urea nitrogen (BUN), lactate dehydrogenase (LDH), and creatine phosphokinase (CPK). Per parameter , it was assessed whether subjects had laboratory values below normal, normal, or above normal range. This outcome presents CREA results, for subjects participating in Phase B of the study.
Number of Subjects With Normal and Abnormal Biochemical Parameters Assessed With Regards to Creatinine (CREA) in Study Phase C	At Days 0, 21 and 42 and at Months 6, 12 and 24	Assessed biochemical parameters were alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine (CREA), blood urea nitrogen (BUN), lactate dehydrogenase (LDH), and creatine phosphokinase (CPK). Per parameter , it was assessed whether subjects had laboratory values below normal, normal, or above normal range. This outcome presents CREA results, for subjects participating to Phase C of the study.
Number of Subjects With Changed Status With Regards to Lactate Dehydrogenase (LDH) in Study Phase C	At Days 21, and 42, and at Months 6, 12 and 24	Changes from baseline are categorised as below, within, or above the normal ranges at each scheduled post-vaccination time point versus the category of the laboratory values at baseline. Assessed parameters were alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine (CREA), blood urea nitrogen (BUN), lactate dehydrogenase (LDH), and creatine phosphokinase (CPK) Per parameter and range, it was assessed according to baseline values whether laboratory values of the subjects were below normal, normal or above the normal range. This outcome presents results for LDH for subjects participating in Phase C of the study.
Number of Subjects With Normal and Abnormal Biochemical Parameters Assessed With Respect to Alanine Aminotransferase (ALT) in Study Phase A	At Days 0, 21, and 42, and at Months 6, 12 and 24	Assessed biochemical parameters were alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine (CREA), blood urea nitrogen (BUN), lactate dehydrogenase (LDH), and creatine phosphokinase (CPK). Per parameter , it was assessed whether subjects had laboratory values below normal, normal, or above normal range. This outcome presents ALT results for subjects participating in Phase A of the study.
Number of Subjects With Normal and Abnormal Biochemical Parameters Assessed With Regards to Creatinine (CREA) in Study Phase A	At Days 0, 21, and 42, and at Months 6, 12 and 24	Assessed biochemical parameters were alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine (CREA), blood urea nitrogen (BUN), lactate dehydrogenase (LDH), and creatine phosphokinase (CPK). Per parameter , it was assessed whether subjects had laboratory values below normal, normal, or above normal range. This outcome presents CREA results, for subjects participating in Phase A of the study.
Number of Subjects With Normal and Abnormal Biochemical Parameters Assessed With Regards to Blood Urea Nitrogen (BUN) in Study Phase B	At Days 0, 21, and 42, and at Months 6, 12 and 24	Assessed biochemical parameters were alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine (CREA), blood urea nitrogen (BUN), lactate dehydrogenase (LDH), and creatine phosphokinase (CPK). Per parameter , it was assessed whether subjects had laboratory values below normal, normal, or above normal range. This outcome presents BUN results, for subjects participating to Phase B of the study.

Secondary Outcome Measures

Name	Time	Method
Number of Subjects With Adverse Events of Specific Interest (AESIs)	Throughout the entire study period, from Day 0 to Month 24	AESIs are adverse events such as clearly autoimmune diseases and also other inflammatory and/or neurologic disorders which may or may not have an autoimmune etiology. AESIs assessed included neuroinflammatory disorders such as cranial nerve disorders, multiple sclerosis,transverse myelitis, Guillain-Barré syndromeor neuritis), musculoskeletal disorders (such as systemic lupus erythematosus, cutaneous lupus, polymyositis, rheumatoid arthritis, reactive arthritis, psoriatic arthropathy, or undifferentiated spondyloarthropathy), gastrointestinal disorders (such as Crohn's disease, ulcerative colitis, ulcerative proctitis, celiac disease), metabolic diseases (such as autoimmune thyroiditis, Addison's disease). skin disorders (such as psoriasis, vitiligo, Raynaud's phenomenon, or autoimmune bullous skin diseases), and other conditions as autoimmune hemolytic anemia, thrombocytopenias, antiphospholipid syndrome, vasculitis, autoimmune hepatitis, or sarcoidosis.
Titers for Serum Neutralizing Antibodies Against 1 Strain of Influenza Disease	At Days 0, 21 and 42	Titers of serum neutralizing antibodies are presented as geometric mean titers (GMTs). The cut-off of the assay was the seropositivity cut-off value of 1:28. The influenza strain assessed was A/Vietnam/1194/04 (A/VIET). Results presented are for subjects participating in Phase C of the study.
Number of Seroconverted Subjects Against 2 Strains of Influenza Disease as Regards to Neutralizing Antibody Response	At Months 6, 12 and 24.	A seroconverted subject as regards to neutralizing antibody response was a subject with a minimum 4-fold increase in neutralizing antibody titer at post-vaccination. The 2 influenza strains assessed were A/Vietnam/1194/04 (A/VIET) and A/Indonesia/05/2005 (A/INDO) strains. Results presented are for subjects participating in Phase A of the study. Subjects participating to Phases B and C of the study were not analysed at these persistence time points for this outcome.
Number of Seroconverted Subjects Against One Strain of Influenza Disease With Respect to Serum Neutralizing Antibodies	At Days 21 and 42	A seroconverted subject as regards to serum neutralizing antibodies against influenza disease was a subject with a minimum 4-fold increase in serum neutralizing antibody titer at post-vaccination. The flu strain assessed was A/Vietnam/1194/2004 (A/VIET). This outcome presents results for subjects participating to Phase C of the study.
Titers for Serum Neutralizing Antibodies Against 2 Strains of Influenza Disease	At Months 6, 12 and 24	Titers of serum neutralizing antibodies are presented as geometric mean titers (GMTs). The cut-off of the assay was the seropositivity cut-off value of 1:28. The 2 influenza strains assessed were A/Vietnam/1194/04 (A/VIET) and A/Indonesia/05/2005 (A/INDO) strains. Results presented are for subjects participating in Phase A of the study. Subjects participating to Phases B and C of the study were not analysed at these persistence time points for this outcome.