Safety and Immunogenicity of Two Doses of a Tetravalent Influenza Vaccine in Adults Aged 18 Years and Above

Study Overview
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Brief Summary
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Evaluate the immune response and reactogenicity of H5N1 vaccination in adults aged 18 years and above (as part of a tetravalent vaccine)

Official Title
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A Phase II, Randomized, Placebo-controlled, Observer-blind, Multi Center Study on the Safety and Immunogenicity of Novartis Tetravalent Influenza Vaccine (Containing Both Interpandemic Strains and H5N1) in Adults Aged 18 Years and Above

Conditions
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Influenza

Intervention / Treatment
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* Biological: MF59-eTIV-H5N1+ placebo /pandemic influenza vaccine
* Biological: Pandemic influenza vaccine + placebo /MF59-eTIV-H5N1
* Biological: Pandemic influenza vaccine + seasonal influenza vaccine /pandemic influenza vaccine
* Biological: Pandemic influenza vaccine + placebo / MF59-eTIV-H5N1
* Biological: Pandemic influenza vaccine + seasonal influenza vaccine / pandemic influenza vaccine
* Biological: MF59-eTIV-H5N1 + Placebo/pandemic influenza vaccine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy subjects (aged 18 years and above) who have signed an informed consent form Exclusion Criteria: Any acute or chronic illness Receipt of seasonal influenza vaccine for the current season 2007/2008 Known or suspected impairment/alteration of immune function Receipt of another vaccine within 3 weeks prior to Visit 1 or planned vaccination within 3 weeks following the last study vaccination Any serious disease Hypersensitivity to eggs, chicken protein, chicken feathers, influenza viral protein,neomycin or kanamycin or any other component of the study vaccine Receipt of blood, blood products or immunoglobulins 3 months prior to vaccination

Ages Eligible for Study
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Minimum Age: 18 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: T/P-A<br>One dose of the tetravalent influenza vaccine (T) and concomitantly, but in a different arm, one dose of placebo (P) on day 1, followed by Aflunov (A) on day 22 | Biological: MF59-eTIV-H5N1+ placebo /pandemic influenza vaccine<br>* Tetravalent influenza vaccine (MF59-eTIV-H5N1)and placebo on day 1 followed 3-5 weeks later by pandemic influenza vaccine, including serology blood draw at V1+V3.<br>|
| Experimental: A/P-T<br>One dose of the Aflunov (A) and concomitantly, but in a different arm, one dose of placebo (P) on day 1, followed by Tetravalent influenza vaccine (T) on day 22. | Biological: Pandemic influenza vaccine + placebo /MF59-eTIV-H5N1<br>* Pandemic influenza vaccine plus placebo on day 1 followed 3-5 weeks later by tetravalent influenza vaccine (MF59-eTIV-H5N1), including serology blood draw at V1+V3.<br>|
| Active Comparator: A/S-A<br>One dose of Aflunov (A) and concomitantly, but in a different arm, one dose of licensed seasonal vaccine (S) on day 1, followed Aflunov (A) on day 22. | Biological: Pandemic influenza vaccine + seasonal influenza vaccine /pandemic influenza vaccine<br>* Pandemic influenza vaccine plus seasonal influenza vaccine, 3-5 weeks later pandemic influenza vaccine , including serology blood draw at V1+V3.<br>|
| Experimental: T/P-A (V2 blood draw)<br>One dose of the tetravalent influenza vaccine (T) and concomitantly, but in a different arm, one dose of placebo (P) on day 1, followed by a blood draw at visit 2 (V2) prior to Aflunov (A) vaccination on day 22. | Biological: MF59-eTIV-H5N1 + Placebo/pandemic influenza vaccine<br>* Tetravalent influenza vaccine (MF59-eTIV-H5N1)plus placebo followed 3-5 weeks later by pandemic influenza vaccine, including serology blood draw at V1, V2 and V3.<br>|
| Experimental: A/P-T (V2 blood draw)<br>One dose of the Aflunov(A) and concomitantly, but in a different arm, one dose of placebo (P) on day 1, followed by additional blood draw at visit 2 (V2) prior to the Tetravalent influenza vaccination (T) on day 22. | Biological: Pandemic influenza vaccine + placebo / MF59-eTIV-H5N1<br>* Pandemic influenza vaccine plus placebo followed 3-5 weeks later by tetravalent influenza vaccine (MF59-eTIV-H5N1), including serology blood draw at V1, V2 and V3.<br>|
| Active Comparator: A/S-A (V2 blood draw)<br>One dose of Aflunov (A)and concomitantly, but in a different arm, one dose of licensed seasonal vaccine (S) on day 1, followed by an additional blood draw at visit 2 (V2) prior to Aflunov (A) vaccination on day 22. | Biological: Pandemic influenza vaccine + seasonal influenza vaccine / pandemic influenza vaccine<br>* Pandemic influenza vaccine plus seasonal influenza vaccine followed 3-5 weeks later by pandemic influenza vaccine, including serology blood draw at V1, V2 and V3.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To Demonstrate the Equivalence of Antibody Response Against A/H5N1 Strain Elicited by the Three Different Immunization Schedules on Day 43. | The antibody response was determined by SRH assay. Geometric mean areas (GMAs) and geometric mean ratios (GMRs) in the SRH assay were used to demonstrate the equivalence. The statistical analysis was done based on the GMRs. | up to day 43 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects (Subjects ≤ 60 Years) With Reported Local Reactions After First Vaccination | Local reactions were collected up to 7 days after 1st vaccinations. All subjects were instructed to complete a diary card to record local reactions starting on the day of vaccination (after 6 hours) and for each of the 6 days following each immunization. The table represents local reactions after first vaccination in each arm differently. | Up to 7 days after 1st vaccination | 
| Number of Subjects (Subjects ≤60 Years) With Reported Local Reactions After Second Vaccination | Local reactions were collected up to 7 days after 1st vaccinations. All subjects were instructed to complete a diary card to record local reactions starting on the day of vaccination (after 6 hours) and for each of the 6 days following each immunization. | Up to 7 days after 2nd vaccination | 
| Number of Subjects (Subjects ≤ 60 Years) With Reported Systemic Reactions After 1st and 2nd Vaccinations. | Systemic reactions were collected upto 7 days after 1st and 2nd vaccinations. All subjects were instructed to complete a diary card to record systemic reactions starting on the day of vaccination (after 6 hours) and for each of the 6 days following each immunization. | 7 days after 1st and 2nd vaccinations each | 
| Percentages of Subjects Achieving Seroconversion/Significant Increase in Antibody Titre/ Area as Measured by SRH and (HI) and at Least 4 Fold Rise in Titres by Micro-neutralization (MN) Assay-H5N1 Strain | Measurement of immunogenicity in terms of significant increase in antibody titer and Seroconversion. Significant increase in antibody titer is defined as at least a four-fold increase from non-negative pre-vaccination serum (≥ 10) for HI or a 50% increase in area for SRH. Seroconversion is defined as negative pre-vaccination serum / post-vaccination titer ≥40 for HI (area ≥25 mm2 for SRH) | up to day 43 | 
| Percentages of Subjects Achieving HI/MN ≥ 1:40 and SRH Area ≥ 25^mm2 | Measurement of immunogenicity in terms of percentage of subjects achieving a titre ≥ 40/area ≥ 25mm^2 after immunization as determined by HI (Haemagglutination Inhibition), MN(Microneutralization) and SRH assay. | Up to 43 days | 
| Antibody Response Determined by HI and MN Assay. | Measurement of immunogenicity in terms of Geometric mean titers (GMTs) as determined by HI and MN assay. | Up to 43 days | 
| Percentages of B-cell Antibodies Against H5N1 and H1N1 After Each Vaccination. | The Cell Mediated Immunity (CMI) response was evaluated in a randomly selected subgroup of approximately 92 subjects from all the vaccine groups out of a total of 601 enrolled subjects. Frequency of circulating memory B cells (MBC), capable of differentiating in vitro into cell secreting IgG (Immunoglobulin G) antibodies specific for H5N1 (the subunit from A/Vietnam/1194/2004) or for H1N1 (the subunit from A/Solomon Island/3/2006) were determined by an ELISA-coupled limiting dilution assay.The frequency of H5N1-IgG MBC and H1N1-IgG MBC was expressed as percentages (%) of total IgG producing MBC. | Three weeks after first vaccination (day 22) and three weeks after second vaccination (day 43) | 
| Mean T-Cells Per Million Total Cells (95% CI) in Response to H5 Peptides and H5N1 Subunit | Frequency and functionality of vaccine antigen-specific CD4+ (cluster of differentiation 4) T cells was assessed in peripheral blood (PBMC) taken at days 1, 22 and 43 after in vitro stimulation with: Library of 70 peptides spanning the whole H5 A/Vietnam/1194/2004 protein (H5 pool of 70 Vietnam) H5N1 subunit from A/Vietnam/1194/2004 (H5N1 Vietnam) H3N2 subunit from A/ Wisconsin/67/2005 (H3N2 Wisconsin) H1N1 subunit from A/Solomon Islands/3/2006 (H1N1 Solomon Islands) Polyclonal stimulus agonistic aCD3 mAb [monoclonal antibody (aCD3)]. The change in frequency of T-cells was measured. | Three weeks after 1st vaccination (day 22) and three weeks after 2nd vaccination (day 43) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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avian flu, seasonal influenza vaccine, influenza vaccine, prepandemic vaccine, virus strain with the potential to cause pandemic, tetravalent vaccine, Prophylaxis of influenza