Safety, Tolerability and Immunogenicity of Two Doses of Adjuvanted Monovalent Influenza Vaccine Administered to Healthy Adult and Elderly Subjects

Study Overview
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Brief Summary
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The present study, phase III, randomized, controlled, observer-blind, multicenter study, will evaluate safety, tolerability and immunogenicity of two doses of an adjuvanted monovalent influenza vaccine compared with an adjuvanted interpandemic trivalent influenza vaccine in a population of healthy adult and elderly subjects.

Official Title
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A Phase III, Randomized, Controlled, Observer-blind, Multicenter Study to Evaluate the Safety, Tolerability and Immunogenicity of Two Doses of a Monovalent A/H5N1 Influenza Vaccine Adjuvanted With MF59 (Fluad-H5N1) in Adult and Elderly Subjects

Conditions
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Pandemic Influenza Disease

Intervention / Treatment
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* Biological: Placebo (PL)
* Biological: Trivalent influenza virus vaccine (TIV)
* Biological: Adjuvanted monovalent influenza virus vaccine (aH5N1)
* Biological: Adjuvanted trivalent influenza virus vaccine (aTIV)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects 18 years of age and older who were mentally competent and who had signed an informed consent form after having received a detailed explanation of the study protocol; In good health as determined by: medical history, physical examination, clinical judgment of the Investigator; Able to understand and comply with all study procedures and to complete study diaries, could be contacted, and were available for study visits; Exclusion Criteria: Receipt of another investigational agent within 4 weeks; Laboratory-confirmed influenza disease within 6 months prior to Visit 1; Receipt of influenza vaccination for current season 2008/2009; Experienced any acute disease or infection requiring systemic antibiotic or antiviral therapy (chronic antibiotic therapy for urinary tract prophylaxis was acceptable) within the past 7 days; Experienced fever (defined as axillary temperature ≥38.0°C) within 7 days prior to Visit 1; Pregnant or breastfeeding; Females of childbearing potential who were sexually active and had not used or did not plan or refused to use an acceptable method of birth control during the active phase of the study (at least up to three weeks after last vaccine injection); Any serious disease, such as: cancer, autoimmune disease (including rheumatoid arthritis); diabetes mellitus type I and type II; diabetes relating to genetic defects/syndromes, diseases of the exocrine pancreas or infections; advanced arteriosclerotic disease; severe chronic obstructive pulmonary disease (COPD), i.e. GOLD stages 3 and 4; acute or progressive hepatic disease and renal disease; congestive heart failure; Body Mass Index (BMI) ≥35 kg/m2 where BMI reflects obesity and not high muscle mass; History of progressive or severe neurologic disorders, of any neurological symptoms or signs, or anaphylactic shock following administration of any study vaccine; Bleeding diathesis; Surgery planned during the study period; Hypersensitivity to eggs, chicken protein, chicken feathers, influenza viral protein, neomycin or polymyxin or any other component of the study vaccines; Known or suspected impairment/alteration of immune function, for example, resulting from: receipt of immunosuppressive therapy (any corticosteroid therapy or cancer chemotherapy) or other immunosuppressive agents within the past 60 days and for the full length of the study; receipt of immunostimulants; receipt of parenteral immunoglobulin preparation, blood products and/or plasma derivates within the past 3 months and for the full length of the study; suspected or known HIV infection or HIV-related disease; Receipt of non study vaccines (with the exception of post-exposure vaccination in a medical emergency, e.g. hepatitis, rabies, tetanus) within 3 weeks prior to Visit 1 or planned vaccination within 3 weeks following the last study vaccination; History of (or current) drug or alcohol abuse that in the investigator's opinion would interfere with safety of the subject or the evaluation of study objectives; Members of research staff and their relatives; 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: 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TIV + aH5N1<br>First dose of the non-adjuvanted trivalent influenza virus vaccine (TIV) followed by two doses of the adjuvanted monovalent influenza virus vaccine (aH5N1). | Biological: Trivalent influenza virus vaccine (TIV)<br>* A single IM injection of a 0.5 ml dose of non-adjuvanted trivalent influenza virus vaccine administered in the deltoid muscle, preferably of the non-dominant arm.<br>Biological: Adjuvanted monovalent influenza virus vaccine (aH5N1)<br>* Two intramuscular (IM) injections of a 0.5 ml dose administered three weeks apart in the deltoid muscle.<br>|
| Active Comparator: PL + aTIV<br>First dose of placebo (PL-saline) followed by two doses of the adjuvanted trivalent influenza virus vaccine (aTIV). | Biological: Placebo (PL)<br>* One dose of 0.5 ml IM injection of isotonic saline solution was administered in the deltoid muscle, preferably of the non-dominant arm.<br>Biological: Adjuvanted trivalent influenza virus vaccine (aTIV)<br>* Two IM injections of a 0.5 ml dose of adjuvanted trivalent influenza virus vaccine administered three weeks apart, in the deltoid muscle.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With at Least One Reactogenicity Sign After Two Doses of the Adjuvanted Pandemic Influenza Vaccine. | To assess the safety and tolerability profile of two doses of the MF59-adjuvanted A/Vietnam/1194/2004 pandemic influenza vaccine (aH5N1), each containing 7.5 μg of H5N1 antigen in terms of the number of participants who reported local and systemic reactions up to 6 days after each vaccination per vaccination group. | Up to 6 days after each vaccination. | 
| Number of Subjects Exposed to Adjuvanted Pandemic Influenza Vaccine. | To report safety data from a large enough number of subjects exposed to adjuvanted pandemic influenza vaccine aH5N1 capable of detecting rare adverse events (AEs), i.e. events occurring at a frequency of <=0.1%, & uncommon AEs in elderly, i.e. occurring at a frequency of <=1% of subjects. | Upto Day 224 post vaccination | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Number of Subjects With at Least One Reactogenicity Sign After Two Doses of the Adjuvanted Pandemic aH5N1 Vaccine as Compared With the Adjuvanted Seasonal Trivalent Influenza Vaccine aTIV. | To evaluate the safety and tolerability profile of two doses of the adjuvanted pandemic H5N1 vaccine (aH5N1) as compared with the MF59-adjuvanted seasonal trivalent influenza vaccine (aTIV), in terms of the number of subjects who reported local and systemic reactions up to 6 days after each vaccination per vaccination group. | Up to 6 days after each vaccination. | 
| Geometric Mean Titers (GMTs) After Two Doses of the Adjuvanted Pandemic aH5N1 Vaccine Against the Homologous A/Vietnam/1194/2004 Strain. | To evaluate the immunogenicity of two doses of the adjuvanted pandemic H5N1 vaccine (aH5N1), each containing 7.5µg of H5N1 antigen, in terms of GMTs against the homologous A/Vietnam/1194/2004 strain, as determined by Hemagglutination Inhibition (HI) assay and Microneutralization (MN) assay. | Day 22, Day 43, Day 64 | 
| Geometric Mean Areas (GMAs) After Two Doses of the Adjuvanted Pandemic Vaccine (aH5N1). | To evaluate the immunogenicity of two doses of the adjuvanted pandemic vaccine aH5N1, in terms of GMAs as determined by Single Radial Hemolysis (SRH) assay. GMA: For each vaccine group, least squares GMAs (for SRH data), associated 2-sided 95% confidence interval and median, minimal, and maximal titer values were determined for study Day 22, Day 43 and Day 64. | Day 22, Day 43, Day 64 | 
| Geometric Mean Ratios (GMRs) After Two Doses of the Adjuvanted Pandemic aH5N1 Vaccine Against the Homologous A/Vietnam/1194/2004 Strain. | To evaluate the immunogenicity of two doses of the adjuvanted pandemic vaccine (aH5N1), each containing 7.5µg of H5N1 antigen,in terms of GMRs against the homologous A/Vietnam/1194/2004 strain, as determined by HI, MN and SRH assays. | Day 43/Day 22, Day 64/Day 22 | 
| Percentages of Subjects With HI Titers ≥ 40 and GMAs ≥ 25mm^2, After Two Doses of the Adjuvanted Pandemic aH5N1 Vaccine Against the Homologous A/Vietnam/1194/2004 Strain. | To evaluate the immunogenicity of two doses of the adjuvanted pandemic vaccine aH5N1, each containing 7.5µg of H5N1 antigen, against the homologous A/Vietnam/1194/2004 strain, in terms of percentages of subjects achieving HI titers ≥ 40 and GMAs ≥ 25mm^2, as determined by HI and SRH assays. GMA: For each vaccine group, least squares GMAs (for SRH data), associated 2-sided 95% confidence interval and median, minimal, and maximal titer values were determined for study Day 22, Day 43 and Day 64. | Day 22, Day 43 and Day 64 | 
| Percentages of Subjects Achieving Seroconversion or Significant Increase in Antibody Titer After Two Doses of the Adjuvanted Pandemic aH5N1 Vaccine Against the Homologous A/Vietnam/1194/2004 Strain. | To evaluate the immunogenicity of two doses of the adjuvanted pandemic vaccine aH5N1, each containing 7.5µg of H5N1 antigen, against the homologous A/Vietnam/1194/2004 strain, in terms of percentages of subjects achieving seroconversion or significant increase in antibody titer as measured by HI and SRH assays. | Day 43/Day 22 and Day 64/Day 22 | 
| GMTs After Two Doses of the Adjuvanted Pandemic aH5N1 Vaccine Against the Heterologous A/Turkey/Turkey/1/2005 Strain. | To evaluate the immunogenicity of two doses of the adjuvanted pandemic vaccine (aH5N1), each containing 7.5µg of H5N1 antigen, in terms of GMTs against the heterologous A/turkey/Turkey/1/2005 strain, as determined by HI and MN assays. | Day 22, Day 43 and Day 64 | 
| GMAs After Two Doses of the Adjuvanted Pandemic aH5N1 Vaccine Against the Heterologous A/Turkey/Turkey/1/2005 Strain. | To evaluate the immunogenicity of two doses of adjuvanted pandemic vaccine aH5N1, each containing 7.5µg of H5N1 antigen, in terms of GMAs against the heterologous A/turkey/Turkey/1/2005 strain, as determined by SRH assay. GMA: For each vaccine group, least squares GMAs (for SRH data), associated 2-sided 95% confidence interval and median, minimal, and maximal titer values were determined for study Day 22, Day 43 and Day 64. | Day 22, Day 43 and Day 64 | 
| GMRs After Two Doses of the Adjuvanted Pandemic aH5N1 Vaccine Against the Heterologous A/Turkey/Turkey/1/2005 Strain. | To evaluate the immunogenicity of two doses of the adjuvanted pandemic vaccine aH5N1, each containing 7.5µg of H5N1 antigen, in terms of GMRs against the heterologous A/turkey/Turkey/1/2005 strain, as determined by HI, MN and SRH assays. | Day 43/Day 22 and Day 64/Day 22 | 
| Percentages of Subjects With HI ≥ 40 and GMAs ≥ 25mm^2, After Two Doses of the Adjuvanted Pandemic aH5N1 Vaccine Against the Heterologous A/Turkey/Turkey/1/2005 Strain. | To evaluate the immunogenicity of two doses of the adjuvanted pandemic vaccine aH5N1, each containing 7.5µg of H5N1 antigen, against the heterologous A/turkey/Turkey/1/2005 strain, in terms of percentages of subjects achieving HI titers ≥ 40 and GMAs ≥ 25mm^2 as determined by HI and SRH assays. GMA: For each vaccine group, least squares GMAs (for SRH data), associated 2-sided 95% confidence interval and median, minimal, and maximal titer values were determined for study Vaccine on Day 22, Day 43, Day 64. | Day 22, Day 43 and Day 64 | 
| Percentages of Subjects Achieving Seroconversion or Significant Increase in Antibody Titers, After Two Doses of the Adjuvanted Pandemic aH5N1 Vaccine Against the Heterologous A/Turkey/Turkey/1/2005 Strain. | To evaluate the immunogenicity of two doses of the adjuvanted pandemic vaccine aH5N1, each containing 7.5µg of H5N1 antigen, against the heterologous A/turkey/Turkey/1/2005 strain, in terms of percentages of subjects achieving seroconversion or significant increase in antibody titer as measured by HI and SRH assays. | Day 43/Day 22 and Day 64/Day 22) | 
| Percentages of Subjects With MN Titers ≥20, ≥40, ≥80, After Two Doses of the Adjuvanted Pandemic aH5N1 Vaccine Against the Homologous A/Vietnam/1194/2004 Strain. | To evaluate the immunogenicity of two doses of the adjuvanted pandemic vaccine (aH5N1), each containing 7.5μg of H5N1 antigen, against the homologous A/Vietnam/1194/2004 strain, in terms of percentages of subjects achieving MN Titers ≥20, ≥ 40, ≥80 on Days 22, Day 43 and Day 64. | Day 22, Day 43 and Day 64 | 
| Percentages of Subjects With MN Titers ≥20, ≥40, ≥80, After Two Doses of the Adjuvanted Pandemic aH5N1 Vaccine Against the Heterologous A/Turkey/Turkey/1/2005 Strain. | To evaluate the immunogenicity of two doses of the adjuvanted pandemic vaccine aH5N1, each containing 7.5μg of H5N1 antigen, against the heterologous A/turkey/Turkey/1/2005 Strain, in terms of percentages of subjects achieving MN Titers ≥20, ≥ 40, ≥80 on Day 22, Day 43 and Day 64. | Day 22, Day 43 and Day 64 | 
| Percentages of Subjects Achieving at Least a Four-fold Rise in MN Antibody Titer on Day 43 and Day 64, Compared to Day 22 Against Homologous Strains. | To evaluate the immunogenicity of two doses of the adjuvanted pandemic vaccine aH5N1, each containing 7.5μg of H5N1 antigen, against the homologous A/Vietnam/1194/2004 strain, in terms of percentages of subjects achieving at least a four-fold rise in MN antibody titer on Day 43 and Day 64, compared to Day 22. | Day 43/Day 22 and Day 64/Day 22 | 
| Percentages of Subjects Achieving at Least a Four-fold Rise in MN Antibody Titer on Day 43 and Day 64, Compared to Day 22 Against Heterologous Strains. | To evaluate the immunogenicity of two doses of the adjuvanted pandemic vaccine (aH5N1), each containing 7.5μg of H5N1 antigen, against Heterologous A/turkey/Turkey/1/2005 Strain, in terms of percentages of subjects achieving at least a four-fold rise in MN antibody titer on Day 43 and Day 64, compared to Day 22. | Day 43/Day 22 and Day 64/Day 22 | 
| Number of Subjects Reporting Unsolicited AEs After Vaccination. | The number of subjects reporting any unsolicited AEs any, Possibly/probably related AEs, serious adverse events (SAEs), AEs leading to withdrawal (WD), AEs leading to death from Day 1 through Day 224 post vaccination. | Day 1 through Day 224 post vaccination | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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virus, pandemic influenza, vaccine