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

• The Number of Participants With at Least One Reactogenicity Sign After Two Doses of the Adjuvanted Pandemic H5N1 Vaccine as Compared With the Adjuvanted Seasonal Trivalent Influenza Vaccine [ Time Frame: Up to 7 days after each vaccination ] [ Designated as safety issue: Yes ]
  To evaluate the safety and tolerability profile of two dose of the adjuvanted pandemic H5N1 vaccine (MF59-eH5N1) as compared with the MF59-adjuvanted seasonal trivalent influenza vaccine (MF59-eTIV), in terms of the number of participants who reported local and systemic reactions up to 7 days after each vaccination per vaccination group.
• Geometric Mean Titers After Two Doses of the Adjuvanted Pandemic H5N1 Vaccine Against the Homologous A/Vietnam/1194/2004 Strain [ Time Frame: 3 weeks after vaccination (day 22, day 43, day 64) ] [ Designated as safety issue: No ]
  To evaluate the immunogenicity of two doses of the adjuvanted pandemic H5N1 vaccine (MF59-eH5N1), each containing 7.5µg of H5N1 antigen,in terms of Geometric Mean Titers(GMTs) against the homologous A/Vietnam/1194/2004 strain, as determined by hemagglutination Inhibition(HI) assay and Microneutralization(MN) assay.
• Geometric Mean Areas After Two Doses of the Adjuvanted Monovalent Influenza Virus Vaccine (aH5N1) [ Time Frame: 3 weeks after vaccination (day22, day 43, day 64) ] [ Designated as safety issue: No ]

  To evaluate the immunogenicity of two doses of the adjuvanted monovalent influenza virus vaccine (aH5N1), in terms of Geometric Mean Areas (GMAs) as determined by Single Radial Haemolysis(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 value were determined for study day 22,43 and 64.

• Geometric Mean Ratios After Two Doses of the Adjuvanted Pandemic H5N1 Vaccine Against the Homologous A/Vietnam/1194/2004 Strain [ Time Frame: 3 weeks after vaccination (day 43/day22, day 64/day43) ] [ Designated as safety issue: No ]
  To evaluate the immunogenicity of two doses of the adjuvanted pandemic H5N1 vaccine (MF59-eH5N1), each containing 7.5µg of H5N1 antigen,in terms of Geometric Mean Ratio(GMRs) against the homologous A/Vietnam/1194/2004 strain, as determined by HI, MN and SRH assays.
• Percentages of Participants Achieving Geometric Mean Titers ≥ 40 and Geometric Mean Areas ≥ 25mm2, After Two Doses of the Adjuvanted Pandemic H5N1 Vaccine Against the Homologous A/Vietnam/1194/2004 Strain) [ Time Frame: 3 weeks after vaccination (day 22, day 43, day 64) ] [ Designated as safety issue: No ]

  To evaluate the immunogenicity of two doses of the adjuvanted pandemic H5N1 vaccine (MF59-eH5N1), each containing 7.5µg of H5N1 antigen, against the homologous A/Vietnam/1194/2004 strain, in terms of percentage of subjects achieving Geometric Mean Titers ≥ 40 and Geometric Mean Areas (GMA) ≥ 25mm2, as determined by HI, MN 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 value were determined for study day 22,43 and 64.

• Percentages of Participants Achieving Seroconversion or Significant Increase in Antibody Titer After Two Doses of the Adjuvanted Pandemic H5N1 Vaccine Against the Homologous A/Vietnam/1194/2004 Strain [ Time Frame: 3 weeks after vaccination (day 43/day22 and day 64/day22) ] [ Designated as safety issue: No ]
  To evaluate the immunogenicity of two doses of the adjuvanted pandemic H5N1 vaccine (MF59-eH5N1), each containing 7.5µg of H5N1 antigen, against the homologous A/Vietnam/1194/2004 strain, in terms of percentage of subjects achieving significant increase or at least 4-Fold increase in antibody titer from baseline, as measured by HI, MN and SRH assays.
• Geometric Mean Titers After Two Doses of the Adjuvanted Pandemic H5N1 Vaccine Against the Heterologous A/Turkey/Turkey/1/2005 Strain. [ Time Frame: 3 weeks after vaccination (day 22, day 43, day 64) ] [ Designated as safety issue: No ]
  To evaluate the immunogenicity of two doses of the adjuvanted pandemic H5N1 vaccine (MF59-eH5N1), each containing 7.5µg of H5N1 antigen, in terms of Geometric Mean Titers (GMTs) against the heterologous A/turkey/Turkey/1/2005 strain, as determined by HI and MN assays.
• Geometric Mean Areas After Two Doses of the Adjuvanted Pandemic H5N1 Vaccine Against the Heterologous A/Turkey/Turkey/1/2005 Strain. [ Time Frame: 3 weeks after vaccination (day 22, day 43, day 64) ] [ Designated as safety issue: No ]

  To evaluate the immunogenicity of two doses of MF59-eH5N1, each containing 7.5µg of H5N1 antigen, in terms of Geometric Mean Areas (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 value were determined for study day 22,43 and 64.

• Geometric Mean Ratios After Two Doses of the Adjuvanted Pandemic H5N1 Vaccine Against the Heterologous A/Turkey/Turkey/1/2005 Strain. [ Time Frame: 3 weeks after vaccination (day 43/day 22 and day 64/day 22) ] [ Designated as safety issue: No ]
  To evaluate the immunogenicity of two doses of the adjuvanted pandemic H5N1 Vaccine (MF59-eH5N1), each containing 7.5µg of H5N1 antigen, in terms of Geometric Mean Ratios (GMRs) against the heterologous A/turkey/Turkey/1/2005 strain, as determined by HI,MN and SRH assays.
• Percentages of Participants Achieving Geometric Mean Titers ≥ 40 and Geometric Mean Areas ≥ 25mm2, After Two Doses of the Adjuvanted Pandemic H5N1 Vaccine Against the Heterologous A/Turkey/Turkey/1/2005 Strain [ Time Frame: 3 weeks after vaccination (day 22, day 43, day 64) ] [ Designated as safety issue: No ]

  To evaluate the immunogenicity of two doses of the adjuvanted pandemic H5N1 vaccine (MF59-eH5N1), each containing 7.5µg of H5N1 antigen, against the heterologous A/turkey/Turkey/1/2005 strain, in terms of percentage of subjects achieving Geometric Mean Titers ≥ 40 and Geometric Mean Areas (GMA) ≥ 25mm2 as determined by HI, MN 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 value were determined for study day 22,43 and 64.

• Percentages of Participants Achieving Seroconversion or Significant Increase in Antibody Titers, After Two Doses of the Adjuvanted Pandemic H5N1 Vaccine Against the Heterologous A/Turkey/Turkey/1/2005 Strain. [ Time Frame: 3 weeks after vaccination (day 43/day 22 and day 64/day 22) ] [ Designated as safety issue: No ]
  To evaluate the immunogenicity of two doses of the adjuvanted pandemic H5N1 vaccine (MF59-eH5N1), each containing 7.5µg of H5N1 antigen, against the heterologous A/turkey/Turkey/1/2005 strain, in terms of percentage of subjects achieving significant increase or at least 4-Fold increase in antibody titers from baseline as measured by HI, MN and SRH assays.

• to evaluate safety and tolerability of adjuvanted monovalent influenza vaccine compared with an adjuvanted interpandemic trivalent influenza vaccine. [ Time Frame: from day 22 up to day 64 ] [ Designated as safety issue: Yes ]
• to evaluate the immunogenicity of two doses of adjuvanted monovalent influenza vaccine in a subgroup of adult and elderly subjects. [ Time Frame: from day 22 up to day 64 ] [ Designated as safety issue: Yes ]

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.

• Biological: Placebo
  One dose of 0.5 ml IM injection of isotonic saline solution was administered in the deltoid muscle.
• Biological: Trivalent influenza virus vaccine (TIV)
  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.
• Biological: Adjuvanted monovalent influenza virus vaccine (aH5N1)
  Two intramuscular (IM) injections of a 0.5 ml dose administered three weeks apart in the deltoid muscle.
• Biological: Adjuvanted trivalent influenza vaccine (aTIV)
  Two IM injections of a 0.5 ml dose of adjuvanted trivalent influenza virus vaccine administered three weeks apart, in the deltoid muscle.

• Experimental: TIV + aH5N1
  First dose of the non-adjuvanted trivalent influenza virus vaccine(TIV) followed by two doses of the adjuvanted monovalent influenza virus vaccine (aH5N1)
  Interventions:

  • Biological: Trivalent influenza virus vaccine (TIV)
  • Biological: Adjuvanted monovalent influenza virus vaccine (aH5N1)
• Active Comparator: PL + aTIV
  First dose of placebo (PL-saline) followed by two doses of the adjuvanted trivalent influenza virus vaccine (aTIV)
  Interventions:

  • Biological: Placebo
  • Biological: Adjuvanted trivalent influenza vaccine (aTIV)

Inclusion Criteria:

• Subjects 18 years of age and older who are mentally competent and who have signed an informed consent form after having received a detailed explanation of the study protocol;

• In good health as determined by:

  1. medical history,
  2. physical examination,
  3. clinical judgment of the Investigator;
• Able to understand and comply with all study procedures and to complete study diaries, can be contacted, and will be 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 is 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 are sexually active and have not used or do not plan or refuse 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 ≥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;
• 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:

  1. 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;
  2. receipt of immunostimulants;
  3. receipt of parenteral immunoglobulin preparation, blood products and/or plasma derivates within the past 3 months and for the full length of the study;
  4. 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.