Phase 3 Study of a H5N1 Vaccine in Adults, Elderly and Specified Risk Groups

• Frequency and severity of systemic reactions until 21 days after the first and second vaccinations [ Time Frame: 42 days ] [ Designated as safety issue: Yes ]
• Number of subjects with antibody response to the vaccine strain associated with protection 21 days after the second vaccination defined as titer measured by microneutralization (MN) assay >= 1:20. [ Time Frame: 42 days ] [ Designated as safety issue: Yes ]
• Antibody response 21 days after the second vaccination as measured by MN assay; [ Time Frame: 42 days ] [ Designated as safety issue: No ]

• Frequency and severity of systemic reactions after the first and second vaccinations [ Time Frame: 42 days ] [ Designated as safety issue: Yes ]
• Number of subjects with antibody response to the vaccine strain associated with protection 21 days after the second vaccination defined as titer measured by microneutralization (MN) test >= 1:20. [ Time Frame: 42 days ] [ Designated as safety issue: Yes ]

• Frequency and severity of injection site reactions until 21 days after the first and second vaccinations [ Time Frame: 42 days ] [ Designated as safety issue: Yes ]
• Number of subjects with fever, malaise or shivering with onset within 7 days after the first and second vaccinations [ Time Frame: 7 days ] [ Designated as safety issue: Yes ]
• Frequency and severity of adverse events observed during the entire study period [ Time Frame: 11 months ] [ Designated as safety issue: Yes ]
• Number of subjects with antibody response associated with protection 21 days after the first and second vaccinations defined as Hemagglutination Inhibition Antibody (HIA) titer >= 1:40 or Single Radial Hemolysis (SRH) area >= 25 mm2 [ Time Frame: 42 days ] [ Designated as safety issue: Yes ]
• Number of subjects with antibody response associated with protection 21 days after the second vaccination defined as titer measured by MN assay >=1:40, >= 1:80, >=1:160 [ Time Frame: 42 days ] [ Designated as safety issue: Yes ]
• Antibody response 21 days after the first and second vaccinations as measured by HI and SRH assays [ Time Frame: 42 days ] [ Designated as safety issue: No ]
• Fold increase of antibody response 21 days after the first and second vaccinations as compared to baseline as measured by MN, HI and SRH assays [ Time Frame: 42 days ] [ Designated as safety issue: No ]
• Number of subjects with seroconversion (MN/HI: min.4-fold titer increase vs baseline;SRH:post-vacc. hemolysis area >=25mm2 or increased by >=50% for pre-vacc. sample <=4mm2 and >4mm2, resp., 21 days after 1st and 2nd vaccinations, measured by MN,HI,SRH [ Time Frame: 42 days ] [ Designated as safety issue: No ]
• Number of subjects with antibody response associated with protection 201 days after the first vaccination as measured by MN, HI and SRH assays [ Time Frame: 201 days ] [ Designated as safety issue: Yes ]
• Antibody response 201 days after the first vaccination as measured by MN, HI and SRH assays [ Time Frame: 201 days ] [ Designated as safety issue: No ]
• Fold increase of antibody response 201 days after the first vaccination as compared to baseline as measured by MN, HI and SRH assays [ Time Frame: 201 days ] [ Designated as safety issue: No ]
• Number of subjects in the subset included in the assessment of antibody kinetics with antibody response associated with protection 28, 35 and 90 days after the first vaccination as measured by MN, HI and SRH assays [ Time Frame: 90 days ] [ Designated as safety issue: Yes ]
• Antibody response in the subset of subjects included in the assessment of antibody kinetics 28, 35 and 90 days after the first vaccination as measured by MN, HI and SRH assays [ Time Frame: 90 days ] [ Designated as safety issue: No ]
• Fold increase of antibody response in the subset of subjects included in the assessment of antibody kinetics 28, 35 and 90 days after the first vaccination as compared to baseline as measured by MN, HI and SRH assays [ Time Frame: 90 days ] [ Designated as safety issue: No ]
• Number of subjects in subset for antibody kinetics evaluation with seroconversion (see definitions above) 28, 35, 90 days after 1st vaccination, measured by MN, HI, SRH [ Time Frame: 90 days ] [ Designated as safety issue: No ]
• T-cell response in the subset of subjects included in the evaluation of cellular immunity after each vaccination as determined by the frequency of cytokine producing T-cells induced by influenza virus antigens [ Time Frame: 201 days ] [ Designated as safety issue: No ]
• Increase in frequency of cytokine producing T-cells induced by influenza virus antigens after each vaccination as compared to baseline [ Time Frame: 201 days ] [ Designated as safety issue: No ]
• Number of subjects with antibody response associated with protection 21 days after the first vaccination defined as titer measured by MN assay >=1:20, >=1:40, >=1:80, >=1:160 [ Time Frame: 21 days ] [ Designated as safety issue: Yes ]
• Antibody response 21 days after the first vaccination as measured by MN assay [ Time Frame: 21 days ] [ Designated as safety issue: No ]

• Frequency and severity of injection site reactions after the first and second vaccinations [ Time Frame: 42 days ] [ Designated as safety issue: Yes ]
• Number of subjects with fever, malaise or shivering with onset within 7 days after the first and second vaccinations [ Time Frame: 7 days ] [ Designated as safety issue: Yes ]
• Frequency and severity of adverse events observed during the entire study period [ Time Frame: 11 months ] [ Designated as safety issue: Yes ]
• Number of subjects with antibody response associated with protection 21 days after the first and second vaccinations defined as Hemagglutination Inhibition Antibody (HIA) titer >= 1:40 or Single Radial Hemolysis (SRH) area >= 25 mm2 [ Time Frame: 42 days ] [ Designated as safety issue: Yes ]
• Number of subjects with antibody response associated with protection 21 days after the first vaccination defined as titer measured by MN test >= 1:20 [ Time Frame: 21 days ] [ Designated as safety issue: Yes ]
• Antibody response 21 days after the first and second vaccinations as measured by MN, HI and SRH assays [ Time Frame: 42 days ] [ Designated as safety issue: No ]
• Fold increase of antibody response 21 days after the first and second vaccinations as compared to baseline as measured by MN, HI and SRH assays [ Time Frame: 42 days ] [ Designated as safety issue: No ]
• Number of subjects with seroconversion (MN/HI: >=4-fold titer increase vs baseline; SRH: post-vacc. hemolysis area >=25mm2 or increased by >=50% for pre-vacc. sample <=4mm2 and >4mm2, resp., 21 days after 1st and 2nd vaccinations, measured by MN, HI, SRH [ Time Frame: 42 days ] [ Designated as safety issue: No ]
• Number of subjects with antibody response associated with protection 201 days after the first vaccination as measured by MN, HI and SRH assays [ Time Frame: 201 days ] [ Designated as safety issue: Yes ]
• Antibody response 201 days after the first vaccination as measured by MN, HI and SRH assays [ Time Frame: 201 days ] [ Designated as safety issue: No ]
• Fold increase of antibody response 201 days after the first vaccination as compared to baseline as measured by MN, HI and SRH assays [ Time Frame: 201 days ] [ Designated as safety issue: No ]
• Number of subjects in the subset included in the assessment of antibody kinetics with antibody response associated with protection 28, 35 and 90 days after the first vaccination as measured by MN, HI and SRH assays [ Time Frame: 90 days ] [ Designated as safety issue: Yes ]
• Antibody response in the subset of subjects included in the assessment of antibody kinetics 28, 35 and 90 days after the first vaccination as measured by MN, HI and SRH assays [ Time Frame: 90 days ] [ Designated as safety issue: No ]
• Fold increase of antibody response in the subset of subjects included in the assessment of antibody kinetics 28, 35 and 90 days after the first vaccination as compared to baseline as measured by MN, HI and SRH assays [ Time Frame: 90 days ] [ Designated as safety issue: No ]
• Number of subjects in subset for antibody kinetics evaluation with seroconversion (see definitions above) 28, 35, 90 days after 1st vaccination, measured by MN, HI, SRH [ Time Frame: 90 days ] [ Designated as safety issue: No ]
• T-cell response in the subset of subjects included in the evaluation of cellular immunity after each vaccination as determined by the frequency of cytokine producing T-cells induced by influenza virus antigens [ Time Frame: 201 days ] [ Designated as safety issue: No ]
• Increase in frequency of cytokine producing T-cells induced by influenza virus antigens after each vaccination as compared to baseline [ Time Frame: 201 days ] [ Designated as safety issue: No ]

The purpose of this study is to assess the safety and tolerability of, and the immune response to a non-adjuvanted H5N1 influenza vaccine in an adult and elderly population and in specified risk groups. Furthermore, persistence of H5N1 influenza antibodies after vaccination with this vaccine will be assessed.

• Biological: H5N1 Influenza Vaccine Whole virion, Vero cell-derived, Inactivated Influenza Vaccine, non-adjuvanted
  Intramuscular injection of 7.5 µg hemagglutinin antigen (A/Vietnam/1203/2004 strain) in a non-adjuvanted formulation on Days 0 and 21.
• Biological: H5N1 Influenza Vaccine Whole virion, Vero cell-derived, Inactivated Influenza Vaccine, non-adjuvanted
  Intramuscular injection of 3.75 µg hemagglutinin antigen (A/Vietnam/1203/2004 strain) in a non-adjuvanted formulation on Days 0 and 21.

• Experimental: Cohort 1, Treatment Arm 1

  Stratum A (18-59 ys)/B(>=60 ys): 120 healthy volunteers per stratum will receive 2 vaccinations with 7.5 µg A/Vietnam/1203/2004 on Days 0 and 21 and participate in immunogenicity evaluation.

  Among Stratum A volunteers, 60 will participate in antibody kinetics evaluation and 30 in cellular immunity evaluation.

  Randomization to Treatment Arms 1 and 2 at 2:1 ratio. Subjects in Treatment Arm 1 will be included in the immunologic determination of lot-to-lot consistency.

  Intervention: Biological: H5N1 Influenza Vaccine Whole virion, Vero cell-derived, Inactivated Influenza Vaccine, non-adjuvanted
• Experimental: Cohort 1, Treatment Arm 2

  Stratum A (18-59 ys)/B(>=60 ys): 60 healthy volunteers per stratum will receive 2 vaccinations with 3.75 µg A/Vietnam/1203/2004 on Days 0 and 21 and participate in immunogenicity evaluation.

  Randomization to Treatment Arms 1 and 2 at 2:1 ratio.

  Intervention: Biological: H5N1 Influenza Vaccine Whole virion, Vero cell-derived, Inactivated Influenza Vaccine, non-adjuvanted
• Experimental: Cohort 1, Treatment Arm 3

  Stratum A (18-59 ys): 2060 healthy volunteers will receive 2 vaccinations with 7.5 µg A/Vietnam/1203/2004 on Days 0 and 21 and participate in safety evaluation only.

  Randomization within Treatment Arms 3 and 4 at 1:1:1 ratio per study site to receive one of three different lots of the H5N1 influenza vaccine.

  Intervention: Biological: H5N1 Influenza Vaccine Whole virion, Vero cell-derived, Inactivated Influenza Vaccine, non-adjuvanted
• Experimental: Cohort 2, Treatment Arm 1

  300 immune compromised individuals 18 years or older will receive 2 vaccinations with 7.5 µg A/Vietnam/1203/2004 on Days 0 and 21.

  100 will participate in immunogenicity evaluation and 30 in cellular immunity evaluation.

  Intervention: Biological: H5N1 Influenza Vaccine Whole virion, Vero cell-derived, Inactivated Influenza Vaccine, non-adjuvanted
• Experimental: Cohort 3, Treatment Arm 1
  300 chronically ill patients 18 years or older will receive 2 vaccinations with 7.5 µg A/Vietnam/1203/2004 on Days 0 and 21 and participate in immunogenicity evaluation.
  Intervention: Biological: H5N1 Influenza Vaccine Whole virion, Vero cell-derived, Inactivated Influenza Vaccine, non-adjuvanted
• Experimental: Cohort 1, Treatment Arm 4

  Stratum A (18-59): 540 healthy volunteers will receive 2 vaccinations with 7.5 µg A/Vietnam/1203/2004 on Days 0 and 21 and participate in immunogenicity assessment.

  Randomization within Treatment Arms 3 and 4 at 1:1:1 ratio per study site to receive one of three different lots of the H5N1 influenza vaccine.

  Subjects in Treatment Arm 4 will be included in the immunologic determination of lot-to-lot consistency.

  Intervention: Biological: H5N1 Influenza Vaccine Whole virion, Vero cell-derived, Inactivated Influenza Vaccine, non-adjuvanted

Inclusion Criteria:

The following inclusion criteria apply to subjects in all three cohorts:

Male and female subjects will be eligible for participation in this study if they:

• Are 18 years of age or older on the day of screening;
• Have an understanding of the study and its procedures, agree to its provisions, and give written informed consent prior to study entry;
• Are physically and mentally capable of participating in the study and follow its procedures;
• Agree to keep a daily record of symptoms for the duration of the study;
• If female of childbearing potential - have a negative urine pregnancy test result within 24 hours prior to the scheduled first vaccination and agree to employ adequate birth control measures for the duration of the study.

The following inclusion criterion applies to subjects in Cohort 1 only:

- Are generally healthy [1], as determined by the investigator's clinical judgment through collection of medical history and performance of a physical examination.

([1]) Subjects with controlled Stage 1 hypertension (blood pressure of 140-159 mmHg systolic and/or 90-99 mmHg diastolic) are eligible for participation in Cohort 1 of this study.

The following inclusion criterion applies to subjects in Cohort 2 only:

- Are immune compromised due to immunosuppressive treatment (e.g. transplant patients [2]) or due to acquired immunodeficiency caused by HIV infection with or without treatment with anti-retrovirals.

([2]) Transplant patients should be at least 6 months after transplantation and in stable clinical condition without complications.

The following inclusion criterion applies to subjects in Cohort 3 only:

- Have a chronic cardiovascular (excluding hypertension) [3], respiratory, renal, or metabolic (e.g. diabetes mellitus) illness in stable clinical condition without major disease complications such as organ failure, infectious complications, severe asthma or respiratory dysfunction.

([3]) Subjects with cardiovascular disease such as coronary heart disease, angina, heart attack or other heart conditions in stable clinical condition, without major disease complications and who are considered at risk for medical complications from influenza. However, subjects with hypertension (see [1] above) not associated with any heart condition will be excluded from participation in Cohort 3 of this study.

Exclusion Criteria:

The following exclusion criteria apply to subjects in all three cohorts:

Subjects will be excluded from participation in this study if they:

• Have a history of exposure to H5N1 virus or a history of vaccination with an H5N1 influenza vaccine;
• Are at high risk of contracting H5N1 influenza infection (e.g. poultry workers);
• Have a history of severe allergic reactions or anaphylaxis;
• Have a rash, dermatological condition or tattoos which may interfere with injection site reaction rating;
• Have donated blood or plasma within 30 days prior to study entry;
• Have received any live vaccine within 4 weeks or inactivated vaccine within 2 weeks prior to vaccination in this study;
• Have a known or suspected problem with alcohol or drug abuse;
• Were administered an investigational drug within 6 weeks prior to study entry or are concurrently participating in a clinical study that includes the administration of an investigational product;
• Are a member of the team conducting this study or are in a dependent relationship with one of the study team members. Dependent relationships include close relatives (i.e., children, partner/spouse, siblings, parents) as well as employees of the investigator or site personnel conducting the study;
• If female: are pregnant or lactating.

The following exclusion criteria apply to subjects in Cohort 1 only:

• Currently have or have a history of a significant neurological, cardiovascular, pulmonary (including asthma), hepatic, metabolic, rheumatic, autoimmune, hematological or renal disorder [4];
• Have any inherited or acquired immunodeficiency;
• Have a disease or are currently undergoing a form of treatment or were undergoing a form of treatment within 30 days prior to study entry that can be expected to influence immune response. Such treatment includes, but is not limited to, systemic or high dose inhaled (>800µg/day of beclomethasone dipropionate or equivalent) corticosteroids, radiation treatment or other immunosuppressive or cytotoxic drugs;
• Have received a blood transfusion or immunoglobulins within 90 days prior to study entry;
• Have a functional or surgical asplenia.

([4]) A significant disorder is defined as a disease or medical condition associated with impaired health status, increased risk for complications, requiring medical treatment and/or follow up.

The following exclusion criteria apply to subjects in Cohort 2 only:

• Are immune compromised due to stem cell or organ-transplantation with significant medical complications such as acute or chronic graft rejection or graft versus host disease requiring intensive immunosuppressive treatment, transplant failure or infectious complications or other conditions that would be considered a contraindication for vaccination with an inactivated vaccine.
• Are immune compromised due to HIV infection with a CD4 count of < 200x10^6/L at screening or significant medical complications such as opportunistic infections, malignant complications (e.g. lymphoma, Kaposi sarcoma), other organ manifestations consistent with advanced acquired immunodeficiency syndrome (AIDS) or other conditions that would be considered a contraindication for vaccination with an inactivated vaccine.

The following exclusion criterion applies to subjects in Cohort 3 only:

- Have a chronic cardiovascular, respiratory, renal, or metabolic (e.g. diabetes mellitus) illness with significant complications such as advanced heart failure, liver failure, renal failure, severe asthma or severe respiratory failure, infectious complications or other conditions that would be considered a contraindication for vaccination with an inactivated vaccine.