The study listed may include approved and non-approved uses, formulations or treatment regimens. The results reported in any single study may not reflect the overall results obtained on studies of a product. Before prescribing any product mentioned in this Register, healthcare professionals should consult prescribing information for the product approved in their country. Study No.: 110624 (Flu Q-Pan-005 PRI) Title: A trial to evaluate the safety and immunogenicity of monovalent A/turkey/Turkey/1/05 (H5N1) vaccine antigen with AS03 adjuvant following a single priming dose of monovalent A/Indonesia/5/05 (H5N1) vaccine antigen with AS03 adjuvant in adults 18 years of age or older. A/turkey/Turkey/1/05 H5N1 vaccine (Flu 1): GlaxoSmithKline (GSK) Biologicals pandemic H5N1 influenza vaccine with A/turkey/Turkey/1/05 antigen Pumarix TM (Flu 2): GSK Biologicals pandemic H5N1 influenza vaccine with A/Indonesia/5/2005 antigen (Quebec manufacturing process) Rationale: This study assessed the safety and immunogenicity of heterologous booster vaccination with Flu 1 vaccine given approximately 6 or 18 months after a single priming dose of Flu 2 vaccine in adults 18 years of age or older. A H5N1 naïve subject group was used as an immunogenicity control group. Phase: II Study Period: 15 July 2008 until 22 April 2010 (last visit Day 591) 15 July 2008 until 21 February 2011 (Day 909) Study Design: Observer-blind, placebo-controlled, randomized (1:1:1:1:1:1:1), multi-center trial with 7 parallel groups. Centers: 13 centers in 2 countries (Canada and the United States) Indication: Immunization against influenza disease caused by an influenza A virus with pandemic potential, sub-type H5N1. Treatment: The treatment groups were as follows: Flu2-Flu1-F1-PBS : subjects received at Day 0 1 dose of Flu 2 vaccine formulation 1, at Day 182 1 dose of Flu 1 vaccine formulation 1 and at Day 549 1 dose of placebo (phosphate buffered saline [PBS]) Flu2-Flu1-F2-PBS : subjects received at Day 0 1 dose of Flu 2 vaccine formulation 2, at Day 182 1 dose of Flu 1 vaccine formulation 2 and at Day 549 1 dose of PBS Flu1-F3 : subjects received at Day 0 1 dose of Flu 2 vaccine formulation 3, at Day 182 1 dose of PBS and at Day 549 1 dose of Flu 1 vaccine formulation 3 Flu1-F1 : subjects received at Day 0 1 dose of Flu 2 vaccine formulation 1, at Day 182 1 dose of PBS and at Day 549 1 dose of Flu 1 vaccine formulation 1 Flu1-F4 : subjects received at Day 0 1 dose of Flu 2 vaccine formulation 4, at Day 182 1 dose of PBS and at Day 549 1 dose of Flu 1 vaccine formulation 4 Flu1-F2 : subjects received at Day 0 1 dose of Flu 2 vaccine formulation 2, at Day 182 1 dose of PBS and at Day 549 1 dose of Flu 1 vaccine formulation 2 PBS-Flu1-Flu1-F3 : subjects received at Day 0 1 dose of PBS, at Day 182 and Day 549 1 dose of Flu 1 vaccine formulation 3 All vaccines and PBS were administered intramuscularly in the non-dominant deltoid at Day 0 and Day 549 and in the dominant deltoid at Day 182. Objectives: To assess whether a single dose of Flu 1 vaccine was more immunogenic when given to subjects who 18 months previously had received a single priming dose of Flu 2 vaccine than when given to H5N1-naïve subjects based on hemagglutination inhibition (HI) seroconversion rates (SCRs) and geometric mean titers (GMTs). Criteria for Evaluation: This objective was to compare the immune responses to Flu 1 vaccine in primed and non-primed vaccine recipients based on the difference in HI antibody SCRs and the ratio of GMTs. For the analysis, booster vaccination was to occur 549 days following the single dose of Flu 2 vaccine. Serologic response was to be measured on Day 559, 10 days following booster vaccination. Control subjects were to receive their first dose of vaccine on Day 182, with SCR assessed on Day 192. Superiority of single-dose booster vaccination over a single dose primary vaccination was established if: a. the lower bound of the 97.5% confidence interval (CI) for the difference in SCR (booster vaccine group* minus H5N1 naïve subject group*) exceeded an absolute difference of 15%, and b. the lower bound of the 97.5% CI for the GMT ratio (booster vaccine group* to H5N1 naïve subject group*) exceeded 2.0. To describe and contrast the safety of Flu 1 vaccine in terms of solicited local and general symptoms, unsolicited
adverse events (AEs), and serious adverse events (SAEs) in subjects previously vaccinated with Flu 2 vaccine and in H5N1 naïve control subjects. *Booster vaccine group was any group receiving Flu 1 vaccine as a booster at Day 549. The H5N1 naïve subject group was the PBS-Flu1-Flu1-F3. Primary Outcome/Efficacy Variable: Immunogenicity A/turkey/Turkey/1/05-homologous virus antibody response, as assessed by HI measured on Day 182 and Day 192 for primary H5N1 vaccine recipients (controls = PBS-Flu1-Flu1-F3 ) or Day 549 and Day 559 for subjects having received a Month 18 booster dose of Flu 1 vaccine Safety The occurrence of specifically-solicited local and general signs and symptoms during a 7-day follow-up period (i.e., day of vaccination and 6 subsequent days) after each dose of vaccine or placebo. The occurrence of all unsolicited AEs during a 42-day follow-up period after each vaccination. The occurrence of SAEs and medically-attended events (MAEs) during the entire study period (Day 0 to 909). Secondary Outcome/Efficacy Variable(s): Booster Flu 1 vaccine (A/turkey/Turkey/1/05)-homologous virus antibody response, as assessed by HI measured on Day 182 (day of primary Flu 1 vaccination or booster Flu 1 vaccination) and Day 192 (10 days after primary Flu 1 vaccination or booster Flu 1 vaccination) Change in the proportion of subjects with A/turkey/Turkey/1/05 HI titers 1:40 from Day 182 to Day 192 or Day 549 to Day 559, and from Day 182 to Day 224 or Day 549 to Day 591, Geometric mean fold-rise (GMFR) in A/turkey/Turkey/1/05 HI titers from Day 182 to Day 192 or Day 549 to Day 559, and from Day 182 to Day 224 or Day 549 to Day 591, The A/turkey/Turkey/1/05 HI SCR from Day 182 to Day 224 or from Day 549 to Day 591, 42 days post boost or primary dose, The A/turkey/Turkey/1/05 HI GMT and proportion of subjects with A/turkey/Turkey/1/05 HI titer 1:40 on Days 0, 182, 192 (if provided Flu 1 vaccine on Day 182), 224 (if provided Flu 1 vaccine on Day 182), 549, 559 (if provided Flu 1 vaccine on Day 549), 591 (if provided Flu 1 vaccine on Day 549), and 729, The A/Indonesia/5/05 HI GMT and proportion of subjects with A/Indonesia/5/05 HI titer 1:40 on Days 0, 10, 42, 182, 549, and 559, The A/Indonesia/5/05 HI SCR from Day 0 to Day 10 and from Day 0 to Day 42. Statistical Methods: The analyses were performed on the Total Vaccinated cohort and the According-To-Protocol (ATP) cohort for immunogenicity. - The Total Vaccinated cohort included all subjects who received at least one dose of vaccine and for whom any postvaccination data were available. - The ATP cohort for immunogenicity included all evaluable subjects (i.e. those meeting all eligibility criteria, complying with the procedures defined in the protocol, with no elimination criteria during the study) for whom a complete set of data concerning immunogenicity primary outcome variables was available. This implied that all subjects must have had at least Day 182 and 192 or Day 549 and 559 HI titer results for the A/turkey/Turkey/1/05 virus. - The ATP cohort for immunogenicity at Day 729 included all evaluable subjects (i.e. those meeting all eligibility criteria, complying with the procedures defined in the protocol, with no elimination criteria during the study) for whom a complete set of data concerning immunogenicity primary outcome variables was available till Day 729 for any virus strain. Analysis of Immunogenicity: The analysis of immunogenicity was performed on the ATP cohort for immunogenicity and the ATP cohort for immunogenicity at Day 729. Inferential analysis Statistical tests were performed sequentially for boost effect, defined as a SCR difference > 15%, and as a GMT ratio > 2, first for a boost effect by testing Flu1-F3 versus PBS-Flu1-Flu1-F3, and Flu1-F4 versus PBS-Flu1-Flu1-F3. If both comparisons successfully established superior immunogenicity for the prime-boost groups, a test for Flu1-F1 versus PBS-Flu1-Flu1-F3 and Flu1-F2 versus PBS-Flu1-Flu1-F3 was performed. Immune response to A/turkey/Turkey/1/05 at 6 months was assessed by computation of the HI SCR 10 days following the booster vaccination, defined as a pre-vaccination titer recorded as < 1:10 for HI and a post-vaccination reciprocal titer 1:40, or a pre-vaccination reciprocal titer 1:10 and at least a 4-fold increase in post-vaccination reciprocal titer. Descriptive statistics
To evaluate homologous virus immune response in naïve versus primed vaccine groups, seroprotection rate (SPR) was calculated for A/turkey/Turkey/1/05 for Days 0, 182, 192 and 224 or for Days 0, 549, 559, and 591. The proportion of subjects with a serum reciprocal HI antibody titer 1:40 at each sampling day along with 95% CIs was presented. Furthermore, GMFRs and corresponding 95% CIs were tabulated for Days 192 and 224 or Days 559 and 591 for the A/turkey/Turkey/1/05 strain relative to the Day 182 or Day 549 reciprocal HI titer. For each vaccine group, the immune response to A/turkey/Turkey/1/05 was also assessed by computation of the HI SCR at Days 224 and 591 relative to Day 182 or Day 549; SCR rates and 95% CIs of these rates were tabulated. For Day 224 or Day 591, GMTs for each vaccine group were also to be tabulated along with 95% CIs. Additional analyses focused on A/Indonesia/5/05 SCRs from Day 0 to Days 10 and 42 and SPRs and GMTs at each of the sample time points for A/turkey/Turkey/5/05, A/Indonesia/5/05 and A/Vietnam/1194/04. Demographics Analysis of Safety : The analysis was performed on the Total Vaccinated cohort. For each solicited symptom, the percentage of subjects with the symptom and its exact 95% CI was summarized for each group, per dose and across doses. The same tabulation was performed for grade 3 solicited symptoms and general solicited symptoms assessed by the investigators as related to the study vaccination. The percentage of subjects reporting unsolicited adverse events within 42 days following vaccination was summarized per group according to the Medical Dictionary for Regulatory Activities (MedDRA) preferred terms. SAEs and MAEs were tabulated according to MedDRA preferred terms up to Day 909. Study Population: Male or female subjects 18 years of age or older at the time of the first vaccination, with a stable health status as defined by the absence of a health event satisfying the definition of an SAE, or a change in an ongoing drug therapy due to therapeutic failure or symptoms of drug toxicity, within 1 month prior to enrolment and with no previous administration of any H5N1 vaccine. Females of child-bearing potential had a negative pregnancy test prior to vaccination and needed a history of reliable contraceptive practices. Written informed consent was obtained from each subject prior to subject entry. Number of subjects Flu2-Flu1-F1-PBS Flu2-Flu1-F2- PBS Flu1- F3 Flu1-F1 Planned, N 120 120 120 120 Randomized, N (Total Vaccinated cohort) 120 121 119 119 Completed to Day 224, n (%) 110 (91.7) 112 (92.6) 111 (93.3) 110 (92.4) Completed to Day 591, n (%) 95 (79.2) 101 (83.5) 103 (86.6) 99 (83.2) Completed to Day 729, n (%) 91 (75.8) 97 (80.2) 102 (86.6) 96 (80.7) Completed to Day 909, n (%) 88 (73.3) 96 (79.3) 99 (83.2) 96 (80.7) Total Number Subjects Withdrawn, n (%) 32 (26.7) 25 (20.7) 20 (16.8) 23 (19.3) Withdrawn due to Adverse Events, n (%) 5 (4.2) 1 (0.9) 2 (1.7) 2 (1.7) Withdrawn due to Lack of Efficacy, n (%) Not applicable Not applicable Not applicable Not applicable Withdrawn for other reasons, n (%) 27 (22.5) 24 (19.8) 18 (15.1) 21 (17.6) Demographics Flu2-Flu1-F1-PBS Flu2-Flu1-F2- PBS Flu1- F3 Flu1-F1 N (Total Vaccinated cohort) 120 121 119 119 Females:Males 80:40 73:48 69:50 70:49 Mean Age, years (SD) 49.8 (18.01) 49.6 (17.93) 50.7 (17.67) 49.2 (17.75) White - Caucasian / European heritage, n (%) 104 (86.7) 104 (86.0) 104 (87.4) 106 (89.1) Number of subjects Flu1- Flu1-F2 PBS-Flu1-Flu1-F3 F4 Planned, N 120 120 120 Randomized, N (Total Vaccinated cohort) 122 120 120 Completed to Day 224, n (%) 118 (96.7) 111 (92.5) 114 (95.0) Completed to Day 591, n (%) 98 (80.3) 89 (74.2) 93 (77.5) Completed to Day 729, n (%) 98 (80.3) 88 (74.2) 92 (76.7) Completed to Day 909, n (%) 95 (77.9) 86 (71.7) 92 (76.7) Total Number Subjects Withdrawn, n (%) 27 (22.1) 34 (28.3) 28 (23.3) Withdrawn due to Adverse Events, n (%) 1 (0.8) 4 (3.3) 4 (3.3) Withdrawn due to Lack of Efficacy, n (%) Not applicable Not applicable Not applicable Withdrawn for other reasons, n (%) 26 (21.3) 30 (25.0) 24 (20.0) Flu1- F4 Flu1-F2 PBS-Flu1-Flu1-F3
N (Total Vaccinated cohort) 122 120 120 Females:Males 68:54 70:50 75:45 Mean Age, years (SD) 50.3 (17.77) 50.1 (18.92) 50.0 (18.03) White - Caucasian / European heritage, n (%) 103 (84.4) 108 (90.0) 102 (85.0) Primary Efficacy Results: Difference in HI SCRs between Flu1-F3 and PBS-Flu1-Flu1-F3 (control group) against A/turkey/Turkey/1/05 at 10 days after the first Flu 1 vaccine administration (ATP cohort for immunogenicity) Antibody Flu1-F3 PBS-Flu1-Flu1-F3 Difference in SCR (Flu1-F3 minus PBS-Flu1-Flu1-F3 ) 97.5% CI N n % N n % % LL* UL A/turkey/Turkey/1/05 83 71 85.5 99 44 44.4 41.10 25.97 54.24 SCR defined as the proportion of subjects who have either a pre-vaccination reciprocal HI titer < 10 and a post-vaccination reciprocal titer 1:40, or a pre-vaccination reciprocal HI titer 1:10 and at least a 4-fold increase in post vaccination reciprocal titer against the vaccine virus. N = Number of subjects with available results n/% = Number/percentage of subjects with titer within the specified range 97.5% CI = Unstandard asymptotic 97.5% confidence interval; LL = lower limit, UL = upper limit *Superiority criterion: LL of the 97.5% CI for the difference in SCR > 15% Primary Efficacy Results: Difference in HI SCRs between Flu1-F4 and PBS-Flu1-Flu1-F3 (control group) against A/turkey/Turkey/1/05 at 10 days after the first Flu 1 vaccine administration (ATP cohort for immunogenicity) Antibody Flu1-F4 PBS-Flu1-Flu1-F3 Difference in SCR (Flu1-F4 minus PBS-Flu1-Flu1-F3 ) 97.5% CI N n % N n % % LL* UL A/turkey/Turkey/1/05 80 73 91.3 99 44 44.4 46.81 32.54 59.10 SCR defined as the proportion of subjects who have either a pre-vaccination reciprocal HI titer < 10 and a post-vaccination reciprocal titer 1:40, or a pre-vaccination reciprocal HI titer 1:10 and at least a 4-fold increase in post vaccination reciprocal titer against the vaccine virus. N = Number of subjects with available results n/% = Number/percentage of subjects with titer within the specified range 97.5% CI = Unstandard asymptotic 97.5% confidence interval; LL = lower limit, UL = upper limit *Superiority criterion: LL of the 97.5% CI for the difference in SCR > 15% Primary Efficacy Results: Difference in HI SCRs between Flu1-F1 and PBS-Flu1-Flu1-F3 (control group) against A/turkey/Turkey/1/05 at 10 days after the first Flu 1 vaccine administration (ATP cohort for immunogenicity) Antibody Flu1-F1 PBS-Flu1-Flu1-F3 Difference in SCR (Flu1-F1 minus PBS-Flu1-Flu1-F3 ) 97.5% CI N n % N n % % LL* UL A/turkey/Turkey/1/05 87 81 93.1 99 44 44.4 48.66 35.09 60.56 SCR defined as the proportion of subjects who have either a pre-vaccination reciprocal HI titer < 10 and a post-vaccination reciprocal titer 1:40, or a pre-vaccination reciprocal HI titer 1:10 and at least a 4-fold increase in post vaccination reciprocal titer against the vaccine virus. N = Number of subjects with available results n/% = Number/percentage of subjects with titer within the specified range 97.5% CI = Unstandard asymptotic 97.5% confidence interval; LL = lower limit, UL = upper limit Total = Subjects either seropositive or seronegative at pre-vaccination *Superiority criterion: LL of the 97.5% CI for the difference in SCR > 15% Primary Efficacy Results: Difference in HI SCRs between Flu1-F2 and PBS-Flu1-Flu1-F3 (control group) against A/turkey/Turkey/1/05 at 10 days after the first Flu 1 vaccine administration (ATP cohort for immunogenicity) Antibody Flu1-F2 PBS-Flu1-Flu1-F3 Difference in SCR (Flu1-F2 minus PBS-Flu1-Flu1-F3 ) 97.5% CI N n % N n % % LL* UL A/turkey/Turkey/1/05 72 65 90.3 99 44 44.4 45.83 30.94 58.42 SCR defined as the proportion of subjects who have either a pre-vaccination reciprocal HI titer < 10 and a post-vaccination reciprocal titer 1:40, or a pre-vaccination reciprocal HI titer 1:10 and at least a 4-fold increase in post vaccination reciprocal
titer against the vaccine virus. N = Number of subjects with available results n/% = Number/percentage of subjects with titer within the specified range 97.5% CI = Unstandard asymptotic 97.5% confidence interval; LL = lower limit, UL = upper limit *Superiority criterion: LL of the 97.5% CI for the difference in SCR > 15% Primary Efficacy Results: SCR for HI antibodies against A/turkey/Turkey/1/05 at 10 days after the first dose of A/turkey/Turkey/1/05 vaccine (ATP cohort for immunogenicity) Seroconversion rate 95% CI N n % LL UL Flu2-Flu1-F1-PBS, Day 192 94 73 77.7 67.9 85.6 Flu2-Flu1-F2-PBS, Day 192 86 81 94.2 87.0 98.1 Flu1-F3, Day 559* 83 71 85.5 76.1 92.3 Flu1-F1, Day 559* 87 81 93.1 85.6 97.4 Flu1-F4, Day 559* 80 73 91.3 82.8 96.4 Flu1-F2, Day 559* 72 65 90.3 81.0 96.0 PBS-Flu1-Flu1-F3, Day 192* 99 44 44.4 34.5 54.8 Seroconversion rate defined as: For initially seronegative subjects, antibody titer 1:40 at Day 192 or Day 559 For initially seropositive subjects: antibody titer at Day 192 or Day 559 4 fold the pre-vaccination antibody titer Seronegative subjects (antibody titer < 1:10 for A/turkey/Turkey/1/05) prior to vaccination Seropositive subjects (antibody titer 1:10 for A/turkey/Turkey/1/05) prior to vaccination N = number of subjects with both pre- and post-vaccination results available n/% = number/percentage of responders 95% CI = exact 95% confidence interval, LL = Lower Limit, UL = Upper Limit *Primary outcome variable Primary Efficacy Results: Adjusted ratios of post-vaccination GMTs for HI against A/turkey/Turkey/1/05 antibodies in Flu2- PBS-Flu1-F3 to PBS-Flu1-Flu1-F3 (control) at 10 days after the first A/turkey/Turkey/1/05 vaccine administration (ATP cohort for immunogenicity) Adjusted GMT ratio (Flu1-F3 / PBS-Flu1- Flu1-F3 ) Flu1-F3 PBS-Flu1-Flu1-F3 97.5% CI N Adjusted GMT N Adjusted GMT Value LL* UL 83 361.6 99 43.0 8.40 5.31 13.29 Adjusted GMT = Geometric mean antibody titer adjusted for Age (Y), baseline titer N = Number of subjects with both pre- and post-vaccination results available 97.5% CI = 97.5% confidence interval for the adjusted GMT ratio; LL = lower limit, UL = upper limit *Superiority criterion: LL of 97.5% CI for the GMT ratio > 2.0 Primary Efficacy Results: Adjusted ratios of post-vaccination GMTs for HI against A/turkey/Turkey/1/05 antibodies in Flu2- PBS-Flu1-F4 to PBS-Flu1-Flu1-F3 (control) at 10 days after the first A/turkey/Turkey/1/05 vaccine administration (ATP cohort for immunogenicity) Adjusted GMT ratio (Flu1-F4 / PBS-Flu1- Flu1-F3 ) Flu1-F4 PBS-Flu1-Flu1-F3 97.5% CI N Adjusted GMT N Adjusted GMT Value LL* UL 80 476.4 99 41.3 11.53 7.30 18.22 Adjusted GMT = Geometric mean antibody titer adjusted for Age (Y), baseline titer N = Number of subjects with both pre- and post-vaccination results available 97.5% CI = 97.5% confidence interval for the adjusted GMT ratio; LL = lower limit, UL = upper limit *Superiority criterion: LL of 97.5% CI for the GMT ratio > 2.0 Primary Efficacy Results: Adjusted ratios of post-vaccination GMTs for HI against A/turkey/Turkey/1/05 antibodies in Flu2- PBS-Flu1-F1 to PBS-Flu1-Flu1-F3 (control) at 10 days after the first A/turkey/Turkey/1/05 vaccine administration (ATP cohort for immunogenicity) Adjusted GMT ratio (Flu1-F1 / PBS-Flu1- Flu1-F3 ) Flu1-F1 PBS-Flu1-Flu1-F3 97.5% CI
N Adjusted GMT N Adjusted GMT Value LL* UL 87 275.0 99 42.3 6.50 4.18 10.10 Adjusted GMT = Geometric mean antibody titer adjusted for Age (Y), baseline titer N = Number of subjects with both pre- and post-vaccination results available 97.5% CI = 97.5% confidence interval for the adjusted GMT ratio; LL = lower limit, UL = upper limit *Superiority criterion: LL of 97.5% CI for the GMT ratio > 2.0 Primary Efficacy Results: Adjusted ratios of post-vaccination GMTs for HI against A/turkey/Turkey/1/05 antibodies in Flu2- PBS-Flu1-F2 to PBS-Flu1-Flu1-F3 (control) at 10 days after the first A/turkey/Turkey/1/05 vaccine administration (ATP cohort for immunogenicity) Adjusted GMT ratio (Flu1-F2 / PBS-Flu1- Flu1-F3 ) Flu1-F2 PBS-Flu1-Flu1-F3 97.5% CI N Adjusted GMT N Adjusted GMT Value LL* UL 72 361.4 99 42.0 8.61 5.37 13.81 Adjusted GMT = Geometric mean antibody titer adjusted for Age (Y), baseline titer N = Number of subjects with both pre- and post-vaccination results available 97.5% CI = 97.5% confidence interval for the adjusted GMT ratio; LL = lower limit, UL = upper limit *Superiority criterion: LL of 97.5% CI for the GMT ratio > 2.0 Primary Efficacy Results: GMT and SPRs for HI antibodies against A/turkey/Turkey/1/05 and A/Indonesia/5/05 at Day 0 through Day 591 (ATP cohort for immunogenicity) 1:40 GMT 95% CI 95% CI Antibody Timing N n % LL UL value LL UL A/turkey/Turkey/ Flu2-Flu1-F1-1/05 PBS Flu2-Flu1-F2- PBS Flu1-F3 Flu1-F1 Flu1-F4 PRE 95 16 16.8 9.9 25.9 9.2 7.4 11.4 PI(D10) 50 26 52.0 37.4 66.3 29.3 20.6 41.6 PI(D42) 50 26 52.0 37.4 66.3 28.5 21.3 38.1 PI(D182) 95 30 31.6 22.4 41.9 17.6 13.1 23.6 PII(D192) 94 89 94.7 88.0 98.3 308.4 231.1 411.5 PII(D224) 89 82 92.1 84.5 96.8 194.5 144.6 261.6 PII(D549) 84 42 50.0 38.9 61.1 32.7 24.4 43.6 PIII(D591) 46 27 58.7 43.2 73.0 45.1 30.8 66.0 PRE 92 7 7.6 3.1 15.1 6.6 5.7 7.7 PI(D10) 49 23 46.9 32.5 61.7 21.3 14.9 30.5 PI(D42) 48 17 35.4 22.2 50.5 20.0 14.6 27.4 PI(D182) 92 25 27.2 18.4 37.4 12.2 9.7 15.4 PII(D192) 86 85 98.8 93.7 100 374.4 297.9 470.5 PII(D224) 86 82 95.3 88.5 98.7 217.3 172.4 274.0 PII(D549) 81 40 49.4 38.1 60.7 28.7 22.6 36.5 PIII(D591) 43 19 44.2 29.1 60.1 26.1 19.1 35.5 PRE 90 11 12.2 6.3 20.8 8.0 6.6 9.8 PI(D10) 44 18 40.9 26.3 56.8 25.5 16.4 39.5 PI(D42) 42 22 52.4 36.4 68.0 27.6 18.8 40.4 PI(D182) 90 25 27.8 18.9 38.2 13.5 10.3 17.8 PII(D549) 83 15 18.1 10.5 28.0 11.1 8.8 14.1 PIII(D559)* 83 79 95.2 88.1 98.7 356.7 265.9 478.5 PIII(D591) 82 77 93.9 86.3 98.0 300.3 225.6 399.7 PRE 98 8 8.2 3.6 15.5 7.0 6.0 8.2 PI(D10) 51 16 31.4 19.1 45.9 14.8 10.8 20.5 PI(D42) 51 14 27.5 15.9 41.7 15.1 11.2 20.5 PI(D182) 98 20 20.4 12.9 29.7 10.8 8.4 13.8 PII(D549) 88 8 9.1 4.0 17.1 8.3 7.0 9.7 PIII(D559)* 87 83 95.4 88.6 98.7 266.4 202.2 351.2 PIII(D591) 88 83 94.3 87.2 98.1 241.1 181.2 320.6 PRE 99 8 8.1 3.6 15.3 6.6 5.7 7.6 PI(D10) 44 22 50.0 34.6 65.4 24.7 16.8 36.4
A/Indonesia/5/0 5 Flu1-F2 PBS-Flu1- Flu1-F3 Flu2-Flu1-F1- PBS Flu2-Flu1-F2- PBS Flu1-F3 Flu1-F1 Flu1-F4 Flu1-F2 PBS-Flu1- Flu1-F3 PI(D42) 43 21 48.8 33.3 64.5 24.3 16.2 36.3 PI(D182) 99 28 28.3 19.7 38.2 12.8 10.0 16.4 PII(D549) 81 10 12.3 6.1 21.5 9.2 7.6 11.2 PIII(D559)* 80 77 96.3 89.4 99.2 446.6 336.0 593.7 PIII(D591) 80 75 93.8 86.0 97.9 326.9 241.6 442.2 PRE 89 6 6.7 2.5 14.1 6.9 5.9 8.0 PI(D10) 46 21 45.7 30.9 61.0 20.9 14.2 30.9 PI(D42) 47 18 38.3 24.5 53.6 18.3 13.2 25.4 PI(D182) 89 31 34.8 25.0 45.7 13.7 10.6 17.7 PII(D549) 72 13 18.1 10.0 28.9 11.4 9.1 14.4 PIII(D559)* 72 69 95.8 88.3 99.1 343.9 254.2 465.3 PIII(D591) 71 67 94.4 86.2 98.4 254.4 188.5 343.3 PRE 100 9 9.0 4.2 16.4 8.2 6.8 9.9 PI(D10) 46 6 13.0 4.9 26.3 8.2 6.4 10.6 PI(D182) 100 24 24.0 16.0 33.6 10.8 8.4 13.9 PII(D192)* 99 64 64.6 54.4 74.0 43.5 32.6 58.0 PII(D224) 98 60 61.2 50.8 70.9 44.3 32.6 60.3 PII(D549) 82 22 26.8 17.6 37.8 15.8 12.2 20.4 PIII(D559) 81 77 95.1 87.8 98.6 311.8 228.4 425.7 PIII(D591) 81 74 91.4 83.0 96.5 237.1 173.6 323.7 PRE 95 6 6.3 2.4 13.2 6.7 5.7 7.9 PI(D10) 95 50 52.6 42.1 63.0 32.3 23.5 44.4 PI(D42) 93 57 61.3 50.6 71.2 44.1 32.4 59.9 PI(D182) 95 42 44.2 34.0 54.8 22.4 16.7 30.0 PII(D192) 50 44 88.0 75.7 95.5 302.9 192.4 477.0 PII(D224) 50 42 84.0 70.9 92.8 190.3 121.1 299.1 PRE 92 1 1.1 0.0 5.9 5.9 5.4 6.5 PI(D10) 92 53 57.6 46.9 67.9 30.7 23.4 40.4 PI(D42) 88 62 70.5 59.8 79.7 44.8 34.7 57.9 PI(D182) 92 30 32.6 23.2 43.2 15.7 12.3 20.0 PII(D192) 46 46 100 92.3 100 363.8 263.1 503.1 PII(D224) 48 46 95.8 85.7 99.5 204.5 150.4 278.1 PRE 90 1 1.1 0.0 6.0 5.9 5.4 6.5 PI(D10) 89 41 46.1 35.4 57.0 27.0 19.4 37.6 PI(D42) 87 50 57.5 46.4 68.0 37.5 27.9 50.4 PI(D182) 90 28 31.1 21.8 41.7 16.4 12.5 21.6 PIII(D591) 43 38 88.4 74.9 96.1 207.1 138.9 308.6 PRE 98 0 0.0 0.0 3.7 5.7 5.3 6.1 PI(D10) 97 36 37.1 27.5 47.5 17.3 13.4 22.4 PI(D42) 96 53 55.2 44.7 65.4 27.6 21.3 35.7 PI(D182) 98 29 29.6 20.8 39.7 13.5 10.6 17.0 PIII(D591) 43 35 81.4 66.6 91.6 163.8 101.3 264.8 PRE 99 3 3.0 0.6 8.6 5.7 5.1 6.3 PI(D10) 98 56 57.1 46.7 67.1 31.7 24.2 41.4 PI(D42) 96 68 70.8 60.7 79.7 45.7 35.0 59.7 PI(D182) 99 35 35.4 26.0 45.6 17.8 14.0 22.6 PIII(D591) 38 38 100 90.7 100 335.0 248.9 451.0 PRE 89 2 2.2 0.3 7.9 5.6 5.1 6.1 PI(D10) 87 44 50.6 39.6 61.5 26.2 19.2 35.8 PI(D42) 87 53 60.9 49.9 71.2 36.6 27.1 49.5 PI(D182) 89 32 36.0 26.1 46.8 16.2 12.5 21.1 PIII(D591) 35 33 94.3 80.8 99.3 215.4 148.4 312.5 PRE 100 2 2.0 0.2 7.0 5.9 5.3 6.5 PI(D10) 98 4 4.1 1.1 10.1 6.4 5.7 7.2
PI(D42) 98 3 3.1 0.6 8.7 6.2 5.5 7.0 PI(D182) 100 9 9.0 4.2 16.4 6.7 5.8 7.7 PII(D192) 47 10 21.3 10.7 35.7 12.2 9.0 16.6 PII(D224) 47 6 12.8 4.8 25.7 10.6 7.8 14.4 PIII(D591) 39 27 69.2 52.4 83.0 54.6 32.1 92.8 SPR = A/turkey/Turkey/1/05 and A/Indonesia/5/05 antibody titers 1:40 GMT = geometric mean antibody titer calculated on all subjects N = number of subjects with available results n/% = number/percentage of subjects with titer within the specified range 95% CI = 95% confidence interval; LL = Lower Limit, UL = Upper Limit *Primary outcome variable Primary Efficacy Results: Number (%) of solicited local symptoms during the 7-day (Days 0-6) post-vaccination period following each dose and across doses (Total Vaccinated cohort) Flu2-Flu1-F1-PBS Flu2-Flu1-F2-PBS Flu1-F3 95 % CI 95 % CI 95 % CI Symptom Intensity N n % LL UL N n % LL UL N n % LL UL Dose 1 Pain Any 120 88 73.3 64.5 81.0 121 95 78.5 70.1 85.5 119 94 79.0 70.6 85.9 Grade 3 120 1 0.8 0.0 4.6 121 4 3.3 0.9 8.2 119 1 0.8 0.0 4.6 Redness Any 120 4 3.3 0.9 8.3 121 3 2.5 0.5 7.1 119 8 6.7 2.9 12.8 > 100 mm 120 0 0.0 0.0 3.0 121 0 0.0 0.0 3.0 119 1 0.8 0.0 4.6 Swelling Any 120 4 3.3 0.9 8.3 121 4 3.3 0.9 8.2 119 11 9.2 4.7 15.9 > 100 mm 120 0 0.0 0.0 3.0 121 0 0.0 0.0 3.0 119 0 0.0 0.0 3.1 Dose 2 Pain Any 110 71 64.5 54.9 73.4 110 63 57.3 47.5 66.7 111 10 9.0 4.4 15.9 Grade 3 110 1 0.9 0.0 5.0 110 4 3.6 1.0 9.0 111 0 0.0 0.0 3.3 Redness Any 110 4 3.6 1.0 9.0 110 1 0.9 0.0 5.0 111 0 0.0 0.0 3.3 > 100 mm 110 0 0.0 0.0 3.3 110 0 0.0 0.0 3.3 111 0 0.0 0.0 3.3 Swelling Any 110 2 1.8 0.2 6.4 110 4 3.6 1.0 9.0 111 1 0.9 0.0 4.9 > 100 mm 110 0 0.0 0.0 3.3 110 0 0.0 0.0 3.3 111 0 0.0 0.0 3.3 Dose 3 Pain Any 98 9 9.2 4.3 16.7 94 9 9.6 4.5 17.4 102 73 71.6 61.8 80.1 Grade 3 98 0 0.0 0.0 3.7 94 0 0.0 0.0 3.8 102 4 3.9 1.1 9.7 Redness Any 98 0 0.0 0.0 3.7 94 0 0.0 0.0 3.8 102 5 4.9 1.6 11.1 > 100 mm 98 0 0.0 0.0 3.7 94 0 0.0 0.0 3.8 102 0 0.0 0.0 3.6 Swelling Any 98 0 0.0 0.0 3.7 94 0 0.0 0.0 3.8 102 8 7.8 3.4 14.9 > 100 mm 98 0 0.0 0.0 3.7 94 0 0.0 0.0 3.8 102 0 0.0 0.0 3.6 Across doses Pain Any 120 98 81.7 73.6 88.1 121 100 82.6 74.7 88.9 119 101 84.9 77.2 90.8 Grade 3 120 2 1.7 0.2 5.9 121 7 5.8 2.4 11.6 119 5 4.2 1.4 9.5 Redness Any 120 8 6.7 2.9 12.7 121 4 3.3 0.9 8.2 119 12 10.1 5.3 17.0 > 100 mm 120 0 0.0 0.0 3.0 121 0 0.0 0.0 3.0 119 1 0.8 0.0 4.6 Swelling Any 120 6 5.0 1.9 10.6 121 7 5.8 2.4 11.6 119 15 12.6 7.2 19.9 > 100 mm 120 0 0.0 0.0 3.0 121 0 0.0 0.0 3.0 119 0 0.0 0.0 3.1 Flu1-F1 Flu1-F4 Flu1-F2 95 % CI 95 % CI 95 % CI Symptom Intensity N n % LL UL N n % LL UL N n % LL UL Dose 1 Pain Any 119 84 70.6 61.5 78.6 122 95 77.9 69.5 84.9 120 82 68.3 59.2 76.5 Grade 3 119 1 0.8 0.0 4.6 122 6 4.9 1.8 10.4 120 2 1.7 0.2 5.9 Redness Any 119 5 4.2 1.4 9.5 122 10 8.2 4.0 14.6 120 3 2.5 0.5 7.1 > 100 mm 119 0 0.0 0.0 3.1 122 0 0.0 0.0 3.0 120 0 0.0 0.0 3.0 Swelling Any 119 3 2.5 0.5 7.2 122 12 9.8 5.2 16.6 120 3 2.5 0.5 7.1 > 100 mm 119 0 0.0 0.0 3.1 122 0 0.0 0.0 3.0 120 0 0.0 0.0 3.0
Dose 2 Pain Any 110 14 12.7 7.1 20.4 116 13 11.2 6.1 18.4 110 13 11.8 6.4 19.4 Grade 3 110 0 0.0 0.0 3.3 116 0 0.0 0.0 3.1 110 0 0.0 0.0 3.3 Redness Any 110 0 0.0 0.0 3.3 116 2 1.7 0.2 6.1 110 0 0.0 0.0 3.3 > 100 mm 110 0 0.0 0.0 3.3 116 0 0.0 0.0 3.1 110 0 0.0 0.0 3.3 Swelling Any 110 0 0.0 0.0 3.3 116 0 0.0 0.0 3.1 110 1 0.9 0.0 5.0 > 100 mm 110 0 0.0 0.0 3.3 116 0 0.0 0.0 3.1 110 0 0.0 0.0 3.3 Dose 3 Pain Any 97 60 61.9 51.4 71.5 98 69 70.4 60.3 79.2 88 59 67.0 56.2 76.7 Grade 3 97 4 4.1 1.1 10.2 98 0 0.0 0.0 3.7 88 1 1.1 0.0 6.2 Redness Any 97 4 4.1 1.1 10.2 98 2 2.0 0.2 7.2 88 1 1.1 0.0 6.2 > 100 mm 97 0 0.0 0.0 3.7 98 0 0.0 0.0 3.7 88 0 0.0 0.0 4.1 Swelling Any 97 1 1.0 0.0 5.6 98 5 5.1 1.7 11.5 88 5 5.7 1.9 12.8 > 100 mm 97 0 0.0 0.0 3.7 98 0 0.0 0.0 3.7 88 0 0.0 0.0 4.1 Across doses Pain Any 119 93 78.2 69.6 85.2 122 102 83.6 75.8 89.7 120 90 75.0 66.3 82.5 Grade 3 119 4 3.4 0.9 8.4 122 6 4.9 1.8 10.4 120 3 2.5 0.5 7.1 Redness Any 119 9 7.6 3.5 13.9 122 14 11.5 6.4 18.5 120 4 3.3 0.9 8.3 > 100 mm 119 0 0.0 0.0 3.1 122 0 0.0 0.0 3.0 120 0 0.0 0.0 3.0 Swelling Any 119 4 3.4 0.9 8.4 122 16 13.1 7.7 20.4 120 9 7.5 3.5 13.8 > 100 mm 119 0 0.0 0.0 3.1 122 0 0.0 0.0 3.0 120 0 0.0 0.0 3.0 PBS-Flu1-Flu1-F3 95 % CI Symptom Intensity N n % LL UL Dose 1 Pain Any 120 10 8.3 4.1 14.8 Grade 3 120 0 0.0 0.0 3.0 Redness Any 120 0 0.0 0.0 3.0 > 100 mm 120 0 0.0 0.0 3.0 Swelling Any 120 0 0.0 0.0 3.0 > 100 mm 120 0 0.0 0.0 3.0 Dose 2 Pain Any 114 85 74.6 65.6 82.3 Grade 3 114 1 0.9 0.0 4.8 Redness Any 114 3 2.6 0.5 7.5 > 100 mm 114 0 0.0 0.0 3.2 Swelling Any 114 5 4.4 1.4 9.9 > 100 mm 114 0 0.0 0.0 3.2 Dose 3 Pain Any 94 64 68.1 57.7 77.3 Grade 3 94 4 4.3 1.2 10.5 Redness Any 94 5 5.3 1.7 12.0 > 100 mm 94 0 0.0 0.0 3.8 Swelling (mm) Any 94 7 7.4 3.0 14.7 > 100 mm 94 0 0.0 0.0 3.8 Across doses Pain Any 120 95 79.2 70.8 86.0 Grade 3 120 5 4.2 1.4 9.5 Redness Any 120 8 6.7 2.9 12.7 > 100 mm 120 0 0.0 0.0 3.0 Swelling Any 120 11 9.2 4.7 15.8 > 100 mm 120 0 0.0 0.0 3.0 N= Number of subjects with at least one administered dose n/%= Number/percentage of subjects reporting at least once the symptom
95% CI= Exact 95% confidence interval; LL = lower limit, UL = upper limit Any = occurrence of local symptom regardless of the intensity grade Grade 3 pain = significant pain at rest; prevented normal activities as assessed by inability to attend/do work or school Primary Efficacy Results: Number (%) of solicited general symptoms reported during the 7-day (Days 0-6) post-vaccination period following each dose and across doses (Total Vaccinated cohort) Flu2-Flu1-F1-PBS Flu2-Flu1-F2-PBS Flu1-F3 95 % CI 95 % CI 95 % CI Symptom Intensity/ Relationship N n % LL UL N n % LL UL N n % LL UL Dose 1 Fatigue Any 120 26 21.7 14.7 30.1 121 37 30.6 22.5 39.6 119 26 21.8 14.8 30.4 Grade 3 120 2 1.7 0.2 5.9 121 3 2.5 0.5 7.1 119 0 0.0 0.0 3.1 Related 120 24 20.0 13.3 28.3 121 37 30.6 22.5 39.6 119 24 20.2 13.4 28.5 Headache Any 120 25 20.8 14.0 29.2 121 32 26.4 18.8 35.2 119 23 19.3 12.7 27.6 Grade 3 120 2 1.7 0.2 5.9 121 2 1.7 0.2 5.8 119 1 0.8 0.0 4.6 Related 120 24 20.0 13.3 28.3 121 32 26.4 18.8 35.2 119 22 18.5 12.0 26.6 Joint pain at other location Any 120 15 12.5 7.2 19.8 121 21 17.4 11.1 25.3 119 17 14.3 8.5 21.9 Grade 3 120 1 0.8 0.0 4.6 121 1 0.8 0.0 4.5 119 0 0.0 0.0 3.1 Related 120 14 11.7 6.5 18.8 121 18 14.9 9.1 22.5 119 17 14.3 8.5 21.9 Muscle aches Any 120 25 20.8 14.0 29.2 121 42 34.7 26.3 43.9 119 39 32.8 24.4 42.0 Grade 3 120 0 0.0 0.0 3.0 121 1 0.8 0.0 4.5 119 0 0.0 0.0 3.1 Related 120 24 20.0 13.3 28.3 121 40 33.1 24.8 42.2 119 39 32.8 24.4 42.0 Shivering Any 120 2 1.7 0.2 5.9 121 11 9.1 4.6 15.7 119 6 5.0 1.9 10.7 Grade 3 120 0 0.0 0.0 3.0 121 1 0.8 0.0 4.5 119 0 0.0 0.0 3.1 Related 120 2 1.7 0.2 5.9 121 10 8.3 4.0 14.7 119 6 5.0 1.9 10.7 Sweating Any 120 10 8.3 4.1 14.8 121 13 10.7 5.8 17.7 119 8 6.7 2.9 12.8 Grade 3 120 1 0.8 0.0 4.6 121 1 0.8 0.0 4.5 119 0 0.0 0.0 3.1 Related 120 9 7.5 3.5 13.8 121 11 9.1 4.6 15.7 119 8 6.7 2.9 12.8 Temperature/ (Orally) 38.0 C 120 1 0.8 0.0 4.6 121 4 3.3 0.9 8.2 119 3 2.5 0.5 7.2 39.0 C 120 0 0.0 0.0 3.0 121 0 0.0 0.0 3.0 119 0 0.0 0.0 3.1 Related 120 1 0.8 0.0 4.6 121 3 2.5 0.5 7.1 119 2 1.7 0.2 5.9 Dose 2 Fatigue Any 110 25 22.7 15.3 31.7 110 22 20.0 13.0 28.7 111 15 13.5 7.8 21.3 Grade 3 110 1 0.9 0.0 5.0 110 2 1.8 0.2 6.4 111 2 1.8 0.2 6.4 Related 110 24 21.8 14.5 30.7 110 22 20.0 13.0 28.7 111 14 12.6 7.1 20.3 Headache Any 110 22 20.0 13.0 28.7 110 24 21.8 14.5 30.7 111 15 13.5 7.8 21.3 Grade 3 110 2 1.8 0.2 6.4 110 0 0.0 0.0 3.3 111 1 0.9 0.0 4.9 Related 110 21 19.1 12.2 27.7 110 22 20.0 13.0 28.7 111 12 10.8 5.7 18.1 Joint pain at other location Any 110 19 17.3 10.7 25.7 110 17 15.5 9.3 23.6 111 11 9.9 5.1 17.0 Grade 3 110 0 0.0 0.0 3.3 110 1 0.9 0.0 5.0 111 0 0.0 0.0 3.3 Related 110 19 17.3 10.7 25.7 110 17 15.5 9.3 23.6 111 8 7.2 3.2 13.7 Muscle aches Any 110 37 33.6 24.9 43.3 110 25 22.7 15.3 31.7 111 12 10.8 5.7 18.1 Grade 3 110 1 0.9 0.0 5.0 110 3 2.7 0.6 7.8 111 1 0.9 0.0 4.9 Related 110 36 32.7 24.1 42.3 110 23 20.9 13.7 29.7 111 10 9.0 4.4 15.9 Shivering Any 110 9 8.2 3.8 15.0 110 8 7.3 3.2 13.8 111 5 4.5 1.5 10.2 Grade 3 110 0 0.0 0.0 3.3 110 0 0.0 0.0 3.3 111 1 0.9 0.0 4.9 Related 110 9 8.2 3.8 15.0 110 8 7.3 3.2 13.8 111 4 3.6 1.0 9.0 Sweating Any 110 6 5.5 2.0 11.5 110 9 8.2 3.8 15.0 111 5 4.5 1.5 10.2 Grade 3 110 0 0.0 0.0 3.3 110 0 0.0 0.0 3.3 111 0 0.0 0.0 3.3 Related 110 6 5.5 2.0 11.5 110 9 8.2 3.8 15.0 111 4 3.6 1.0 9.0 Temperature/ (Orally) 38.0 C 110 0 0.0 0.0 3.3 110 0 0.0 0.0 3.3 111 2 1.8 0.2 6.4 39.0 C 110 0 0.0 0.0 3.3 110 0 0.0 0.0 3.3 111 0 0.0 0.0 3.3 Related 110 0 0.0 0.0 3.3 110 0 0.0 0.0 3.3 111 1 0.9 0.0 4.9 Dose 3
Fatigue Any 98 18 18.4 11.3 27.5 94 17 18.1 10.9 27.4 102 26 25.5 17.4 35.1 Grade 3 98 1 1.0 0.0 5.6 94 2 2.1 0.3 7.5 102 1 1.0 0.0 5.3 Related 98 17 17.3 10.4 26.3 94 14 14.9 8.4 23.7 102 26 25.5 17.4 35.1 Headache Any 98 17 17.3 10.4 26.3 94 17 18.1 10.9 27.4 102 20 19.6 12.4 28.6 Grade 3 98 1 1.0 0.0 5.6 94 2 2.1 0.3 7.5 102 1 1.0 0.0 5.3 Related 98 16 16.3 9.6 25.2 94 16 17.0 10.1 26.2 102 20 19.6 12.4 28.6 Joint pain at other location Any 98 10 10.2 5.0 18.0 94 8 8.5 3.7 16.1 102 17 16.7 10.0 25.3 Grade 3 98 0 0.0 0.0 3.7 94 0 0.0 0.0 3.8 102 1 1.0 0.0 5.3 Related 98 9 9.2 4.3 16.7 94 8 8.5 3.7 16.1 102 17 16.7 10.0 25.3 Muscle aches Any 98 9 9.2 4.3 16.7 94 11 11.7 6.0 20.0 102 30 29.4 20.8 39.3 Grade 3 98 0 0.0 0.0 3.7 94 0 0.0 0.0 3.8 102 2 2.0 0.2 6.9 Related 98 8 8.2 3.6 15.5 94 10 10.6 5.2 18.7 102 30 29.4 20.8 39.3 Shivering Any 98 2 2.0 0.2 7.2 94 3 3.2 0.7 9.0 102 9 8.8 4.1 16.1 Grade 3 98 0 0.0 0.0 3.7 94 1 1.1 0.0 5.8 102 0 0.0 0.0 3.6 Related 98 1 1.0 0.0 5.6 94 2 2.1 0.3 7.5 102 9 8.8 4.1 16.1 Sweating Any 98 1 1.0 0.0 5.6 94 0 0.0 0.0 3.8 102 4 3.9 1.1 9.7 Grade 3 98 0 0.0 0.0 3.7 94 0 0.0 0.0 3.8 102 0 0.0 0.0 3.6 Related 98 0 0.0 0.0 3.7 94 0 0.0 0.0 3.8 102 4 3.9 1.1 9.7 Temperature/ (Orally) 38.0 C 98 1 1.0 0.0 5.6 94 1 1.1 0.0 5.8 102 1 1.0 0.0 5.3 39.0 C 98 0 0.0 0.0 3.7 94 0 0.0 0.0 3.8 102 0 0.0 0.0 3.6 Related 98 1 1.0 0.0 5.6 94 0 0.0 0.0 3.8 102 1 1.0 0.0 5.3 Across doses Fatigue Any 120 45 37.5 28.8 46.8 121 50 41.3 32.4 50.6 119 47 39.5 30.7 48.9 Grade 3 120 4 3.3 0.9 8.3 121 7 5.8 2.4 11.6 119 3 2.5 0.5 7.2 Related 120 44 36.7 28.1 45.9 121 47 38.8 30.1 48.1 119 44 37.0 28.3 46.3 Headache Any 120 44 36.7 28.1 45.9 121 50 41.3 32.4 50.6 119 42 35.3 26.8 44.6 Grade 3 120 5 4.2 1.4 9.5 121 4 3.3 0.9 8.2 119 3 2.5 0.5 7.2 Related 120 43 35.8 27.3 45.1 121 48 39.7 30.9 49.0 119 40 33.6 25.2 42.8 Joint pain at other location Any 120 33 27.5 19.7 36.4 121 37 30.6 22.5 39.6 119 36 30.3 22.2 39.3 Grade 3 120 1 0.8 0.0 4.6 121 1 0.8 0.0 4.5 119 1 0.8 0.0 4.6 Related 120 32 26.7 19.0 35.5 121 34 28.1 20.3 37.0 119 34 28.6 20.7 37.6 Muscle aches Any 120 54 45.0 35.9 54.3 121 52 43.0 34.0 52.3 119 59 49.6 40.3 58.9 Grade 3 120 1 0.8 0.0 4.6 121 3 2.5 0.5 7.1 119 3 2.5 0.5 7.2 Related 120 53 44.2 35.1 53.5 121 48 39.7 30.9 49.0 119 58 48.7 39.5 58.1 Shivering Any 120 12 10.0 5.3 16.8 121 18 14.9 9.1 22.5 119 16 13.4 7.9 20.9 Grade 3 120 0 0.0 0.0 3.0 121 2 1.7 0.2 5.8 119 1 0.8 0.0 4.6 Related 120 11 9.2 4.7 15.8 121 16 13.2 7.8 20.6 119 15 12.6 7.2 19.9 Sweating Any 120 15 12.5 7.2 19.8 121 20 16.5 10.4 24.4 119 15 12.6 7.2 19.9 Grade 3 120 1 0.8 0.0 4.6 121 1 0.8 0.0 4.5 119 0 0.0 0.0 3.1 Related 120 13 10.8 5.9 17.8 121 18 14.9 9.1 22.5 119 14 11.8 6.6 19.0 Temperature/ (Orally) Symptom 38.0 C 120 2 1.7 0.2 5.9 121 5 4.1 1.4 9.4 119 6 5.0 1.9 10.7 39.0 C 120 0 0.0 0.0 3.0 121 0 0.0 0.0 3.0 119 0 0.0 0.0 3.1 Related 120 2 1.7 0.2 5.9 121 3 2.5 0.5 7.1 119 4 3.4 0.9 8.4 Flu1-F1 Flu1-F4 Flu1-F2 95 % CI 95 % CI 95 % CI Intensity/R elationship N n % LL UL N n % LL UL N n % LL UL Dose 1 Fatigue Any 119 27 22.7 15.5 31.3 122 30 24.6 17.2 33.2 120 22 18.3 11.9 26.4 Grade 3 119 2 1.7 0.2 5.9 122 3 2.5 0.5 7.0 120 0 0.0 0.0 3.0 Related 119 26 21.8 14.8 30.4 122 29 23.8 16.5 32.3 120 22 18.3 11.9 26.4 Headache Any 119 25 21.0 14.1 29.4 122 25 20.5 13.7 28.7 120 19 15.8 9.8 23.6 Grade 3 119 1 0.8 0.0 4.6 122 1 0.8 0.0 4.5 120 1 0.8 0.0 4.6 Related 119 24 20.2 13.4 28.5 122 23 18.9 12.3 26.9 120 18 15.0 9.1 22.7
Joint pain at other location Any 119 15 12.6 7.2 19.9 122 21 17.2 11.0 25.1 120 5 4.2 1.4 9.5 Grade 3 119 0 0.0 0.0 3.1 122 0 0.0 0.0 3.0 120 0 0.0 0.0 3.0 Related 119 14 11.8 6.6 19.0 122 20 16.4 10.3 24.2 120 5 4.2 1.4 9.5 Muscle aches Any 119 35 29.4 21.4 38.5 122 41 33.6 25.3 42.7 120 29 24.2 16.8 32.8 Grade 3 119 1 0.8 0.0 4.6 122 2 1.6 0.2 5.8 120 0 0.0 0.0 3.0 Related 119 34 28.6 20.7 37.6 122 39 32.0 23.8 41.0 120 28 23.3 16.1 31.9 Shivering Any 119 1 0.8 0.0 4.6 122 12 9.8 5.2 16.6 120 5 4.2 1.4 9.5 Grade 3 119 0 0.0 0.0 3.1 122 1 0.8 0.0 4.5 120 0 0.0 0.0 3.0 Related 119 1 0.8 0.0 4.6 122 11 9.0 4.6 15.6 120 5 4.2 1.4 9.5 Sweating Any 119 6 5.0 1.9 10.7 122 10 8.2 4.0 14.6 120 9 7.5 3.5 13.8 Grade 3 119 0 0.0 0.0 3.1 122 1 0.8 0.0 4.5 120 0 0.0 0.0 3.0 Related 119 6 5.0 1.9 10.7 122 9 7.4 3.4 13.5 120 7 5.8 2.4 11.6 Temperature/ (Orally) 38.0 C 119 0 0.0 0.0 3.1 122 6 4.9 1.8 10.4 120 1 0.8 0.0 4.6 39.0 C 119 0 0.0 0.0 3.1 122 0 0.0 0.0 3.0 120 0 0.0 0.0 3.0 Related 119 0 0.0 0.0 3.1 122 6 4.9 1.8 10.4 120 1 0.8 0.0 4.6 Dose 2 Fatigue Any 110 17 15.5 9.3 23.6 116 17 14.7 8.8 22.4 110 16 14.5 8.5 22.5 Grade 3 110 1 0.9 0.0 5.0 116 2 1.7 0.2 6.1 110 1 0.9 0.0 5.0 Related 110 15 13.6 7.8 21.5 116 15 12.9 7.4 20.4 110 15 13.6 7.8 21.5 Headache Any 110 15 13.6 7.8 21.5 116 18 15.5 9.5 23.4 110 15 13.6 7.8 21.5 Grade 3 110 0 0.0 0.0 3.3 116 1 0.9 0.0 4.7 110 1 0.9 0.0 5.0 Related 110 11 10.0 5.1 17.2 116 14 12.1 6.8 19.4 110 11 10.0 5.1 17.2 Joint pain at other location Any 110 3 2.7 0.6 7.8 116 8 6.9 3.0 13.1 110 7 6.4 2.6 12.7 Grade 3 110 0 0.0 0.0 3.3 116 0 0.0 0.0 3.1 110 0 0.0 0.0 3.3 Related 110 2 1.8 0.2 6.4 116 7 6.0 2.5 12.0 110 5 4.5 1.5 10.3 Muscle aches Any 110 5 4.5 1.5 10.3 116 12 10.3 5.5 17.4 110 11 10.0 5.1 17.2 Grade 3 110 0 0.0 0.0 3.3 116 0 0.0 0.0 3.1 110 0 0.0 0.0 3.3 Related 110 4 3.6 1.0 9.0 116 11 9.5 4.8 16.3 110 9 8.2 3.8 15.0 Shivering Any 110 5 4.5 1.5 10.3 116 3 2.6 0.5 7.4 110 4 3.6 1.0 9.0 Grade 3 110 0 0.0 0.0 3.3 116 0 0.0 0.0 3.1 110 0 0.0 0.0 3.3 Related 110 4 3.6 1.0 9.0 116 3 2.6 0.5 7.4 110 4 3.6 1.0 9.0 Sweating Any 110 1 0.9 0.0 5.0 116 2 1.7 0.2 6.1 110 2 1.8 0.2 6.4 Grade 3 110 0 0.0 0.0 3.3 116 0 0.0 0.0 3.1 110 0 0.0 0.0 3.3 Related 110 1 0.9 0.0 5.0 116 1 0.9 0.0 4.7 110 2 1.8 0.2 6.4 Temperature/ (Orally) 38.0 C 110 1 0.9 0.0 5.0 116 3 2.6 0.5 7.4 110 0 0.0 0.0 3.3 39.0 C 110 0 0.0 0.0 3.3 116 1 0.9 0.0 4.7 110 0 0.0 0.0 3.3 Related 110 1 0.9 0.0 5.0 116 2 1.7 0.2 6.1 110 0 0.0 0.0 3.3 Dose 3 Fatigue Any 97 24 24.7 16.5 34.5 98 17 17.3 10.4 26.3 88 17 19.3 11.7 29.1 Grade 3 97 1 1.0 0.0 5.6 98 0 0.0 0.0 3.7 88 1 1.1 0.0 6.2 Related 97 23 23.7 15.7 33.4 98 16 16.3 9.6 25.2 88 17 19.3 11.7 29.1 Headache Any 97 23 23.7 15.7 33.4 98 18 18.4 11.3 27.5 88 17 19.3 11.7 29.1 Grade 3 97 1 1.0 0.0 5.6 98 0 0.0 0.0 3.7 88 0 0.0 0.0 4.1 Related 97 20 20.6 13.1 30.0 98 14 14.3 8.0 22.8 88 14 15.9 9.0 25.2 Joint pain at other location Any 97 12 12.4 6.6 20.6 98 7 7.1 2.9 14.2 88 8 9.1 4.0 17.1 Grade 3 97 1 1.0 0.0 5.6 98 0 0.0 0.0 3.7 88 0 0.0 0.0 4.1 Related 97 11 11.3 5.8 19.4 98 7 7.1 2.9 14.2 88 8 9.1 4.0 17.1 Muscle aches Any 97 25 25.8 17.4 35.7 98 19 19.4 12.1 28.6 88 19 21.6 13.5 31.6 Grade 3 97 3 3.1 0.6 8.8 98 0 0.0 0.0 3.7 88 0 0.0 0.0 4.1 Related 97 24 24.7 16.5 34.5 98 19 19.4 12.1 28.6 88 19 21.6 13.5 31.6 Shivering Any 97 2 2.1 0.3 7.3 98 9 9.2 4.3 16.7 88 1 1.1 0.0 6.2 Grade 3 97 1 1.0 0.0 5.6 98 0 0.0 0.0 3.7 88 0 0.0 0.0 4.1 Related 97 2 2.1 0.3 7.3 98 9 9.2 4.3 16.7 88 0 0.0 0.0 4.1 Sweating Any 97 4 4.1 1.1 10.2 98 4 4.1 1.1 10.1 88 1 1.1 0.0 6.2
Temperature/ (Orally) Grade 3 97 1 1.0 0.0 5.6 98 0 0.0 0.0 3.7 88 0 0.0 0.0 4.1 Related 97 4 4.1 1.1 10.2 98 3 3.1 0.6 8.7 88 1 1.1 0.0 6.2 38.0 C 97 2 2.1 0.3 7.3 98 1 1.0 0.0 5.6 88 1 1.1 0.0 6.2 39.0 C 97 0 0.0 0.0 3.7 98 0 0.0 0.0 3.7 88 1 1.1 0.0 6.2 Related 97 2 2.1 0.3 7.3 98 1 1.0 0.0 5.6 88 0 0.0 0.0 4.1 Across doses Fatigue Any 119 44 37.0 28.3 46.3 122 42 34.4 26.1 43.6 120 39 32.5 24.2 41.7 Grade 3 119 4 3.4 0.9 8.4 122 5 4.1 1.3 9.3 120 2 1.7 0.2 5.9 Related 119 43 36.1 27.5 45.4 122 41 33.6 25.3 42.7 120 39 32.5 24.2 41.7 Headache Any 119 44 37.0 28.3 46.3 122 44 36.1 27.6 45.3 120 35 29.2 21.2 38.2 Grade 3 119 2 1.7 0.2 5.9 122 2 1.6 0.2 5.8 120 2 1.7 0.2 5.9 Related 119 41 34.5 26.0 43.7 122 37 30.3 22.3 39.3 120 33 27.5 19.7 36.4 Joint pain at other location Any 119 26 21.8 14.8 30.4 122 28 23.0 15.8 31.4 120 16 13.3 7.8 20.7 Grade 3 119 1 0.8 0.0 4.6 122 0 0.0 0.0 3.0 120 0 0.0 0.0 3.0 Related 119 23 19.3 12.7 27.6 122 26 21.3 14.4 29.6 120 14 11.7 6.5 18.8 Muscle aches Any 119 49 41.2 32.2 50.6 122 48 39.3 30.6 48.6 120 42 35.0 26.5 44.2 Grade 3 119 3 2.5 0.5 7.2 122 2 1.6 0.2 5.8 120 0 0.0 0.0 3.0 Related 119 46 38.7 29.9 48.0 122 47 38.5 29.9 47.8 120 42 35.0 26.5 44.2 Shivering Any 119 8 6.7 2.9 12.8 122 20 16.4 10.3 24.2 120 10 8.3 4.1 14.8 Grade 3 119 1 0.8 0.0 4.6 122 1 0.8 0.0 4.5 120 0 0.0 0.0 3.0 Related 119 7 5.9 2.4 11.7 122 19 15.6 9.6 23.2 120 9 7.5 3.5 13.8 Sweating Any 119 11 9.2 4.7 15.9 122 14 11.5 6.4 18.5 120 10 8.3 4.1 14.8 Grade 3 119 1 0.8 0.0 4.6 122 1 0.8 0.0 4.5 120 0 0.0 0.0 3.0 Related 119 11 9.2 4.7 15.9 122 11 9.0 4.6 15.6 120 8 6.7 2.9 12.7 Temperature/ (Orally) 38.0 C 119 3 2.5 0.5 7.2 122 8 6.6 2.9 12.5 120 2 1.7 0.2 5.9 39.0 C 119 0 0.0 0.0 3.1 122 1 0.8 0.0 4.5 120 1 0.8 0.0 4.6 Related 119 3 2.5 0.5 7.2 122 7 5.7 2.3 11.5 120 1 0.8 0.0 4.6 PBS-Flu1-Flu1-F3 95 % CI Symptom Intensity/Relationship N n % LL UL Dose 1 Fatigue Any 120 14 11.7 6.5 18.8 Grade 3 120 0 0.0 0.0 3.0 Related 120 14 11.7 6.5 18.8 Headache Any 120 16 13.3 7.8 20.7 Grade 3 120 1 0.8 0.0 4.6 Related 120 14 11.7 6.5 18.8 Joint pain at other location Any 120 10 8.3 4.1 14.8 Grade 3 120 0 0.0 0.0 3.0 Related 120 9 7.5 3.5 13.8 Muscle aches Any 120 11 9.2 4.7 15.8 Grade 3 120 0 0.0 0.0 3.0 Related 120 11 9.2 4.7 15.8 Shivering Any 120 3 2.5 0.5 7.1 Grade 3 120 0 0.0 0.0 3.0 Related 120 3 2.5 0.5 7.1 Sweating Any 120 3 2.5 0.5 7.1 Grade 3 120 0 0.0 0.0 3.0 Related 120 3 2.5 0.5 7.1 Temperature/(Orally) 38.0 C 120 1 0.8 0.0 4.6 39.0 C 120 0 0.0 0.0 3.0 Related 120 1 0.8 0.0 4.6 Dose 2 Fatigue Any 114 34 29.8 21.6 39.1
Grade 3 114 3 2.6 0.5 7.5 Related 114 33 28.9 20.8 38.2 Headache Any 114 24 21.1 14.0 29.7 Grade 3 114 2 1.8 0.2 6.2 Related 114 22 19.3 12.5 27.7 Joint pain at other location Any 114 18 15.8 9.6 23.8 Grade 3 114 0 0.0 0.0 3.2 Related 114 17 14.9 8.9 22.8 Muscle aches Any 114 40 35.1 26.4 44.6 Grade 3 114 2 1.8 0.2 6.2 Related 114 38 33.3 24.8 42.8 Shivering Any 114 12 10.5 5.6 17.7 Grade 3 114 0 0.0 0.0 3.2 Related 114 10 8.8 4.3 15.5 Sweating Any 114 3 2.6 0.5 7.5 Grade 3 114 0 0.0 0.0 3.2 Related 114 3 2.6 0.5 7.5 Temperature/(Orally) 38.0 C 114 0 0.0 0.0 3.2 39.0 C 114 0 0.0 0.0 3.2 Related 114 0 0.0 0.0 3.2 Dose 3 Fatigue Any 94 21 22.3 14.4 32.1 Grade 3 94 1 1.1 0.0 5.8 Related 94 21 22.3 14.4 32.1 Headache Any 94 27 28.7 19.9 39.0 Grade 3 94 1 1.1 0.0 5.8 Related 94 27 28.7 19.9 39.0 Joint pain at other location Any 94 10 10.6 5.2 18.7 Grade 3 94 2 2.1 0.3 7.5 Related 94 10 10.6 5.2 18.7 Muscle aches Any 94 30 31.9 22.7 42.3 Grade 3 94 2 2.1 0.3 7.5 Related 94 30 31.9 22.7 42.3 Shivering Any 94 8 8.5 3.7 16.1 Grade 3 94 1 1.1 0.0 5.8 Related 94 8 8.5 3.7 16.1 Sweating Any 94 6 6.4 2.4 13.4 Grade 3 94 1 1.1 0.0 5.8 Related 94 6 6.4 2.4 13.4 Temperature/(Orally) 38.0 C 94 1 1.1 0.0 5.8 39.0 C 94 0 0.0 0.0 3.8 Related 94 1 1.1 0.0 5.8 Across doses Fatigue Any 120 47 39.2 30.4 48.5 Grade 3 120 4 3.3 0.9 8.3 Related 120 46 38.3 29.6 47.6 Headache Any 120 47 39.2 30.4 48.5 Grade 3 120 4 3.3 0.9 8.3 Related 120 46 38.3 29.6 47.6 Joint pain at other location Any 120 30 25.0 17.5 33.7 Grade 3 120 2 1.7 0.2 5.9 Related 120 28 23.3 16.1 31.9 Muscle aches Any 120 55 45.8 36.7 55.2 Grade 3 120 4 3.3 0.9 8.3
Related 120 55 45.8 36.7 55.2 Shivering Any 120 18 15.0 9.1 22.7 Grade 3 120 1 0.8 0.0 4.6 Related 120 17 14.2 8.5 21.7 Sweating Any 120 11 9.2 4.7 15.8 Grade 3 120 1 0.8 0.0 4.6 Related 120 11 9.2 4.7 15.8 Temperature/(Orally) 38.0 C 120 2 1.7 0.2 5.9 39.0 C 120 0 0.0 0.0 3.0 Related 120 2 1.7 0.2 5.9 N= Number of subjects with at least one administered dose n/%= Number/percentage of subjects reporting at least once the symptom 95% CI= Exact 95% confidence interval; LL = lower limit, UL = upper limit Any = occurrence of general symptom regardless of intensity grade or relationship to vaccination Grade 3 = general symptom that prevented normal everyday activities as assessed by inability to attend/do work or school, or required intervention of a physician/healthcare provider Related = general symptom assessed by the investigator as causally related to the vaccination Primary Efficacy Results: Number (%) of subjects reporting the occurrence of MAEs occurring during the entire study period (Days 0-909) (Total Vaccinated Cohort) MAEs Flu2-Flu1- F1-PBS N = 120 Flu2-Flu1- F2-PBS N = 121 Flu1-F3 N = 119 Flu1-F1 N = 119 Flu1-F4 N = 122 Flu1-F2 N = 120 PBS-Flu1- Flu1-F3 N = 120 Subjects with any MAE(s), n (%) 68 (56.7) 66 (54.5) 77 (64.7) 75 (63.0) 62 (50.8) 63 (52.5) 70 (58.3) Sinusitis 7 (5.8) 8 (6.6) 10 (8.4) 9 (7.6) 4 (3.3) 5 (4.2) 12 (10.0) Bronchitis 5 (4.2) 7 (5.8) 4 (3.4) 8 (6.7) 5 (4.1) 6 (5.0) - Upper respiratory tract infection 4 (3.3) 4 (3.3) 5 (4.2) 3 (2.5) - - - Hypertension - - - - 5 (4.1) 4 (3.3) 4 (3.3) Lymphadenopathy 5 (4.2) 4 (3.3) - - 3 (2.5) - - Urinary tract infection - - - 3 (2.5) - 4 (3.3) 4 (3.3) Cystitis 5 (4.2) - 5 (4.2) - - - - Back pain - - - 3 (2.5) - 6 (5.0) - Cough - - - 3 (2.5) 6 (4.9) - - Pneumonia 4 (3.3) 4 (3.3) - - - - - Arthralgia 4 (3.3) - - - - - - Asthma - - 4 (3.4) - - - - Depression - - - - - - 4 (3.3) Ear infection - - - - - - 4 (3.3) Muscle strain - - 4 (3.4) - - - - Musculoskeletal pain - - 4 (3.4) - - - - Procedural pain - - - - - - 4 (3.3) Cataract - - - - 3 (2.5) - - Contusion - - - - 3 (2.5) - - Eye infection - - - - 3 (2.5) - - Influenza like illness - - - 3 (2.5) - - - Joint sprain - - - - 3 (2.5) - - Nasopharyngitis - - - - 3 (2.5) - - Nausea - - - - 3 (2.5) - - Pharyngitis streptococcal - - - 3 (2.5) - - - Counting rule applied: As there were more than 30 subjects per treatment group and > 3 groups, only the 5 most frequent events in each treatment group are to be listed. -: Implies that adverse event was not reported in the particular group or that the adverse event was reported in the particular group but did not fall within the pre-defined counting rule of 5 most frequent events for that group. Primary Efficacy Results: Please refer to the safety section of this document for the results on unsolicited AEs and SAEs. Secondary Outcome Variable(s): GMT and SPR for HI antibodies against A/turkey/Turkey/5/05, A/Indonesia/5/05, and A/Vietnam/1194/04 at Days 0, 182, 192, 224, 549, 559, 591 and 729 (ATP cohort for immunogenicity at Day 729)
1:40 GMT 95% CI 95% CI Antibody Timing N n % LL UL Value LL UL A/turkey/ Turkey/5/05 Flu2-Flu1-F1- PBS Flu2-Flu1-F2- PBS Flu1- F3 Flu1- F1 Flu1- F4 Flu1- F2 PBS-Flu1-Flu1- F3 PRE 95 16 16.8 9.9 25.9 9.2 7.4 11.4 PI(D10) 50 26 52.0 37.4 66.3 29.3 20.6 41.6 PI(D42) 50 26 52.0 37.4 66.3 28.5 21.3 38.1 PI(D182) 95 30 31.6 22.4 41.9 17.6 13.1 23.6 PII(D192) 94 89 94.7 88.0 98.3 308.4 231.1 411.5 PII(D224) 93 86 92.5 85.1 96.9 195.0 146.7 259.1 PII(D549) 84 42 50.0 38.9 61.1 32.7 24.4 43.6 PIII(D591) 46 27 58.7 43.2 73.0 45.1 30.8 66.0 PIII(D729) 78 47 60.3 48.5 71.2 41.8 32.1 54.4 PRE 92 7 7.6 3.1 15.1 6.6 5.7 7.7 PI(D10) 49 23 46.9 32.5 61.7 21.3 14.9 30.5 PI(D42) 48 17 35.4 22.2 50.5 20.0 14.6 27.4 PI(D182) 92 25 27.2 18.4 37.4 12.2 9.7 15.4 PII(D192) 86 85 98.8 93.7 100 374.4 297.9 470.5 PII(D224) 91 87 95.6 89.1 98.8 213.7 170.7 267.5 PII(D549) 81 40 49.4 38.1 60.7 28.7 22.6 36.5 PIII(D591) 44 20 45.5 30.4 61.2 27.2 19.9 37.1 PIII(D729) 78 49 62.8 51.1 73.5 31.2 24.8 39.2 PRE 90 11 12.2 6.3 20.8 8.0 6.6 9.8 PI(D10) 44 18 40.9 26.3 56.8 25.5 16.4 39.5 PI(D42) 42 22 52.4 36.4 68.0 27.6 18.8 40.4 PI(D182) 90 25 27.8 18.9 38.2 13.5 10.3 17.8 PII(D549) 83 15 18.1 10.5 28.0 11.1 8.8 14.1 PIII(D559) 83 79 95.2 88.1 98.7 356.7 265.9 478.5 PIII(D591) 82 77 93.9 86.3 98.0 300.3 225.6 399.7 PIII(D729) 81 75 92.6 84.6 97.2 119.2 95.3 149.0 PRE 96 8 8.3 3.7 15.8 7.1 6.0 8.3 PI(D10) 50 16 32.0 19.5 46.7 14.8 10.7 20.6 PI(D42) 50 14 28.0 16.2 42.5 15.5 11.4 21.0 PI(D182) 96 20 20.8 13.2 30.3 10.8 8.4 13.9 PII(D549) 86 8 9.3 4.1 17.5 8.4 7.1 9.9 PIII(D559) 85 81 95.3 88.4 98.7 266.4 202.2 350.9 PIII(D591) 86 82 95.3 88.5 98.7 242.4 182.8 321.5 PIII(D729) 83 73 88.0 79.0 94.1 96.6 75.1 124.2 PRE 99 8 8.1 3.6 15.3 6.6 5.7 7.6 PI(D10) 44 22 50.0 34.6 65.4 24.7 16.8 36.4 PI(D42) 43 21 48.8 33.3 64.5 24.3 16.2 36.3 PI(D182) 99 28 28.3 19.7 38.2 12.8 10.0 16.4 PII(D549) 81 10 12.3 6.1 21.5 9.2 7.6 11.2 PIII(D559) 80 77 96.3 89.4 99.2 446.6 336.0 593.7 PIII(D591) 80 75 93.8 86.0 97.9 326.9 241.6 442.2 PIII(D729) 79 71 89.9 81.0 95.5 134.8 106.4 170.9 PRE 89 6 6.7 2.5 14.1 6.9 5.9 8.0 PI(D10) 46 21 45.7 30.9 61.0 20.9 14.2 30.9 PI(D42) 47 18 38.3 24.5 53.6 18.3 13.2 25.4 PI(D182) 89 31 34.8 25.0 45.7 13.7 10.6 17.7 PII(D549) 72 13 18.1 10.0 28.9 11.4 9.1 14.4 PIII(D559) 72 69 95.8 88.3 99.1 343.9 254.2 465.3 PIII(D591) 71 67 94.4 86.2 98.4 254.4 188.5 343.3 PIII(D729) 70 66 94.3 86.0 98.4 105.6 84.1 132.6 PRE 99 8 8.1 3.6 15.3 8.0 6.6 9.7 PI(D10) 46 6 13.0 4.9 26.3 8.2 6.4 10.6