Trial Outcomes & Findings for Safety and Immunogenicity of Two Doses of a Tetravalent Influenza Vaccine in Adults Aged 18 Years and Above (NCT NCT00620815)

NCT ID: NCT00620815

Last Updated: 2016-03-28

Results Overview

The antibody response was determined by SRH assay. Geometric mean areas (GMAs) and geometric mean ratios (GMRs) in the SRH assay were used to demonstrate the equivalence. The statistical analysis was done based on the GMRs.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

601 participants

Primary outcome timeframe

up to day 43

Results posted on

2016-03-28

Participant Flow

Participants were enrolled at 2 sites in Germany

All subjects were included in the trial. The data entered is for the overall study.

Participant milestones

Participant milestones
Measure	T/P-A one dose of the tetravalent (T) influenza vaccine administered concomitantly, in a different arm, with one dose of the placebo (P) control, on study day 1, followed by Aflunov, on study day 22	A/P-T one dose of the Aflunov (A; A/H5N1) avian influenza vaccine administered concomitantly, in a different arm, with one dose of the placebo (P) control, on study day 1, followed by the tetravalent (T) influenza vaccine, on study day 22	A/S-A one dose of the Aflunov (A, A/H5N1) avian influenza vaccine administered concomitantly, in a different arm, one dose of licensed seasonal (S) vaccine, on study day 1, followed by Aflunov (A), on study day 22
Overall Study STARTED	199	203	199
Overall Study COMPLETED	195	192	192
Overall Study NOT COMPLETED	4	11	7

Reasons for withdrawal

Reasons for withdrawal
Measure	T/P-A one dose of the tetravalent (T) influenza vaccine administered concomitantly, in a different arm, with one dose of the placebo (P) control, on study day 1, followed by Aflunov, on study day 22	A/P-T one dose of the Aflunov (A; A/H5N1) avian influenza vaccine administered concomitantly, in a different arm, with one dose of the placebo (P) control, on study day 1, followed by the tetravalent (T) influenza vaccine, on study day 22	A/S-A one dose of the Aflunov (A, A/H5N1) avian influenza vaccine administered concomitantly, in a different arm, one dose of licensed seasonal (S) vaccine, on study day 1, followed by Aflunov (A), on study day 22
Overall Study Adverse Event	1	1	2
Overall Study Withdrawal by Subject	1	2	0
Overall Study Lost to Follow-up	1	6	3
Overall Study Inappropriate enrolment	0	0	1
Overall Study Protocol Violation	1	2	1

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	T/P-A n=199 Participants one dose of the tetravalent (T) influenza vaccine administered concomitantly, in a different arm, with one dose of the placebo (P) control, on study day 1, followed by Aflunov, on study day 22	A/P-T n=203 Participants one dose of the Aflunov (A; A/H5N1) avian influenza vaccine administered concomitantly, in a different arm, with one dose of the placebo (P) control, on study day 1, followed by the tetravalent (T) influenza vaccine, on study day 22	A/S-A n=199 Participants one dose of the Aflunov (A; A/H5N1) avian influenza vaccine administered concomitantly, in a different arm, one dose of licensed seasonal(S) vaccine, on study day 1, followed by Aflunov (A), on study day 22	Total n=601 Participants Total of all reporting groups
Age, Customized ≤60 years	196 participants 8 • n=5 Participants	202 participants 9.8 • n=7 Participants	198 participants 9.6 • n=5 Participants	596 participants n=4 Participants
Age, Customized ≥ 61 Years	3 participants 1 • n=5 Participants	1 participants 0 • n=7 Participants	0 participants NA • n=5 Participants	4 participants n=4 Participants
Sex/Gender, Customized Female (≤60 years of age)	126 participants n=5 Participants	129 participants n=7 Participants	114 participants n=5 Participants	369 participants n=4 Participants
Sex/Gender, Customized Male (≤60 years of age)	70 participants n=5 Participants	73 participants n=7 Participants	84 participants n=5 Participants	227 participants n=4 Participants
Sex/Gender, Customized Female (≥61 years of age)	1 participants n=5 Participants	1 participants n=7 Participants	0 participants n=5 Participants	2 participants n=4 Participants
Sex/Gender, Customized Male (≥61 years of age)	2 participants n=5 Participants	0 participants n=7 Participants	0 participants n=5 Participants	2 participants n=4 Participants

PRIMARY outcome

Timeframe: up to day 43

Population: The analysis was done on Per Protocol Set (PPS)

Outcome measures

Outcome measures
Measure	T/P-A n=194 Participants One dose of the tetravalent influenza vaccine (T) and concomitantly, but in a different arm, one dose of placebo (P) on day 1, followed by Aflunov (A) on day 22	A/P-T n=202 Participants One dose of the Aflunov (A) and concomitantly, but in a different arm, one dose of placebo (P) on day 1, followed by Tetravalent influenza vaccine (T) on day 22	A/S-A n=198 Participants One dose of Aflunov (A) and concomitantly, but in a different arm, one dose of licensed seasonal vaccine (S) on day 1, followed Aflunov (A) on day 22	A/P-T: In Arm Receiving Placebo (P) Local reactions after first vaccination in arm receiving Placebo in group receiving one dose of the Aflunov (A) and concomitantly, but in a different arm, one dose of placebo (P) on day 1, followed by Tetravalent influenza vaccine (T) on day 22	A/S-A: In Arm Receiving Aflunov (A) Local reactions after first vaccination in arm receiving Aflunov in group receiving one dose of Aflunov (A) and concomitantly, but in a different arm, one dose of licensed seasonal vaccine (S) on day 1, followed Aflunov (A) bon day 22	A/S-A: In Arm Receiving Seasonal Influenza Vaccine (S) Local reactions after first vaccination in arm receiving seasonal influenza vaccination in group receiving one dose of Aflunov (A) and concomitantly, but in a different arm, one dose of licensed seasonal vaccine (S) on day 1, followed Aflunov (A) on day 22
To Demonstrate the Equivalence of Antibody Response Against A/H5N1 Strain Elicited by the Three Different Immunization Schedules on Day 43. Day 1	4.64 Area (mm^2) Interval 4.17 to 5.17	4.10 Area (mm^2) Interval 3.69 to 4.56	4.61 Area (mm^2) Interval 4.14 to 5.13	—	—	—
To Demonstrate the Equivalence of Antibody Response Against A/H5N1 Strain Elicited by the Three Different Immunization Schedules on Day 43. Day 22 (N= 31, 31, 30)	14 Area (mm^2) Interval 10.0 to 19.0	12 Area (mm^2) Interval 8.51 to 16.0	16 Area (mm^2) Interval 12.0 to 23.0	—	—	—
To Demonstrate the Equivalence of Antibody Response Against A/H5N1 Strain Elicited by the Three Different Immunization Schedules on Day 43. Day 43 (N=181, 189, 189)	41 Area (mm^2) Interval 36.0 to 47.0	35 Area (mm^2) Interval 31.0 to 40.0	39 Area (mm^2) Interval 34.0 to 44.0	—	—	—

SECONDARY outcome

Timeframe: Up to 7 days after 1st vaccination

Population: The analysis was performed on Safety Population

Local reactions were collected up to 7 days after 1st vaccinations. All subjects were instructed to complete a diary card to record local reactions starting on the day of vaccination (after 6 hours) and for each of the 6 days following each immunization. The table represents local reactions after first vaccination in each arm differently.

Outcome measures

Outcome measures
Measure	T/P-A n=195 Participants One dose of the tetravalent influenza vaccine (T) and concomitantly, but in a different arm, one dose of placebo (P) on day 1, followed by Aflunov (A) on day 22	A/P-T n=194 Participants One dose of the Aflunov (A) and concomitantly, but in a different arm, one dose of placebo (P) on day 1, followed by Tetravalent influenza vaccine (T) on day 22	A/S-A n=201 Participants One dose of Aflunov (A) and concomitantly, but in a different arm, one dose of licensed seasonal vaccine (S) on day 1, followed Aflunov (A) on day 22	A/P-T: In Arm Receiving Placebo (P) n=201 Participants Local reactions after first vaccination in arm receiving Placebo in group receiving one dose of the Aflunov (A) and concomitantly, but in a different arm, one dose of placebo (P) on day 1, followed by Tetravalent influenza vaccine (T) on day 22	A/S-A: In Arm Receiving Aflunov (A) n=197 Participants Local reactions after first vaccination in arm receiving Aflunov in group receiving one dose of Aflunov (A) and concomitantly, but in a different arm, one dose of licensed seasonal vaccine (S) on day 1, followed Aflunov (A) bon day 22	A/S-A: In Arm Receiving Seasonal Influenza Vaccine (S) n=196 Participants Local reactions after first vaccination in arm receiving seasonal influenza vaccination in group receiving one dose of Aflunov (A) and concomitantly, but in a different arm, one dose of licensed seasonal vaccine (S) on day 1, followed Aflunov (A) on day 22
Number of Subjects (Subjects ≤ 60 Years) With Reported Local Reactions After First Vaccination Induration	22 Participants	1 Participants	5 Participants	0 Participants	9 Participants	3 Participants
Number of Subjects (Subjects ≤ 60 Years) With Reported Local Reactions After First Vaccination Swelling	19 Participants	1 Participants	6 Participants	0 Participants	7 Participants	3 Participants
Number of Subjects (Subjects ≤ 60 Years) With Reported Local Reactions After First Vaccination Erythema	10 Participants	0 Participants	5 Participants	0 Participants	6 Participants	5 Participants
Number of Subjects (Subjects ≤ 60 Years) With Reported Local Reactions After First Vaccination Ecchymosis	2 Participants	1 Participants	2 Participants	0 Participants	2 Participants	1 Participants
Number of Subjects (Subjects ≤ 60 Years) With Reported Local Reactions After First Vaccination Pain	164 Participants	30 Participants	138 Participants	32 Participants	131 Participants	80 Participants

SECONDARY outcome

Timeframe: Up to 7 days after 2nd vaccination

Population: The analysis was performed on Safety Population

Outcome measures

Outcome measures
Measure	T/P-A n=188 Participants One dose of the tetravalent influenza vaccine (T) and concomitantly, but in a different arm, one dose of placebo (P) on day 1, followed by Aflunov (A) on day 22	A/P-T n=192 Participants One dose of the Aflunov (A) and concomitantly, but in a different arm, one dose of placebo (P) on day 1, followed by Tetravalent influenza vaccine (T) on day 22	A/S-A n=192 Participants One dose of Aflunov (A) and concomitantly, but in a different arm, one dose of licensed seasonal vaccine (S) on day 1, followed Aflunov (A) on day 22	A/P-T: In Arm Receiving Placebo (P) Local reactions after first vaccination in arm receiving Placebo in group receiving one dose of the Aflunov (A) and concomitantly, but in a different arm, one dose of placebo (P) on day 1, followed by Tetravalent influenza vaccine (T) on day 22	A/S-A: In Arm Receiving Aflunov (A) Local reactions after first vaccination in arm receiving Aflunov in group receiving one dose of Aflunov (A) and concomitantly, but in a different arm, one dose of licensed seasonal vaccine (S) on day 1, followed Aflunov (A) bon day 22	A/S-A: In Arm Receiving Seasonal Influenza Vaccine (S) Local reactions after first vaccination in arm receiving seasonal influenza vaccination in group receiving one dose of Aflunov (A) and concomitantly, but in a different arm, one dose of licensed seasonal vaccine (S) on day 1, followed Aflunov (A) on day 22
Number of Subjects (Subjects ≤60 Years) With Reported Local Reactions After Second Vaccination Swelling	5 Participants	8 Participants	6 Participants	—	—	—
Number of Subjects (Subjects ≤60 Years) With Reported Local Reactions After Second Vaccination Pain	98 Participants	136 Participants	91 Participants	—	—	—
Number of Subjects (Subjects ≤60 Years) With Reported Local Reactions After Second Vaccination Erythema (N=188,192,191)	2 Participants	7 Participants	5 Participants	—	—	—
Number of Subjects (Subjects ≤60 Years) With Reported Local Reactions After Second Vaccination Induration	7 Participants	10 Participants	7 Participants	—	—	—
Number of Subjects (Subjects ≤60 Years) With Reported Local Reactions After Second Vaccination Ecchymosis	3 Participants	3 Participants	2 Participants	—	—	—

SECONDARY outcome

Timeframe: 7 days after 1st and 2nd vaccinations each

Population: The analysis was performed on Per Protocol Safety Population

Systemic reactions were collected upto 7 days after 1st and 2nd vaccinations. All subjects were instructed to complete a diary card to record systemic reactions starting on the day of vaccination (after 6 hours) and for each of the 6 days following each immunization.

Outcome measures

Outcome measures
Measure	T/P-A n=195 Participants One dose of the tetravalent influenza vaccine (T) and concomitantly, but in a different arm, one dose of placebo (P) on day 1, followed by Aflunov (A) on day 22	A/P-T n=201 Participants One dose of the Aflunov (A) and concomitantly, but in a different arm, one dose of placebo (P) on day 1, followed by Tetravalent influenza vaccine (T) on day 22	A/S-A n=196 Participants One dose of Aflunov (A) and concomitantly, but in a different arm, one dose of licensed seasonal vaccine (S) on day 1, followed Aflunov (A) on day 22	A/P-T: In Arm Receiving Placebo (P) n=188 Participants Local reactions after first vaccination in arm receiving Placebo in group receiving one dose of the Aflunov (A) and concomitantly, but in a different arm, one dose of placebo (P) on day 1, followed by Tetravalent influenza vaccine (T) on day 22	A/S-A: In Arm Receiving Aflunov (A) n=192 Participants Local reactions after first vaccination in arm receiving Aflunov in group receiving one dose of Aflunov (A) and concomitantly, but in a different arm, one dose of licensed seasonal vaccine (S) on day 1, followed Aflunov (A) bon day 22	A/S-A: In Arm Receiving Seasonal Influenza Vaccine (S) n=192 Participants Local reactions after first vaccination in arm receiving seasonal influenza vaccination in group receiving one dose of Aflunov (A) and concomitantly, but in a different arm, one dose of licensed seasonal vaccine (S) on day 1, followed Aflunov (A) on day 22
Number of Subjects (Subjects ≤ 60 Years) With Reported Systemic Reactions After 1st and 2nd Vaccinations. Chills (N=195,201,196,187,192,192)	24 Participants	8 Participants	9 Participants	6 Participants	11 Participants	3 Participants
Number of Subjects (Subjects ≤ 60 Years) With Reported Systemic Reactions After 1st and 2nd Vaccinations. Malaise (N=195,201,196,187,192,192)	62 Participants	29 Participants	28 Participants	15 Participants	38 Participants	15 Participants
Number of Subjects (Subjects ≤ 60 Years) With Reported Systemic Reactions After 1st and 2nd Vaccinations. Myalgia (N=195,201,196,187,192,192)	68 Participants	47 Participants	42 Participants	22 Participants	53 Participants	27 Participants
Number of Subjects (Subjects ≤ 60 Years) With Reported Systemic Reactions After 1st and 2nd Vaccinations. Arthralgia (N=195,201,196,187,192,192)	34 Participants	14 Participants	12 Participants	6 Participants	15 Participants	6 Participants
Number of Subjects (Subjects ≤ 60 Years) With Reported Systemic Reactions After 1st and 2nd Vaccinations. Sweating (N=195,201,196,187,192,192)	13 Participants	16 Participants	10 Participants	6 Participants	13 Participants	7 Participants
Number of Subjects (Subjects ≤ 60 Years) With Reported Systemic Reactions After 1st and 2nd Vaccinations. Fatigue (N=195,201,196,187,192,192)	79 Participants	58 Participants	52 Participants	32 Participants	60 Participants	35 Participants
Number of Subjects (Subjects ≤ 60 Years) With Reported Systemic Reactions After 1st and 2nd Vaccinations. Nausea (N=195,201,196,187,192,192)	24 Participants	16 Participants	8 Participants	7 Participants	16 Participants	6 Participants
Number of Subjects (Subjects ≤ 60 Years) With Reported Systemic Reactions After 1st and 2nd Vaccinations. Coughing (N=195,201,196,187,192,192)	14 Participants	16 Participants	16 Participants	13 Participants	12 Participants	13 Participants
Number of Subjects (Subjects ≤ 60 Years) With Reported Systemic Reactions After 1st and 2nd Vaccinations. Fever (>= 38 C) [N=195,201,195,188,192,192]	8 Participants	1 Participants	3 Participants	2 Participants	5 Participants	0 Participants
Number of Subjects (Subjects ≤ 60 Years) With Reported Systemic Reactions After 1st and 2nd Vaccinations. Analgesic, Antipyretic Medicines Used	27 Participants	21 Participants	15 Participants	6 Participants	16 Participants	6 Participants
Number of Subjects (Subjects ≤ 60 Years) With Reported Systemic Reactions After 1st and 2nd Vaccinations. Headache (N=195, 201, 196, 187, 192, 192)	70 Participants	52 Participants	43 Participants	33 Participants	50 Participants	27 Participants
Number of Subjects (Subjects ≤ 60 Years) With Reported Systemic Reactions After 1st and 2nd Vaccinations. Body Temp. (< 38C)[N=195,201,195,188,192,192]	187 Participants	200 Participants	192 Participants	186 Participants	187 Participants	192 Participants
Number of Subjects (Subjects ≤ 60 Years) With Reported Systemic Reactions After 1st and 2nd Vaccinations. Stayed home due to reactions	8 Participants	7 Participants	2 Participants	1 Participants	8 Participants	1 Participants

SECONDARY outcome

Timeframe: up to day 43

Population: The population was analyzed on per protocol set.

Measurement of immunogenicity in terms of significant increase in antibody titer and Seroconversion. Significant increase in antibody titer is defined as at least a four-fold increase from non-negative pre-vaccination serum (≥ 10) for HI or a 50% increase in area for SRH. Seroconversion is defined as negative pre-vaccination serum / post-vaccination titer ≥40 for HI (area ≥25 mm2 for SRH)

Outcome measures

Outcome measures
Measure	T/P-A n=181 Participants One dose of the tetravalent influenza vaccine (T) and concomitantly, but in a different arm, one dose of placebo (P) on day 1, followed by Aflunov (A) on day 22	A/P-T n=189 Participants One dose of the Aflunov (A) and concomitantly, but in a different arm, one dose of placebo (P) on day 1, followed by Tetravalent influenza vaccine (T) on day 22	A/S-A n=189 Participants One dose of Aflunov (A) and concomitantly, but in a different arm, one dose of licensed seasonal vaccine (S) on day 1, followed Aflunov (A) on day 22	A/P-T: In Arm Receiving Placebo (P) Local reactions after first vaccination in arm receiving Placebo in group receiving one dose of the Aflunov (A) and concomitantly, but in a different arm, one dose of placebo (P) on day 1, followed by Tetravalent influenza vaccine (T) on day 22	A/S-A: In Arm Receiving Aflunov (A) Local reactions after first vaccination in arm receiving Aflunov in group receiving one dose of Aflunov (A) and concomitantly, but in a different arm, one dose of licensed seasonal vaccine (S) on day 1, followed Aflunov (A) bon day 22	A/S-A: In Arm Receiving Seasonal Influenza Vaccine (S) Local reactions after first vaccination in arm receiving seasonal influenza vaccination in group receiving one dose of Aflunov (A) and concomitantly, but in a different arm, one dose of licensed seasonal vaccine (S) on day 1, followed Aflunov (A) on day 22
Percentages of Subjects Achieving Seroconversion/Significant Increase in Antibody Titre/ Area as Measured by SRH and (HI) and at Least 4 Fold Rise in Titres by Micro-neutralization (MN) Assay-H5N1 Strain Seroconversion/significant rise SRH(N=181,189,189)	90 Percentage of subjects Interval 84.0 to 94.0	86 Percentage of subjects Interval 80.0 to 90.0	86 Percentage of subjects Interval 80.0 to 91.0	—	—	—
Percentages of Subjects Achieving Seroconversion/Significant Increase in Antibody Titre/ Area as Measured by SRH and (HI) and at Least 4 Fold Rise in Titres by Micro-neutralization (MN) Assay-H5N1 Strain Seroconversion/significant rise HI (N=180,186,184)	69 Percentage of subjects Interval 62.0 to 76.0	67 Percentage of subjects Interval 59.0 to 73.0	75 Percentage of subjects Interval 68.0 to 81.0	—	—	—
Percentages of Subjects Achieving Seroconversion/Significant Increase in Antibody Titre/ Area as Measured by SRH and (HI) and at Least 4 Fold Rise in Titres by Micro-neutralization (MN) Assay-H5N1 Strain Four fold increase MN (N=181,189,189)	90 Percentage of subjects Interval 84.0 to 94.0	86 Percentage of subjects Interval 80.0 to 90.0	89 Percentage of subjects Interval 84.0 to 93.0	—	—	—

SECONDARY outcome

Timeframe: Up to 43 days

Population: The analysis was done on Per Protocol Set

Measurement of immunogenicity in terms of percentage of subjects achieving a titre ≥ 40/area ≥ 25mm\^2 after immunization as determined by HI (Haemagglutination Inhibition), MN(Microneutralization) and SRH assay.

Outcome measures

Outcome measures
Measure	T/P-A n=196 Participants One dose of the tetravalent influenza vaccine (T) and concomitantly, but in a different arm, one dose of placebo (P) on day 1, followed by Aflunov (A) on day 22	A/P-T n=202 Participants One dose of the Aflunov (A) and concomitantly, but in a different arm, one dose of placebo (P) on day 1, followed by Tetravalent influenza vaccine (T) on day 22	A/S-A n=198 Participants One dose of Aflunov (A) and concomitantly, but in a different arm, one dose of licensed seasonal vaccine (S) on day 1, followed Aflunov (A) on day 22	A/P-T: In Arm Receiving Placebo (P) Local reactions after first vaccination in arm receiving Placebo in group receiving one dose of the Aflunov (A) and concomitantly, but in a different arm, one dose of placebo (P) on day 1, followed by Tetravalent influenza vaccine (T) on day 22	A/S-A: In Arm Receiving Aflunov (A) Local reactions after first vaccination in arm receiving Aflunov in group receiving one dose of Aflunov (A) and concomitantly, but in a different arm, one dose of licensed seasonal vaccine (S) on day 1, followed Aflunov (A) bon day 22	A/S-A: In Arm Receiving Seasonal Influenza Vaccine (S) Local reactions after first vaccination in arm receiving seasonal influenza vaccination in group receiving one dose of Aflunov (A) and concomitantly, but in a different arm, one dose of licensed seasonal vaccine (S) on day 1, followed Aflunov (A) on day 22
Percentages of Subjects Achieving HI/MN ≥ 1:40 and SRH Area ≥ 25^mm2 SRH-Day 1 (N=194,202,198)	4 Percentages of subjects Interval 1.0 to 7.0	0 Percentages of subjects Interval 0.0 to 2.0	4 Percentages of subjects Interval 2.0 to 8.0	—	—	—
Percentages of Subjects Achieving HI/MN ≥ 1:40 and SRH Area ≥ 25^mm2 SRH-Day 43 (N=181,189,189)	93 Percentages of subjects Interval 88.0 to 96.0	86 Percentages of subjects Interval 80.0 to 90.0	89 Percentages of subjects Interval 84.0 to 93.0	—	—	—
Percentages of Subjects Achieving HI/MN ≥ 1:40 and SRH Area ≥ 25^mm2 HI-Day 1 (N=192,198,193)	2 Percentages of subjects Interval 0.0 to 4.0	0 Percentages of subjects Interval 0.0 to 2.0	2 Percentages of subjects Interval 0.0 to 4.0	—	—	—
Percentages of Subjects Achieving HI/MN ≥ 1:40 and SRH Area ≥ 25^mm2 HI-Day 43 (N=181,187,186)	70 Percentages of subjects Interval 62.0 to 76.0	66 Percentages of subjects Interval 59.0 to 73.0	74 Percentages of subjects Interval 67.0 to 80.0	—	—	—
Percentages of Subjects Achieving HI/MN ≥ 1:40 and SRH Area ≥ 25^mm2 MN-Day 1 (N=194,202,198)	1 Percentages of subjects Interval 0.0 to 4.0	3 Percentages of subjects Interval 1.0 to 6.0	3 Percentages of subjects Interval 1.0 to 6.0	—	—	—
Percentages of Subjects Achieving HI/MN ≥ 1:40 and SRH Area ≥ 25^mm2 MN-Day 43 (N=181,189,189)	90 Percentages of subjects Interval 85.0 to 94.0	87 Percentages of subjects Interval 82.0 to 92.0	89 Percentages of subjects Interval 84.0 to 93.0	—	—	—

SECONDARY outcome

Timeframe: Up to 43 days

Population: The population was analyzed on Per protocol set

Measurement of immunogenicity in terms of Geometric mean titers (GMTs) as determined by HI and MN assay.

Outcome measures

Outcome measures
Measure	T/P-A n=192 Participants One dose of the tetravalent influenza vaccine (T) and concomitantly, but in a different arm, one dose of placebo (P) on day 1, followed by Aflunov (A) on day 22	A/P-T n=198 Participants One dose of the Aflunov (A) and concomitantly, but in a different arm, one dose of placebo (P) on day 1, followed by Tetravalent influenza vaccine (T) on day 22	A/S-A n=193 Participants One dose of Aflunov (A) and concomitantly, but in a different arm, one dose of licensed seasonal vaccine (S) on day 1, followed Aflunov (A) on day 22	A/P-T: In Arm Receiving Placebo (P) Local reactions after first vaccination in arm receiving Placebo in group receiving one dose of the Aflunov (A) and concomitantly, but in a different arm, one dose of placebo (P) on day 1, followed by Tetravalent influenza vaccine (T) on day 22	A/S-A: In Arm Receiving Aflunov (A) Local reactions after first vaccination in arm receiving Aflunov in group receiving one dose of Aflunov (A) and concomitantly, but in a different arm, one dose of licensed seasonal vaccine (S) on day 1, followed Aflunov (A) bon day 22	A/S-A: In Arm Receiving Seasonal Influenza Vaccine (S) Local reactions after first vaccination in arm receiving seasonal influenza vaccination in group receiving one dose of Aflunov (A) and concomitantly, but in a different arm, one dose of licensed seasonal vaccine (S) on day 1, followed Aflunov (A) on day 22
Antibody Response Determined by HI and MN Assay. HI-Day 22 (N=31,31,30)	8.36 titers Interval 5.79 to 12.0	6.76 titers Interval 4.68 to 9.77	9.66 titers Interval 6.65 to 14.0	—	—	—
Antibody Response Determined by HI and MN Assay. HI-Day 43 (N=181,187,186)	46 titers Interval 30.0 to 70.0	33 titers Interval 22.0 to 50.0	49 titers Interval 32.0 to 75.0	—	—	—
Antibody Response Determined by HI and MN Assay. MN-Day 1 (N=194,202,198)	10 titers Interval 9.28 to 11.0	10 titers Interval 9.67 to 11.0	10 titers Interval 9.55 to 11.0	—	—	—
Antibody Response Determined by HI and MN Assay. HI-Day 1	5.93 titers Interval 5.49 to 6.4	5.58 titers Interval 5.18 to 6.02	5.85 titers Interval 5.42 to 6.32	—	—	—
Antibody Response Determined by HI and MN Assay. MN-Day 22 (N=31,31,30)	14 titers Interval 11.0 to 19.0	16 titers Interval 12.0 to 22.0	17 titers Interval 13.0 to 23.0	—	—	—
Antibody Response Determined by HI and MN Assay. MN-Day 43 (N=181,189,189)	141 titers Interval 110.0 to 180.0	111 titers Interval 87.0 to 141.0	133 titers Interval 105.0 to 169.0	—	—	—

SECONDARY outcome

Timeframe: Three weeks after first vaccination (day 22) and three weeks after second vaccination (day 43)

Population: The analysis was done on Full analysis set

The Cell Mediated Immunity (CMI) response was evaluated in a randomly selected subgroup of approximately 92 subjects from all the vaccine groups out of a total of 601 enrolled subjects. Frequency of circulating memory B cells (MBC), capable of differentiating in vitro into cell secreting IgG (Immunoglobulin G) antibodies specific for H5N1 (the subunit from A/Vietnam/1194/2004) or for H1N1 (the subunit from A/Solomon Island/3/2006) were determined by an ELISA-coupled limiting dilution assay.The frequency of H5N1-IgG MBC and H1N1-IgG MBC was expressed as percentages (%) of total IgG producing MBC.

Outcome measures

Outcome measures
Measure	T/P-A n=30 Participants One dose of the tetravalent influenza vaccine (T) and concomitantly, but in a different arm, one dose of placebo (P) on day 1, followed by Aflunov (A) on day 22	A/P-T n=30 Participants One dose of the Aflunov (A) and concomitantly, but in a different arm, one dose of placebo (P) on day 1, followed by Tetravalent influenza vaccine (T) on day 22	A/S-A n=29 Participants One dose of Aflunov (A) and concomitantly, but in a different arm, one dose of licensed seasonal vaccine (S) on day 1, followed Aflunov (A) on day 22	A/P-T: In Arm Receiving Placebo (P) Local reactions after first vaccination in arm receiving Placebo in group receiving one dose of the Aflunov (A) and concomitantly, but in a different arm, one dose of placebo (P) on day 1, followed by Tetravalent influenza vaccine (T) on day 22	A/S-A: In Arm Receiving Aflunov (A) Local reactions after first vaccination in arm receiving Aflunov in group receiving one dose of Aflunov (A) and concomitantly, but in a different arm, one dose of licensed seasonal vaccine (S) on day 1, followed Aflunov (A) bon day 22	A/S-A: In Arm Receiving Seasonal Influenza Vaccine (S) Local reactions after first vaccination in arm receiving seasonal influenza vaccination in group receiving one dose of Aflunov (A) and concomitantly, but in a different arm, one dose of licensed seasonal vaccine (S) on day 1, followed Aflunov (A) on day 22
Percentages of B-cell Antibodies Against H5N1 and H1N1 After Each Vaccination. H1N1-IgG MBC - Day 1 (N=30, 30, 29)	2.35 Percentages of B-cell antibodies Interval 0.81 to 3.89	2.64 Percentages of B-cell antibodies Interval 1.1 to 4.18	1.61 Percentages of B-cell antibodies Interval 0.039 to 3.18	—	—	—
Percentages of B-cell Antibodies Against H5N1 and H1N1 After Each Vaccination. H5N1-IgG MBC - Day 1 (N=30, 30, 29)	0.7 Percentages of B-cell antibodies Interval 0.11 to 1.28	0.42 Percentages of B-cell antibodies Interval -0.168 to 1.01	0.53 Percentages of B-cell antibodies Interval -0.073 to 1.12	—	—	—
Percentages of B-cell Antibodies Against H5N1 and H1N1 After Each Vaccination. H5N1-IgG MBC - Day 22 (N=30, 30, 28)	5.39 Percentages of B-cell antibodies Interval 2.66 to 8.11	6.08 Percentages of B-cell antibodies Interval 3.36 to 8.8	7.58 Percentages of B-cell antibodies Interval 4.77 to 10.0	—	—	—
Percentages of B-cell Antibodies Against H5N1 and H1N1 After Each Vaccination. H5N1-IgG MBC - Day 43 (N=30, 30, 29)	6.67 Percentages of B-cell antibodies Interval 4.71 to 8.64	7.21 Percentages of B-cell antibodies Interval 5.24 to 9.18	6.84 Percentages of B-cell antibodies Interval 4.84 to 8.83	—	—	—
Percentages of B-cell Antibodies Against H5N1 and H1N1 After Each Vaccination. H1N1-IgG MBC - Day 22 (N=30, 30, 28)	13 Percentages of B-cell antibodies Interval 9.29 to 17.0	8.55 Percentages of B-cell antibodies Interval 4.76 to 12.0	15 Percentages of B-cell antibodies Interval 11.0 to 19.0	—	—	—
Percentages of B-cell Antibodies Against H5N1 and H1N1 After Each Vaccination. H1N1-IgG MBC - Day 43 (N=30, 30, 29)	12 Percentages of B-cell antibodies Interval 6.98 to 17.0	16 Percentages of B-cell antibodies Interval 11.0 to 21.0	15 Percentages of B-cell antibodies Interval 10.0 to 20.0	—	—	—

SECONDARY outcome

Timeframe: Three weeks after 1st vaccination (day 22) and three weeks after 2nd vaccination (day 43)

Population: Analysis was done on full analysis set

Frequency and functionality of vaccine antigen-specific CD4+ (cluster of differentiation 4) T cells was assessed in peripheral blood (PBMC) taken at days 1, 22 and 43 after in vitro stimulation with: Library of 70 peptides spanning the whole H5 A/Vietnam/1194/2004 protein (H5 pool of 70 Vietnam) H5N1 subunit from A/Vietnam/1194/2004 (H5N1 Vietnam) H3N2 subunit from A/ Wisconsin/67/2005 (H3N2 Wisconsin) H1N1 subunit from A/Solomon Islands/3/2006 (H1N1 Solomon Islands) Polyclonal stimulus agonistic aCD3 mAb \[monoclonal antibody (aCD3)\]. The change in frequency of T-cells was measured.

Outcome measures

Outcome measures
Measure	T/P-A n=31 Participants One dose of the tetravalent influenza vaccine (T) and concomitantly, but in a different arm, one dose of placebo (P) on day 1, followed by Aflunov (A) on day 22	A/P-T n=31 Participants One dose of the Aflunov (A) and concomitantly, but in a different arm, one dose of placebo (P) on day 1, followed by Tetravalent influenza vaccine (T) on day 22	A/S-A n=30 Participants One dose of Aflunov (A) and concomitantly, but in a different arm, one dose of licensed seasonal vaccine (S) on day 1, followed Aflunov (A) on day 22	A/P-T: In Arm Receiving Placebo (P) Local reactions after first vaccination in arm receiving Placebo in group receiving one dose of the Aflunov (A) and concomitantly, but in a different arm, one dose of placebo (P) on day 1, followed by Tetravalent influenza vaccine (T) on day 22	A/S-A: In Arm Receiving Aflunov (A) Local reactions after first vaccination in arm receiving Aflunov in group receiving one dose of Aflunov (A) and concomitantly, but in a different arm, one dose of licensed seasonal vaccine (S) on day 1, followed Aflunov (A) bon day 22	A/S-A: In Arm Receiving Seasonal Influenza Vaccine (S) Local reactions after first vaccination in arm receiving seasonal influenza vaccination in group receiving one dose of Aflunov (A) and concomitantly, but in a different arm, one dose of licensed seasonal vaccine (S) on day 1, followed Aflunov (A) on day 22
Mean T-Cells Per Million Total Cells (95% CI) in Response to H5 Peptides and H5N1 Subunit H5 Pool of 70 Vietnam Day 1 (N=30, 31, 30)	162 Mean cells per million total cells Interval 106.0 to 218.0	175 Mean cells per million total cells Interval 120.0 to 230.0	167 Mean cells per million total cells Interval 111.0 to 223.0	—	—	—
Mean T-Cells Per Million Total Cells (95% CI) in Response to H5 Peptides and H5N1 Subunit H5 Pool of 70 Vietnam Day 22 (N=31, 31, 30)	273 Mean cells per million total cells Interval 198.0 to 348.0	358 Mean cells per million total cells Interval 284.0 to 431.0	365 Mean cells per million total cells Interval 290.0 to 440.0	—	—	—
Mean T-Cells Per Million Total Cells (95% CI) in Response to H5 Peptides and H5N1 Subunit H5 Pool of 70 Vietnam Day 43 (N=31, 31, 30)	311 Mean cells per million total cells Interval 246.0 to 376.0	328 Mean cells per million total cells Interval 264.0 to 392.0	290 Mean cells per million total cells Interval 225.0 to 355.0	—	—	—
Mean T-Cells Per Million Total Cells (95% CI) in Response to H5 Peptides and H5N1 Subunit H5N1 Vietnam Day 1 (N=31, 31, 30)	136 Mean cells per million total cells Interval 93.0 to 178.0	180 Mean cells per million total cells Interval 137.0 to 222.0	155 Mean cells per million total cells Interval 112.0 to 198.0	—	—	—
Mean T-Cells Per Million Total Cells (95% CI) in Response to H5 Peptides and H5N1 Subunit H5N1 Vietnam Day 22 (N=31, 31, 30)	604 Mean cells per million total cells Interval 420.0 to 788.0	711 Mean cells per million total cells Interval 526.0 to 895.0	938 Mean cells per million total cells Interval 752.0 to 1124.0	—	—	—
Mean T-Cells Per Million Total Cells (95% CI) in Response to H5 Peptides and H5N1 Subunit H5N1 Vietnam Day 43 (N=31, 31, 30)	784 Mean cells per million total cells Interval 615.0 to 952.0	813 Mean cells per million total cells Interval 644.0 to 982.0	750 Mean cells per million total cells Interval 579.0 to 921.0	—	—	—
Mean T-Cells Per Million Total Cells (95% CI) in Response to H5 Peptides and H5N1 Subunit H3N2 Wisconsin Day 1 (N=31, 31, 30)	329 Mean cells per million total cells Interval 266.0 to 392.0	344 Mean cells per million total cells Interval 281.0 to 407.0	349 Mean cells per million total cells Interval 285.0 to 413.0	—	—	—
Mean T-Cells Per Million Total Cells (95% CI) in Response to H5 Peptides and H5N1 Subunit H3N2 Wisconsin Day 22 (N=31, 31, 30)	1050 Mean cells per million total cells Interval 853.0 to 1247.0	616 Mean cells per million total cells Interval 419.0 to 813.0	1129 Mean cells per million total cells Interval 929.0 to 1329.0	—	—	—
Mean T-Cells Per Million Total Cells (95% CI) in Response to H5 Peptides and H5N1 Subunit H3N2 Wisconsin Day 43 (N=31, 31, 30)	910 Mean cells per million total cells Interval 750.0 to 1071.0	1034 Mean cells per million total cells Interval 874.0 to 1195.0	814 Mean cells per million total cells Interval 651.0 to 978.0	—	—	—
Mean T-Cells Per Million Total Cells (95% CI) in Response to H5 Peptides and H5N1 Subunit H1N1 Solomon Islands Day 1 (N=30, 31, 30)	275 Mean cells per million total cells Interval 186.0 to 365.0	427 Mean cells per million total cells Interval 339.0 to 515.0	331 Mean cells per million total cells Interval 241.0 to 420.0	—	—	—
Mean T-Cells Per Million Total Cells (95% CI) in Response to H5 Peptides and H5N1 Subunit H1N1 Solomon Islands Day 22 (N=30, 30, 30)	998 Mean cells per million total cells Interval 795.0 to 1201.0	729 Mean cells per million total cells Interval 528.0 to 930.0	1040 Mean cells per million total cells Interval 842.0 to 1237.0	—	—	—
Mean T-Cells Per Million Total Cells (95% CI) in Response to H5 Peptides and H5N1 Subunit H1N1 Solomon Islands Day 43 (N=30, 30, 29)	930 Mean cells per million total cells Interval 735.0 to 1125.0	973 Mean cells per million total cells Interval 781.0 to 1166.0	792 Mean cells per million total cells Interval 599.0 to 984.0	—	—	—
Mean T-Cells Per Million Total Cells (95% CI) in Response to H5 Peptides and H5N1 Subunit aCD3 Day 1 (N=31, 31, 30)	38714 Mean cells per million total cells Interval 29922.0 to 47505.0	32703 Mean cells per million total cells Interval 23912.0 to 41494.0	27824 Mean cells per million total cells Interval 18887.0 to 36760.0	—	—	—
Mean T-Cells Per Million Total Cells (95% CI) in Response to H5 Peptides and H5N1 Subunit aCD3 Day 22 (N=31, 31, 30)	29134 Mean cells per million total cells Interval 26356.0 to 31911.0	27324 Mean cells per million total cells Interval 24571.0 to 30077.0	32324 Mean cells per million total cells Interval 29504.0 to 35144.0	—	—	—
Mean T-Cells Per Million Total Cells (95% CI) in Response to H5 Peptides and H5N1 Subunit aCD3 Day 43 (N=31, 31, 30)	31001 Mean cells per million total cells Interval 27850.0 to 34153.0	29327 Mean cells per million total cells Interval 26203.0 to 32451.0	34680 Mean cells per million total cells Interval 31480.0 to 37880.0	—	—	—

Adverse Events

T/P-A

Serious events: 2 serious events

Other events: 190 other events

Deaths: 0 deaths

A/P-T

Serious events: 3 serious events

Other events: 185 other events

Deaths: 0 deaths

A/S-A

Serious events: 4 serious events

Other events: 183 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Posting Director

Novartis Vaccines and Diagnostics

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: GT60

Measure	T/P-A n=199 participants at risk one dose of the tetravalent (T) influenza vaccine administered concomitantly, in a different arm, with one dose of the placebo (P) control, on study day 1, followed by Aflunov, on study day 22	A/P-T n=203 participants at risk one dose of the Aflunov (A; A/H5N1) avian influenza vaccine administered concomitantly, in a different arm, with one dose of the placebo (P) control, on study day 1, followed by the tetravalent (T) influenza vaccine, on study day 22	A/S-A n=198 participants at risk one dose of the Aflunov (A, A/H5N1) avian influenza vaccine administered concomitantly, in a different arm, one dose of licensed seasonal (S) vaccine, on study day 1, followed by Aflunov (A), on study day 22
Eye disorders Retinal Detachment	0.00% 0/199 • Throughout the entire study period Data provided in the "other Adverse Events (\>5%)" includes solicited local and systemic reactions along with unsolicited Adverse Events (AEs) that persisted for more than 7 days after each study vaccination. Events not otherwise noted as occurring in the \>= 61 year old population were limited to the \<= 60 year old population.	0.49% 1/203 • Throughout the entire study period Data provided in the "other Adverse Events (\>5%)" includes solicited local and systemic reactions along with unsolicited Adverse Events (AEs) that persisted for more than 7 days after each study vaccination. Events not otherwise noted as occurring in the \>= 61 year old population were limited to the \<= 60 year old population.	0.00% 0/198 • Throughout the entire study period Data provided in the "other Adverse Events (\>5%)" includes solicited local and systemic reactions along with unsolicited Adverse Events (AEs) that persisted for more than 7 days after each study vaccination. Events not otherwise noted as occurring in the \>= 61 year old population were limited to the \<= 60 year old population.
Gastrointestinal disorders Diarrhoea	0.00% 0/199 • Throughout the entire study period Data provided in the "other Adverse Events (\>5%)" includes solicited local and systemic reactions along with unsolicited Adverse Events (AEs) that persisted for more than 7 days after each study vaccination. Events not otherwise noted as occurring in the \>= 61 year old population were limited to the \<= 60 year old population.	0.49% 1/203 • Throughout the entire study period Data provided in the "other Adverse Events (\>5%)" includes solicited local and systemic reactions along with unsolicited Adverse Events (AEs) that persisted for more than 7 days after each study vaccination. Events not otherwise noted as occurring in the \>= 61 year old population were limited to the \<= 60 year old population.	0.00% 0/198 • Throughout the entire study period Data provided in the "other Adverse Events (\>5%)" includes solicited local and systemic reactions along with unsolicited Adverse Events (AEs) that persisted for more than 7 days after each study vaccination. Events not otherwise noted as occurring in the \>= 61 year old population were limited to the \<= 60 year old population.
Gastrointestinal disorders Intestinal Polyp	0.50% 1/199 • Throughout the entire study period Data provided in the "other Adverse Events (\>5%)" includes solicited local and systemic reactions along with unsolicited Adverse Events (AEs) that persisted for more than 7 days after each study vaccination. Events not otherwise noted as occurring in the \>= 61 year old population were limited to the \<= 60 year old population.	0.00% 0/203 • Throughout the entire study period Data provided in the "other Adverse Events (\>5%)" includes solicited local and systemic reactions along with unsolicited Adverse Events (AEs) that persisted for more than 7 days after each study vaccination. Events not otherwise noted as occurring in the \>= 61 year old population were limited to the \<= 60 year old population.	0.00% 0/198 • Throughout the entire study period Data provided in the "other Adverse Events (\>5%)" includes solicited local and systemic reactions along with unsolicited Adverse Events (AEs) that persisted for more than 7 days after each study vaccination. Events not otherwise noted as occurring in the \>= 61 year old population were limited to the \<= 60 year old population.
Hepatobiliary disorders Bile Duct Stenosis	0.00% 0/199 • Throughout the entire study period Data provided in the "other Adverse Events (\>5%)" includes solicited local and systemic reactions along with unsolicited Adverse Events (AEs) that persisted for more than 7 days after each study vaccination. Events not otherwise noted as occurring in the \>= 61 year old population were limited to the \<= 60 year old population.	0.00% 0/203 • Throughout the entire study period Data provided in the "other Adverse Events (\>5%)" includes solicited local and systemic reactions along with unsolicited Adverse Events (AEs) that persisted for more than 7 days after each study vaccination. Events not otherwise noted as occurring in the \>= 61 year old population were limited to the \<= 60 year old population.	0.51% 1/198 • Throughout the entire study period Data provided in the "other Adverse Events (\>5%)" includes solicited local and systemic reactions along with unsolicited Adverse Events (AEs) that persisted for more than 7 days after each study vaccination. Events not otherwise noted as occurring in the \>= 61 year old population were limited to the \<= 60 year old population.
Infections and infestations Pyelonephritis	0.00% 0/199 • Throughout the entire study period Data provided in the "other Adverse Events (\>5%)" includes solicited local and systemic reactions along with unsolicited Adverse Events (AEs) that persisted for more than 7 days after each study vaccination. Events not otherwise noted as occurring in the \>= 61 year old population were limited to the \<= 60 year old population.	0.49% 1/203 • Throughout the entire study period Data provided in the "other Adverse Events (\>5%)" includes solicited local and systemic reactions along with unsolicited Adverse Events (AEs) that persisted for more than 7 days after each study vaccination. Events not otherwise noted as occurring in the \>= 61 year old population were limited to the \<= 60 year old population.	0.00% 0/198 • Throughout the entire study period Data provided in the "other Adverse Events (\>5%)" includes solicited local and systemic reactions along with unsolicited Adverse Events (AEs) that persisted for more than 7 days after each study vaccination. Events not otherwise noted as occurring in the \>= 61 year old population were limited to the \<= 60 year old population.
Investigations Endoscopic Retrograde Cholangiopancreatography	0.00% 0/199 • Throughout the entire study period Data provided in the "other Adverse Events (\>5%)" includes solicited local and systemic reactions along with unsolicited Adverse Events (AEs) that persisted for more than 7 days after each study vaccination. Events not otherwise noted as occurring in the \>= 61 year old population were limited to the \<= 60 year old population.	0.00% 0/203 • Throughout the entire study period Data provided in the "other Adverse Events (\>5%)" includes solicited local and systemic reactions along with unsolicited Adverse Events (AEs) that persisted for more than 7 days after each study vaccination. Events not otherwise noted as occurring in the \>= 61 year old population were limited to the \<= 60 year old population.	0.51% 1/198 • Throughout the entire study period Data provided in the "other Adverse Events (\>5%)" includes solicited local and systemic reactions along with unsolicited Adverse Events (AEs) that persisted for more than 7 days after each study vaccination. Events not otherwise noted as occurring in the \>= 61 year old population were limited to the \<= 60 year old population.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Ovarian Cancer	0.00% 0/199 • Throughout the entire study period Data provided in the "other Adverse Events (\>5%)" includes solicited local and systemic reactions along with unsolicited Adverse Events (AEs) that persisted for more than 7 days after each study vaccination. Events not otherwise noted as occurring in the \>= 61 year old population were limited to the \<= 60 year old population.	0.00% 0/203 • Throughout the entire study period Data provided in the "other Adverse Events (\>5%)" includes solicited local and systemic reactions along with unsolicited Adverse Events (AEs) that persisted for more than 7 days after each study vaccination. Events not otherwise noted as occurring in the \>= 61 year old population were limited to the \<= 60 year old population.	0.51% 1/198 • Throughout the entire study period Data provided in the "other Adverse Events (\>5%)" includes solicited local and systemic reactions along with unsolicited Adverse Events (AEs) that persisted for more than 7 days after each study vaccination. Events not otherwise noted as occurring in the \>= 61 year old population were limited to the \<= 60 year old population.
Nervous system disorders Cerebral Haemorrhage	0.00% 0/199 • Throughout the entire study period Data provided in the "other Adverse Events (\>5%)" includes solicited local and systemic reactions along with unsolicited Adverse Events (AEs) that persisted for more than 7 days after each study vaccination. Events not otherwise noted as occurring in the \>= 61 year old population were limited to the \<= 60 year old population.	0.00% 0/203 • Throughout the entire study period Data provided in the "other Adverse Events (\>5%)" includes solicited local and systemic reactions along with unsolicited Adverse Events (AEs) that persisted for more than 7 days after each study vaccination. Events not otherwise noted as occurring in the \>= 61 year old population were limited to the \<= 60 year old population.	0.51% 1/198 • Throughout the entire study period Data provided in the "other Adverse Events (\>5%)" includes solicited local and systemic reactions along with unsolicited Adverse Events (AEs) that persisted for more than 7 days after each study vaccination. Events not otherwise noted as occurring in the \>= 61 year old population were limited to the \<= 60 year old population.
Nervous system disorders Intracranial Aneurysm	0.00% 0/199 • Throughout the entire study period Data provided in the "other Adverse Events (\>5%)" includes solicited local and systemic reactions along with unsolicited Adverse Events (AEs) that persisted for more than 7 days after each study vaccination. Events not otherwise noted as occurring in the \>= 61 year old population were limited to the \<= 60 year old population.	0.00% 0/203 • Throughout the entire study period Data provided in the "other Adverse Events (\>5%)" includes solicited local and systemic reactions along with unsolicited Adverse Events (AEs) that persisted for more than 7 days after each study vaccination. Events not otherwise noted as occurring in the \>= 61 year old population were limited to the \<= 60 year old population.	0.51% 1/198 • Throughout the entire study period Data provided in the "other Adverse Events (\>5%)" includes solicited local and systemic reactions along with unsolicited Adverse Events (AEs) that persisted for more than 7 days after each study vaccination. Events not otherwise noted as occurring in the \>= 61 year old population were limited to the \<= 60 year old population.
Pregnancy, puerperium and perinatal conditions Abortion Spontaneous	0.50% 1/199 • Throughout the entire study period Data provided in the "other Adverse Events (\>5%)" includes solicited local and systemic reactions along with unsolicited Adverse Events (AEs) that persisted for more than 7 days after each study vaccination. Events not otherwise noted as occurring in the \>= 61 year old population were limited to the \<= 60 year old population.	0.00% 0/203 • Throughout the entire study period Data provided in the "other Adverse Events (\>5%)" includes solicited local and systemic reactions along with unsolicited Adverse Events (AEs) that persisted for more than 7 days after each study vaccination. Events not otherwise noted as occurring in the \>= 61 year old population were limited to the \<= 60 year old population.	0.00% 0/198 • Throughout the entire study period Data provided in the "other Adverse Events (\>5%)" includes solicited local and systemic reactions along with unsolicited Adverse Events (AEs) that persisted for more than 7 days after each study vaccination. Events not otherwise noted as occurring in the \>= 61 year old population were limited to the \<= 60 year old population.
Psychiatric disorders Bulimia Nervosa	0.00% 0/199 • Throughout the entire study period Data provided in the "other Adverse Events (\>5%)" includes solicited local and systemic reactions along with unsolicited Adverse Events (AEs) that persisted for more than 7 days after each study vaccination. Events not otherwise noted as occurring in the \>= 61 year old population were limited to the \<= 60 year old population.	0.00% 0/203 • Throughout the entire study period Data provided in the "other Adverse Events (\>5%)" includes solicited local and systemic reactions along with unsolicited Adverse Events (AEs) that persisted for more than 7 days after each study vaccination. Events not otherwise noted as occurring in the \>= 61 year old population were limited to the \<= 60 year old population.	0.51% 1/198 • Throughout the entire study period Data provided in the "other Adverse Events (\>5%)" includes solicited local and systemic reactions along with unsolicited Adverse Events (AEs) that persisted for more than 7 days after each study vaccination. Events not otherwise noted as occurring in the \>= 61 year old population were limited to the \<= 60 year old population.
Psychiatric disorders Depression Suicidal	0.00% 0/199 • Throughout the entire study period Data provided in the "other Adverse Events (\>5%)" includes solicited local and systemic reactions along with unsolicited Adverse Events (AEs) that persisted for more than 7 days after each study vaccination. Events not otherwise noted as occurring in the \>= 61 year old population were limited to the \<= 60 year old population.	0.00% 0/203 • Throughout the entire study period Data provided in the "other Adverse Events (\>5%)" includes solicited local and systemic reactions along with unsolicited Adverse Events (AEs) that persisted for more than 7 days after each study vaccination. Events not otherwise noted as occurring in the \>= 61 year old population were limited to the \<= 60 year old population.	0.51% 1/198 • Throughout the entire study period Data provided in the "other Adverse Events (\>5%)" includes solicited local and systemic reactions along with unsolicited Adverse Events (AEs) that persisted for more than 7 days after each study vaccination. Events not otherwise noted as occurring in the \>= 61 year old population were limited to the \<= 60 year old population.
Surgical and medical procedures Eye Operation	0.00% 0/199 • Throughout the entire study period Data provided in the "other Adverse Events (\>5%)" includes solicited local and systemic reactions along with unsolicited Adverse Events (AEs) that persisted for more than 7 days after each study vaccination. Events not otherwise noted as occurring in the \>= 61 year old population were limited to the \<= 60 year old population.	0.49% 1/203 • Throughout the entire study period Data provided in the "other Adverse Events (\>5%)" includes solicited local and systemic reactions along with unsolicited Adverse Events (AEs) that persisted for more than 7 days after each study vaccination. Events not otherwise noted as occurring in the \>= 61 year old population were limited to the \<= 60 year old population.	0.00% 0/198 • Throughout the entire study period Data provided in the "other Adverse Events (\>5%)" includes solicited local and systemic reactions along with unsolicited Adverse Events (AEs) that persisted for more than 7 days after each study vaccination. Events not otherwise noted as occurring in the \>= 61 year old population were limited to the \<= 60 year old population.
Surgical and medical procedures Hysterosalpingo-Oophorectomy	0.00% 0/199 • Throughout the entire study period Data provided in the "other Adverse Events (\>5%)" includes solicited local and systemic reactions along with unsolicited Adverse Events (AEs) that persisted for more than 7 days after each study vaccination. Events not otherwise noted as occurring in the \>= 61 year old population were limited to the \<= 60 year old population.	0.00% 0/203 • Throughout the entire study period Data provided in the "other Adverse Events (\>5%)" includes solicited local and systemic reactions along with unsolicited Adverse Events (AEs) that persisted for more than 7 days after each study vaccination. Events not otherwise noted as occurring in the \>= 61 year old population were limited to the \<= 60 year old population.	0.51% 1/198 • Throughout the entire study period Data provided in the "other Adverse Events (\>5%)" includes solicited local and systemic reactions along with unsolicited Adverse Events (AEs) that persisted for more than 7 days after each study vaccination. Events not otherwise noted as occurring in the \>= 61 year old population were limited to the \<= 60 year old population.
Surgical and medical procedures Lymphadenectomy	0.00% 0/199 • Throughout the entire study period Data provided in the "other Adverse Events (\>5%)" includes solicited local and systemic reactions along with unsolicited Adverse Events (AEs) that persisted for more than 7 days after each study vaccination. Events not otherwise noted as occurring in the \>= 61 year old population were limited to the \<= 60 year old population.	0.00% 0/203 • Throughout the entire study period Data provided in the "other Adverse Events (\>5%)" includes solicited local and systemic reactions along with unsolicited Adverse Events (AEs) that persisted for more than 7 days after each study vaccination. Events not otherwise noted as occurring in the \>= 61 year old population were limited to the \<= 60 year old population.	0.51% 1/198 • Throughout the entire study period Data provided in the "other Adverse Events (\>5%)" includes solicited local and systemic reactions along with unsolicited Adverse Events (AEs) that persisted for more than 7 days after each study vaccination. Events not otherwise noted as occurring in the \>= 61 year old population were limited to the \<= 60 year old population.