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Human Vaccines & Immunotherapeutics Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/khvi20
A randomized, controlled, blinded study of the safety, immunogenicity and batch consistency of Aleph inactivated split influenza vaccine made in China in Chinese people a
a
a
a
a
a
b
Shuming Li , Li Li , Xing Ai , Liqing Yang , Yunhua Bai , Zhaoyun Wang , Huixia Han , Qiang a
a
a
c
d
a
Lu , Fengji Luo , Zheng Zhang , Chunyu Liu , Jun Xiao & Nianmin Shi a
Click for updates
Chaoyang Diseases Control and Prevention Center; Beijing, PR China
b
Xiaohongmen Hospital; Beijing, PR China
c
Dongba Hospital; Beijing, PR China
d
Zuojiazhuang Hospital; Beijing, PR China Published online: 03 Dec 2013.
To cite this article: Shuming Li, Li Li, Xing Ai, Liqing Yang, Yunhua Bai, Zhaoyun Wang, Huixia Han, Qiang Lu, Fengji Luo, Zheng Zhang, Chunyu Liu, Jun Xiao & Nianmin Shi (2014) A randomized, controlled, blinded study of the safety, immunogenicity and batch consistency of Aleph inactivated split influenza vaccine made in China in Chinese people, Human Vaccines & Immunotherapeutics, 10:3, 557-565, DOI: 10.4161/hv.27329 To link to this article: http://dx.doi.org/10.4161/hv.27329
PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content. This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http:// www.tandfonline.com/page/terms-and-conditions
Research Paper
Research Paper
Human Vaccines & Immunotherapeutics 10:3, 557–565; March 2014; © 2014 Landes Bioscience
A randomized, controlled, blinded study of the safety, immunogenicity and batch consistency of Aleph inactivated split influenza vaccine made in China in Chinese people Chaoyang Diseases Control and Prevention Center; Beijing, PR China; 2Xiaohongmen Hospital; Beijing, PR China; 3Dongba Hospital; Beijing, PR China; 4Zuojiazhuang Hospital; Beijing, PR China
Downloaded by [University of Wyoming Libraries] at 07:11 30 March 2015
1
Keywords: inactivated split influenza vaccine, safety, immunogenicity, batch consistency Abbreviations: HI, hemagglutination-inhibition assay; GMT, geometric mean titer; Seroconversion rate, the proportion of subjects whose antibody GMT met the definition of seroconversion after vaccination; Seroprotection rate, the proportion of subjects whose antibody GMT met the definition of seroprotection after vaccination
To evaluate the safety, immunogenicity and batch consistency of Aleph inactivated split influenza vaccine, 3308 healthy Chinese people more than 3 years old were enrolled in a randomized, controlled, blinded study and divided into four age groups: 3–10 years, 11–17 years, 18–54 years, and more than 55 years. Each age group was then randomized (2:1) to receive either influenza vaccine or control vaccine (recombinant hepatitis B) for one dose. Also each influenza vaccine group was randomized (1:1:1) to receive three different batches of influenza vaccine. Systematic and local adverse reactions for 28 days after vaccination were recorded, and influenza antibody titer was determined by hemagglutination inhibition (HI) assay at 28 days after vaccination. There were significant differences in seroconversion and seroprotection rates achieved post-immunization of three strains of influenza antibody (H1N1, H3N2, B) between experimental group and control group in all age groups (P < 0.05). In addition, there were no statistically significant differences in local and systematic reaction rates after vaccination between the experimental and control group in all age groups (P > 0.05), except for the systematic reaction rates in the 18–54 years and ≥ 55 years age groups (P < 0.05). Thus, Aleph inactivated split influenza vaccine has good safety and immunogenicity.
Introduction Influenza is an acute respiratory infectious disease caused by influenza virus. Primary influenza illness is characterized by the abrupt start of fever, sore throat, headache, myalgia, chills, anorexia, and extreme fatigue.1,2 Illness typically improves within a week. The risk of developing serious complications from influenza infection is elevated in persons at both age extremes as well as in those with certain underlying conditions.3,4 The most common serious complications of influenza include exacerbation of underlying chronic pulmonary and cardiopulmonary diseases, such as chronic obstructive pulmonary disease, asthma, and congestive heart failure, as well development of bacterial pneumonia usually associated with Streptococcus pneumonia, Staphylococcus aureus, or Hemophilus influenza. Epidemics and pandemics of respiratory disease, consistent with influenza, have been recorded since the 16th century.5,6
During seasonal epidemics, large numbers of influenza infections can occur in all age groups. In most individuals, influenza is a self-limited illness, but serious secondary complications develop in some of those infected. The resulting illnesses, often requiring ambulatory medical care or hospitalization, substantially contribute to lost work and school time, overwhelmed hospitals and regional medical care systems, and increases in influenzarelated hospitalizations and deaths.7-9 Few other infectious diseases have adversely affected the health and economies of global populations as consistently and extensively as influenza. Influenza vaccination is considered as one of the most effective strategy for preventing influenza. WHO encourages influenza vaccine used in persons at increased risk for complications of influenza in all countries where epidemic surveillance is well established and where reduction of influenza and its complications are public health priorities.10 However, nearly all of the world’s vaccine production capacity is contained in
*Correspondence to: Nianmin Shi; Email: [email protected] Submitted: 07/25/2013; Revised: 11/13/2013; Accepted: 11/24/2013 http://dx.doi.org/10.4161/hv.27329 www.landesbioscience.com Human Vaccines & Immunotherapeutics 557
©2014 Landes Bioscience. Do not distribute.
Shuming Li1, Li Li1, Xing Ai1, Liqing Yang1, Yunhua Bai1, Zhaoyun Wang1, Huixia Han2, Qiang Lu1, Fengji Luo1, Zheng Zhang1, Chunyu Liu3, Jun Xiao4, and Nianmin Shi1,*
Age group
Subgroup
No. of subjects
Mean age ± SD (years)
No. completing observations
No. with paired serum samples
3–10 y
T1
187
6.85 ± 2.36*
186
149
T2
190
6.93 ± 2.57
189
146
T3
183
6.74 ± 2.35
183
140
11–17 y
Downloaded by [University of Wyoming Libraries] at 07:11 30 March 2015
18–54 y
≥55 y
C
284
6.89 ± 2.67
284
218
T1
180
10.81 ± 4.81†
132
166
T2
180
11.13 ± 4.43
133
166
T3
178
11.04 ± 4.68
130
159
C
272
10.74 ± 5.24
201
251
T1
180
41.53 ± 11.06§
178
155
T2
185
42.10 ± 11.60
185
156
T3
180
42.14 ± 10.14
180
151
C
271
41.34 ± 10.89
268
229
T1
188
59.86 ± 9.10¥
188
152
T2
186
59.19 ± 14.42
185
150
T3
188
59.17 ± 11.54
188
162
C
276
59.52 ± 10.22
276
234
*P = 0.8981 vs control group; †P = 0.8557 vs control group; §P = 0.8326 vs control group; ¥P = 0.9145 vs control group.
nine countries, mostly in Western Europe and North America, and these countries utilize approximately 60% of the vaccine produced. Thus, comparatively little vaccine is utilized outside of these countries and in the developing world.11 Efforts to improve influenza vaccine capacity for pandemic influenza preparedness are likely to result in worldwide increases in influenzamanufacturing capacity for seasonal vaccine and encourage expanded use of annual vaccine. Aleph influenza vaccine is a highly-purified inactivated, eggbased trivalent influenza vaccine made in China. It was initially licensed in China in 2005. The aim of this post-marketing clinical study was to assess the safety, immunogenicity and batch consistency of the split inactivated influenza vaccine produced by Aleph Biomedical Co., Ltd.
Results Subjects and baseline analysis A total of 3308 healthy people more than 3 y old met the inclusion/exclusion criteria for the study and were randomized to the experimental (influenza vaccine) and control (hepatitis B) groups (2205 in experimental group and 1103 in control group). During the study, 222 subjects dropped out (56 cases did not agree to attend follow-ups while 166 subjects were lost to follow-up;,for the absence of participants who were students taking part of a special activity, so there was a much higher drop-out rate in the 11–17 y old group); 3086 (93%) people completed the safety observation (2057 in experimental group and 1029 in control group), and 2784 (84%) had serum antibody level data available from paired (pre – and post-immunization)
blood samples (Table 1). There were no statistically significant differences in subjects’ age between the experimental and control groups in all age groups, nor among three experimental groups (three batches of influenza vaccine) (P > 0.05; Table 1). Also there were no statistically significant differences in the pre-immunization influenza antibody against three strains of influenza (H1N1, H3N2, B) geometric mean titer (GMT) between the experimental and control groups in all age groups, nor among three experimental groups (three batches of influenza vaccine) (P > 0.05; Table 2). From Table 2, the GMT of B strain before immunization was higher than other two strains in all four age groups. This indicated that there might be a inapparent infection of B strain in study area. Immunogenicity results The seroconversion rates (proportions of subjects with Influenza antibody GMT ≥ 1:40 or increase 4-folds in GMT) of experimental group after immunization in the 3–10 y age group were 86.5% (against H1N1, T1 85.9%, T2 83.7%, T3 90.0%), 94.7% (against H3N2, T1 94.0%, T2 95.2%, T3 95.0%), and 91.1% (against B, T1 91.3%, T2 89.9%, T3 92.1%), compared with 16.4% (against H1N1), 14.2% (against H3N2) and 36.5% (against B) in control group; in the 11–17 y age group were 93.5% (against H1N1, T1 97.0%, T2 91.6%, T3 91.9%), 98.0% (against H3N2, T1 98.8%, T2 97.0%, T3 98.1%), and 79.3% (against B, T1 75.3%, T2 81.3%, T3 81.3%), compared with 5.6% (against H1N1), 2.4% (against H3N2) and 4.4% (against B) in control group; in the 18–54 y age group were 88.3% (against H1N1, T1 89.1%, T2 87.2%, T3 88.7%), 76.3% (against H3N2, T1 73.7%, T2 77.6%, T3 77.5%), and 62.9% (against B, T1 60.9%, T2 60.9%, T3 66.9%), compared with 15.2% (against
558 Human Vaccines & Immunotherapeutics
Volume 10 Issue 3
©2014 Landes Bioscience. Do not distribute.
Table 1. Numbers and mean ages of subjects in the study groups
Table 2. GMTs of H1N1, H3N2 and B antibodies before immunization in the study groups Age group
Subgroup
No. of subjects
Antibody GMT (H1N1)
P value
Antibody GMT (H3N2)
P value
Antibody GMT (B)
P value
3–10 y
T1
149
3.27 ± 4.47
1.294
4.33 ± 5.14
0.74
31.52 ± 4.13
0.676
T2
146
2.97 ± 4.11
3.66 ± 4.80
36.94 ± 3.82
T3
140
3.41 ± 4.21
3.88 ± 4.65
30.74 ± 4.62
C
218
3.41 ± 4.34
4.29 ± 5.08
34.02 ± 3.91
T1
166
T2
166
3.89 ± 4.29
3.48 ± 4.18
51.63 ± 3.92
T3
159
2.86 ± 3.92
3.27 ± 4.06
47.52 ± 3.72
C
251
3.37 ± 4.17
3.93 ± 4.21
51.21 ± 3.51
T1
155
T2
156
1.75 ± 3.22
1.57 ± 2.75
58.40 ± 4.94
T3
151
1.83 ± 3.25
1.51 ± 2.62
55.53 ± 4.27
C
229
1.52 ± 2.63
1.48 ± 2.51
56.60 ± 4.32
T1
152
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18–54 y
≥55 y
3.21 ± 4.13
1.76 ± 3.22
2.18 ± 3.71
0.276
0.334
0.455
3.09 ± 4.05
1.64 ± 2.81
3.09 ± 3.60
0.352
0.771
0.353
54.36 ± 4.04
51.34 ± 4.98
78.56 ± 2.13
0.837
0.892
0.709
GMT, geometric mean titer; H1N1, H3N2, B, three strains of influenza.
H1N1), 6.1% (against H3N2) and 20.0% (against B) in control group; in the ≥ 55 y age group were 85.6% (against H1N1, T1 83.0%, T2 86.7%, T3 87.0%), 95.9% (against H3N2, T1 94.8%, T2 96.7%, T3 96.3%), and 78.5% (against B, T1 75.8%, T2 81.3%, T3 78.4%), compared with 7.7% (against H1N1), 7.7% (against H3N2) and 6.0% (against B) in control group. The seroconversion rates of experimental groups were much higher than that of control groups. There were significant differences in seroconversion rates achieved post-immunization of three strains of influenza antibody (H1N1, H3N2, B) between experimental group and control group in all age groups (P < 0.05; Table 3). There were no significant differences in seroconversion rates achieved post-immunization of three strains of influenza antibody (H1N1, H3N2, B) among three experimental groups (three batches of influenza vaccine) in all age groups (P > 0.05; Table 3). The seroprotection rates (proportions of subjects whose influenza antibody GMT ≥ 1:40) of experimental group after immunization in the 3–10 y age group were 87.6% (against H1N1, T1 87.9%, T2 85.0%, T3 90.0%), 99.3% (against H3N2, T1 100.0%, T2 100.0%, T3 97.9%), and 99.3% (against B, T1 99.3%, T2 98.6%, T3 100.0%), while they were 25.1% (against H1N1), 25.1% (against H3N2) and 72.6% (against B) in control group; in the 11–17 y age group were 95.3% (against H1N1, T1 97.6%, T2 94.0%, T3 94.4%), 100.0% (against H3N2, T1 100.0%, T2 100.0%, T3 100.0%), and 99.5% (against B, T1 99.4%, T2 99.4%, T3 98.8%), while they were 9.2% (against H1N1), 6.0% (against H3N2) and 30.7% (against B) in control group; in the 18–54 y age group were 90.3% (against H1N1, T1 90.4%, T2 89.7%, T3 90.7%), 78.2% (against H3N2, T1 75.6%, T2 80.1%, T3 78.8%), and 98.7% (against B, T1 98.7%, T2 98.7%, T3 98.7%), while they were 17.4% (against H1N1), 7.0% (against H3N2) and 52.2% (against B) in control group; in the ≥ 55 y age group were 88.8% (against H1N1, T1 86.3%, T2 89.3%, T3 90.7%), 96.1% (against H3N2,
T1 94.8%, T2 96.7%, T3 96.9%), and 99.5% (against B, T1 99.3%, T2 99.3%, T3 100.0%), while they were 10.3% (against H1N1), 9.4% (against H3N2) and 49.1% (against B) in control group. The seroprotection rates of experimental groups were much higher than that of control groups. There were significant differences in seroprotection rates achieved post-immunization of three strains of influenza antibody (H1N1, H3N2, B) between experimental group and control group in all age groups (P < 0.05; Table 4). There were no significant differences in seroprotection rates achieved post-immunization of three strains of influenza antibody (H1N1, H3N2, B) among three experimental groups (three batches of influenza vaccine) in all age groups (P > 0.05; Table 4), except for influenza antibody against H3N2 in the 3–10 y age group (P < 0.05; Table 4). The mean fold increase ratios of GMT in experimental group after immunization in the 3–10 y age group were 65.7 (against H1N1, T1 69.2, T2 70.9, T3 57.1), 89.2 (against H3N2, T1 90.2, T2 92.6, T3 84.9), and 28.5 (against B, T1 32.0, T2 24.0, T3 29.6); in the 11–17 y age group were 84.2 (against H1N1, T1 86.4, T2 70.6, T3 95.6), 60.2 (against H3N2, T1 65.1, T2 58.4, T3 57.2), and 8.9 (against B, T1 8.5, T2 8.4, T3 9.9); in the 18–54 y age group were 87.2 (against H1N1, T1 82.5, T2 87.3, T3 91.8), 38.9 (against H3N2, T1 32.8, T2 41.1, T3 42.7), and 6.3 (against B, T1 6.6, T2 6.0, T3 6.2); in the ≥ 55 y age group were 54.0 (against H1N1, T1 54.2, T2 58.4, T3 49.5), 47.5 (against H3N2, T1 45.8, T2 54.7, T3 41.9), and 6.8 (against B, T1 6.2, T2 6.7, T3 7.6) (Table 5). Furthermore, equivalence study was used to analysis the batch consistency of the study influenza vaccine. A range from – 10% to 10% was set as the equivalence interval at the beginning of the study. From the study, the 95% CI when comparing the seroprotection rates of three batches of influenza vaccine were all included in the range from – 10% to 10%, so it could be considered that three batches of influenza vaccine are equivalence (Table 6).
www.landesbioscience.com Human Vaccines & Immunotherapeutics 559
©2014 Landes Bioscience. Do not distribute.
11–17 y
Table 3. Seroconversion rates of influenza antibody after immunization in the study groups
3–10 y
11–17 y
Downloaded by [University of Wyoming Libraries] at 07:11 30 March 2015
18–54 y
≥55 y
Subgroup
No. of subjects
Antibody seroconversion (H1N1) No.
Percentage
P value
Antibody seroconversion (H3N2) No.
Percentage
Antibody seroconversion (B)
P value
No.
Percentage
P value
T1
149
128
85.9
140
94
136
91.3
T2
146
123
83.7
Human Vaccines & Immunotherapeutics Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/khvi20
A randomized, controlled, blinded study of the safety, immunogenicity and batch consistency of Aleph inactivated split influenza vaccine made in China in Chinese people a
a
a
a
a
a
b
Shuming Li , Li Li , Xing Ai , Liqing Yang , Yunhua Bai , Zhaoyun Wang , Huixia Han , Qiang a
a
a
c
d
a
Lu , Fengji Luo , Zheng Zhang , Chunyu Liu , Jun Xiao & Nianmin Shi a
Click for updates
Chaoyang Diseases Control and Prevention Center; Beijing, PR China
b
Xiaohongmen Hospital; Beijing, PR China
c
Dongba Hospital; Beijing, PR China
d
Zuojiazhuang Hospital; Beijing, PR China Published online: 03 Dec 2013.
To cite this article: Shuming Li, Li Li, Xing Ai, Liqing Yang, Yunhua Bai, Zhaoyun Wang, Huixia Han, Qiang Lu, Fengji Luo, Zheng Zhang, Chunyu Liu, Jun Xiao & Nianmin Shi (2014) A randomized, controlled, blinded study of the safety, immunogenicity and batch consistency of Aleph inactivated split influenza vaccine made in China in Chinese people, Human Vaccines & Immunotherapeutics, 10:3, 557-565, DOI: 10.4161/hv.27329 To link to this article: http://dx.doi.org/10.4161/hv.27329
PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content. This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http:// www.tandfonline.com/page/terms-and-conditions
Research Paper
Research Paper
Human Vaccines & Immunotherapeutics 10:3, 557–565; March 2014; © 2014 Landes Bioscience
A randomized, controlled, blinded study of the safety, immunogenicity and batch consistency of Aleph inactivated split influenza vaccine made in China in Chinese people Chaoyang Diseases Control and Prevention Center; Beijing, PR China; 2Xiaohongmen Hospital; Beijing, PR China; 3Dongba Hospital; Beijing, PR China; 4Zuojiazhuang Hospital; Beijing, PR China
Downloaded by [University of Wyoming Libraries] at 07:11 30 March 2015
1
Keywords: inactivated split influenza vaccine, safety, immunogenicity, batch consistency Abbreviations: HI, hemagglutination-inhibition assay; GMT, geometric mean titer; Seroconversion rate, the proportion of subjects whose antibody GMT met the definition of seroconversion after vaccination; Seroprotection rate, the proportion of subjects whose antibody GMT met the definition of seroprotection after vaccination
To evaluate the safety, immunogenicity and batch consistency of Aleph inactivated split influenza vaccine, 3308 healthy Chinese people more than 3 years old were enrolled in a randomized, controlled, blinded study and divided into four age groups: 3–10 years, 11–17 years, 18–54 years, and more than 55 years. Each age group was then randomized (2:1) to receive either influenza vaccine or control vaccine (recombinant hepatitis B) for one dose. Also each influenza vaccine group was randomized (1:1:1) to receive three different batches of influenza vaccine. Systematic and local adverse reactions for 28 days after vaccination were recorded, and influenza antibody titer was determined by hemagglutination inhibition (HI) assay at 28 days after vaccination. There were significant differences in seroconversion and seroprotection rates achieved post-immunization of three strains of influenza antibody (H1N1, H3N2, B) between experimental group and control group in all age groups (P < 0.05). In addition, there were no statistically significant differences in local and systematic reaction rates after vaccination between the experimental and control group in all age groups (P > 0.05), except for the systematic reaction rates in the 18–54 years and ≥ 55 years age groups (P < 0.05). Thus, Aleph inactivated split influenza vaccine has good safety and immunogenicity.
Introduction Influenza is an acute respiratory infectious disease caused by influenza virus. Primary influenza illness is characterized by the abrupt start of fever, sore throat, headache, myalgia, chills, anorexia, and extreme fatigue.1,2 Illness typically improves within a week. The risk of developing serious complications from influenza infection is elevated in persons at both age extremes as well as in those with certain underlying conditions.3,4 The most common serious complications of influenza include exacerbation of underlying chronic pulmonary and cardiopulmonary diseases, such as chronic obstructive pulmonary disease, asthma, and congestive heart failure, as well development of bacterial pneumonia usually associated with Streptococcus pneumonia, Staphylococcus aureus, or Hemophilus influenza. Epidemics and pandemics of respiratory disease, consistent with influenza, have been recorded since the 16th century.5,6
During seasonal epidemics, large numbers of influenza infections can occur in all age groups. In most individuals, influenza is a self-limited illness, but serious secondary complications develop in some of those infected. The resulting illnesses, often requiring ambulatory medical care or hospitalization, substantially contribute to lost work and school time, overwhelmed hospitals and regional medical care systems, and increases in influenzarelated hospitalizations and deaths.7-9 Few other infectious diseases have adversely affected the health and economies of global populations as consistently and extensively as influenza. Influenza vaccination is considered as one of the most effective strategy for preventing influenza. WHO encourages influenza vaccine used in persons at increased risk for complications of influenza in all countries where epidemic surveillance is well established and where reduction of influenza and its complications are public health priorities.10 However, nearly all of the world’s vaccine production capacity is contained in
*Correspondence to: Nianmin Shi; Email: [email protected] Submitted: 07/25/2013; Revised: 11/13/2013; Accepted: 11/24/2013 http://dx.doi.org/10.4161/hv.27329 www.landesbioscience.com Human Vaccines & Immunotherapeutics 557
©2014 Landes Bioscience. Do not distribute.
Shuming Li1, Li Li1, Xing Ai1, Liqing Yang1, Yunhua Bai1, Zhaoyun Wang1, Huixia Han2, Qiang Lu1, Fengji Luo1, Zheng Zhang1, Chunyu Liu3, Jun Xiao4, and Nianmin Shi1,*
Age group
Subgroup
No. of subjects
Mean age ± SD (years)
No. completing observations
No. with paired serum samples
3–10 y
T1
187
6.85 ± 2.36*
186
149
T2
190
6.93 ± 2.57
189
146
T3
183
6.74 ± 2.35
183
140
11–17 y
Downloaded by [University of Wyoming Libraries] at 07:11 30 March 2015
18–54 y
≥55 y
C
284
6.89 ± 2.67
284
218
T1
180
10.81 ± 4.81†
132
166
T2
180
11.13 ± 4.43
133
166
T3
178
11.04 ± 4.68
130
159
C
272
10.74 ± 5.24
201
251
T1
180
41.53 ± 11.06§
178
155
T2
185
42.10 ± 11.60
185
156
T3
180
42.14 ± 10.14
180
151
C
271
41.34 ± 10.89
268
229
T1
188
59.86 ± 9.10¥
188
152
T2
186
59.19 ± 14.42
185
150
T3
188
59.17 ± 11.54
188
162
C
276
59.52 ± 10.22
276
234
*P = 0.8981 vs control group; †P = 0.8557 vs control group; §P = 0.8326 vs control group; ¥P = 0.9145 vs control group.
nine countries, mostly in Western Europe and North America, and these countries utilize approximately 60% of the vaccine produced. Thus, comparatively little vaccine is utilized outside of these countries and in the developing world.11 Efforts to improve influenza vaccine capacity for pandemic influenza preparedness are likely to result in worldwide increases in influenzamanufacturing capacity for seasonal vaccine and encourage expanded use of annual vaccine. Aleph influenza vaccine is a highly-purified inactivated, eggbased trivalent influenza vaccine made in China. It was initially licensed in China in 2005. The aim of this post-marketing clinical study was to assess the safety, immunogenicity and batch consistency of the split inactivated influenza vaccine produced by Aleph Biomedical Co., Ltd.
Results Subjects and baseline analysis A total of 3308 healthy people more than 3 y old met the inclusion/exclusion criteria for the study and were randomized to the experimental (influenza vaccine) and control (hepatitis B) groups (2205 in experimental group and 1103 in control group). During the study, 222 subjects dropped out (56 cases did not agree to attend follow-ups while 166 subjects were lost to follow-up;,for the absence of participants who were students taking part of a special activity, so there was a much higher drop-out rate in the 11–17 y old group); 3086 (93%) people completed the safety observation (2057 in experimental group and 1029 in control group), and 2784 (84%) had serum antibody level data available from paired (pre – and post-immunization)
blood samples (Table 1). There were no statistically significant differences in subjects’ age between the experimental and control groups in all age groups, nor among three experimental groups (three batches of influenza vaccine) (P > 0.05; Table 1). Also there were no statistically significant differences in the pre-immunization influenza antibody against three strains of influenza (H1N1, H3N2, B) geometric mean titer (GMT) between the experimental and control groups in all age groups, nor among three experimental groups (three batches of influenza vaccine) (P > 0.05; Table 2). From Table 2, the GMT of B strain before immunization was higher than other two strains in all four age groups. This indicated that there might be a inapparent infection of B strain in study area. Immunogenicity results The seroconversion rates (proportions of subjects with Influenza antibody GMT ≥ 1:40 or increase 4-folds in GMT) of experimental group after immunization in the 3–10 y age group were 86.5% (against H1N1, T1 85.9%, T2 83.7%, T3 90.0%), 94.7% (against H3N2, T1 94.0%, T2 95.2%, T3 95.0%), and 91.1% (against B, T1 91.3%, T2 89.9%, T3 92.1%), compared with 16.4% (against H1N1), 14.2% (against H3N2) and 36.5% (against B) in control group; in the 11–17 y age group were 93.5% (against H1N1, T1 97.0%, T2 91.6%, T3 91.9%), 98.0% (against H3N2, T1 98.8%, T2 97.0%, T3 98.1%), and 79.3% (against B, T1 75.3%, T2 81.3%, T3 81.3%), compared with 5.6% (against H1N1), 2.4% (against H3N2) and 4.4% (against B) in control group; in the 18–54 y age group were 88.3% (against H1N1, T1 89.1%, T2 87.2%, T3 88.7%), 76.3% (against H3N2, T1 73.7%, T2 77.6%, T3 77.5%), and 62.9% (against B, T1 60.9%, T2 60.9%, T3 66.9%), compared with 15.2% (against
558 Human Vaccines & Immunotherapeutics
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Table 1. Numbers and mean ages of subjects in the study groups
Table 2. GMTs of H1N1, H3N2 and B antibodies before immunization in the study groups Age group
Subgroup
No. of subjects
Antibody GMT (H1N1)
P value
Antibody GMT (H3N2)
P value
Antibody GMT (B)
P value
3–10 y
T1
149
3.27 ± 4.47
1.294
4.33 ± 5.14
0.74
31.52 ± 4.13
0.676
T2
146
2.97 ± 4.11
3.66 ± 4.80
36.94 ± 3.82
T3
140
3.41 ± 4.21
3.88 ± 4.65
30.74 ± 4.62
C
218
3.41 ± 4.34
4.29 ± 5.08
34.02 ± 3.91
T1
166
T2
166
3.89 ± 4.29
3.48 ± 4.18
51.63 ± 3.92
T3
159
2.86 ± 3.92
3.27 ± 4.06
47.52 ± 3.72
C
251
3.37 ± 4.17
3.93 ± 4.21
51.21 ± 3.51
T1
155
T2
156
1.75 ± 3.22
1.57 ± 2.75
58.40 ± 4.94
T3
151
1.83 ± 3.25
1.51 ± 2.62
55.53 ± 4.27
C
229
1.52 ± 2.63
1.48 ± 2.51
56.60 ± 4.32
T1
152
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18–54 y
≥55 y
3.21 ± 4.13
1.76 ± 3.22
2.18 ± 3.71
0.276
0.334
0.455
3.09 ± 4.05
1.64 ± 2.81
3.09 ± 3.60
0.352
0.771
0.353
54.36 ± 4.04
51.34 ± 4.98
78.56 ± 2.13
0.837
0.892
0.709
GMT, geometric mean titer; H1N1, H3N2, B, three strains of influenza.
H1N1), 6.1% (against H3N2) and 20.0% (against B) in control group; in the ≥ 55 y age group were 85.6% (against H1N1, T1 83.0%, T2 86.7%, T3 87.0%), 95.9% (against H3N2, T1 94.8%, T2 96.7%, T3 96.3%), and 78.5% (against B, T1 75.8%, T2 81.3%, T3 78.4%), compared with 7.7% (against H1N1), 7.7% (against H3N2) and 6.0% (against B) in control group. The seroconversion rates of experimental groups were much higher than that of control groups. There were significant differences in seroconversion rates achieved post-immunization of three strains of influenza antibody (H1N1, H3N2, B) between experimental group and control group in all age groups (P < 0.05; Table 3). There were no significant differences in seroconversion rates achieved post-immunization of three strains of influenza antibody (H1N1, H3N2, B) among three experimental groups (three batches of influenza vaccine) in all age groups (P > 0.05; Table 3). The seroprotection rates (proportions of subjects whose influenza antibody GMT ≥ 1:40) of experimental group after immunization in the 3–10 y age group were 87.6% (against H1N1, T1 87.9%, T2 85.0%, T3 90.0%), 99.3% (against H3N2, T1 100.0%, T2 100.0%, T3 97.9%), and 99.3% (against B, T1 99.3%, T2 98.6%, T3 100.0%), while they were 25.1% (against H1N1), 25.1% (against H3N2) and 72.6% (against B) in control group; in the 11–17 y age group were 95.3% (against H1N1, T1 97.6%, T2 94.0%, T3 94.4%), 100.0% (against H3N2, T1 100.0%, T2 100.0%, T3 100.0%), and 99.5% (against B, T1 99.4%, T2 99.4%, T3 98.8%), while they were 9.2% (against H1N1), 6.0% (against H3N2) and 30.7% (against B) in control group; in the 18–54 y age group were 90.3% (against H1N1, T1 90.4%, T2 89.7%, T3 90.7%), 78.2% (against H3N2, T1 75.6%, T2 80.1%, T3 78.8%), and 98.7% (against B, T1 98.7%, T2 98.7%, T3 98.7%), while they were 17.4% (against H1N1), 7.0% (against H3N2) and 52.2% (against B) in control group; in the ≥ 55 y age group were 88.8% (against H1N1, T1 86.3%, T2 89.3%, T3 90.7%), 96.1% (against H3N2,
T1 94.8%, T2 96.7%, T3 96.9%), and 99.5% (against B, T1 99.3%, T2 99.3%, T3 100.0%), while they were 10.3% (against H1N1), 9.4% (against H3N2) and 49.1% (against B) in control group. The seroprotection rates of experimental groups were much higher than that of control groups. There were significant differences in seroprotection rates achieved post-immunization of three strains of influenza antibody (H1N1, H3N2, B) between experimental group and control group in all age groups (P < 0.05; Table 4). There were no significant differences in seroprotection rates achieved post-immunization of three strains of influenza antibody (H1N1, H3N2, B) among three experimental groups (three batches of influenza vaccine) in all age groups (P > 0.05; Table 4), except for influenza antibody against H3N2 in the 3–10 y age group (P < 0.05; Table 4). The mean fold increase ratios of GMT in experimental group after immunization in the 3–10 y age group were 65.7 (against H1N1, T1 69.2, T2 70.9, T3 57.1), 89.2 (against H3N2, T1 90.2, T2 92.6, T3 84.9), and 28.5 (against B, T1 32.0, T2 24.0, T3 29.6); in the 11–17 y age group were 84.2 (against H1N1, T1 86.4, T2 70.6, T3 95.6), 60.2 (against H3N2, T1 65.1, T2 58.4, T3 57.2), and 8.9 (against B, T1 8.5, T2 8.4, T3 9.9); in the 18–54 y age group were 87.2 (against H1N1, T1 82.5, T2 87.3, T3 91.8), 38.9 (against H3N2, T1 32.8, T2 41.1, T3 42.7), and 6.3 (against B, T1 6.6, T2 6.0, T3 6.2); in the ≥ 55 y age group were 54.0 (against H1N1, T1 54.2, T2 58.4, T3 49.5), 47.5 (against H3N2, T1 45.8, T2 54.7, T3 41.9), and 6.8 (against B, T1 6.2, T2 6.7, T3 7.6) (Table 5). Furthermore, equivalence study was used to analysis the batch consistency of the study influenza vaccine. A range from – 10% to 10% was set as the equivalence interval at the beginning of the study. From the study, the 95% CI when comparing the seroprotection rates of three batches of influenza vaccine were all included in the range from – 10% to 10%, so it could be considered that three batches of influenza vaccine are equivalence (Table 6).
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11–17 y
Table 3. Seroconversion rates of influenza antibody after immunization in the study groups
3–10 y
11–17 y
Downloaded by [University of Wyoming Libraries] at 07:11 30 March 2015
18–54 y
≥55 y
Subgroup
No. of subjects
Antibody seroconversion (H1N1) No.
Percentage
P value
Antibody seroconversion (H3N2) No.
Percentage
Antibody seroconversion (B)
P value
No.
Percentage
P value
T1
149
128
85.9
140
94
136
91.3
T2
146
123
83.7
