HUMAN VACCINES & IMMUNOTHERAPEUTICS 2016, VOL. 12, NO. 10, 2595–2602 http://dx.doi.org/10.1080/21645515.2016.1197450
RESEARCH PAPER
Comparison of immunogenicity and persistence between inactivated hepatitis A vaccine HealiveÒ and HavrixÒ among children: A 5-year follow-up study Chengkai Yua,#, Yufei Songb,#, Yangyang Qia, Chanjuan Lia, Zhiwei Jianga, Chen Lia, Wei Zhanga, Ling Wanga, and Jielai Xiaa a Department of Health Statistics, School of Preventive Medicine, Fourth Military Medical University, Xi’an, Shaanxi, China; bSinovac Biotech, Beijing, China
ABSTRACT
ARTICLE HISTORY
Background: Inactivated vaccines for hepatitis A virus (HAV) infection are widely used in China. Mass vaccination programs drive the need for data on long-term persistence of vaccine-induced protection. Methods: A prospective, randomized, open-label clinical trial was conducted to compare geometric mean concentrations (GMCs) and seroconversion rates (SRs) of anti-HAV antibody elicited by the inactivated vaccines Healive and Havrix for 5 y post immunization, in which 400 healthy children were randomly assigned in a 3:1 ratio to receive 2 doses of Healive or Havrix at 0 and 6 month. Anti-HAV antibody concentration was detected by microparticle enzyme immunoassay (MEIA) during the study. Furthermore, an attempt was made to predict persistence of protective immunogenicity by using a suitable statistical model. Results: The GMCs were significantly higher after vaccination with Healive than after Havrix as comparator vaccine at 1, 6, 7, 18, 30, 42, 54 and 66 month (P < 0.01) with the peak point at 7 month (3427.2 mIU/ml for Healive and 1441.9 mIU/ml for Comparator). Similarly significant differences of SRs were found between the 2 groups at 1 and 6 month (P < 0.01). Afterwards, the SRs of both groups reached 100% at 7 month and did not decline until 66 month(99.1% for Healive and 97.5% for Comparator). A linear mixed model with a change point at 18 month(Model 3) was found to be suitable to predict persistence of protective immunogenicity induced by vaccines. It was estimated that the duration of protection for Healive was at least 20 y with a lower limit of GMC 95% confidence interval (CI) no less than 20 mIU/mL. Conclusions: Compared with Havrix, the new preservative-free inactivated hepatitis A vaccine (Healive) in 2 doses showed better persistence of antibody concentrations for 5 y after full-course immunization among children and the persistence of protective immunogenicity was estimated for at least 20 y.
Received 18 February 2016 Revised 11 May 2016 Accepted 24 May 2016 KEYWORDS
immunogenicity; inactivated hepatitis A vaccine; long term follow-up; persistence of protective immunogenicity
Introduction Hepatitis A which can cause asymptomatic-to-severe illness is a significant endemic and epidemic disease of global importance.1-3 The prevalence of hepatitis A infection varies according to hygienic conditions, being very high in countries where the majority of infections are clinically undetected.4-7 In May, 2013, an outbreak of symptomatic hepatitis A virus (HAV) infections occurred in the USA.8 In Japan, 342 cases of HAV infection had been reported in 2014, which was considered as a nationwide HAV outbreak.9 In China, hepatitis is also a huge public health problem and infection with HAV remains the leading cause of acute viral hepatitis, especially for children and young adults.10 China has long experience using inactivated HAV vaccines.11,12 The review reported by Cui et al.12 demonstrated that inactivated HAV vaccines manufactured in China were immunogenic, effective, and safe. Liu et al.2 conducted a study in the healthy young adults at colleges in Nanchang City, China and found that 1 or 2 doses of inactivated hepatitis A vaccine HealiveÒ (Sinovac Biotech, Beijing, China) induced high rates
CONTACT Ling Wang [email protected]; Jielai Xia # Chengkai Yu and Yufei Song contributed equally to this article. © 2016 Taylor & Francis
of seroconversion (anti-HAV IgG concentration 20 mIU/mL) persisting for at least 36 months. However, mass vaccination programs drive the need for data on long-term persistence of vaccine-induced protection.13 In 2006, a double-blind, randomized and controlled clinical trial was conducted in healthy volunteers aged 1-8 y from Changzhou city, Jiangsu province of China to compare the immunogenicity of anti-HAV antibodies among 3 consecutive production lots of HealiveÒ and HavrixÒ (GlaxoSmithKline Biologicals) as comparator vaccine. Total 400 subjects were randomized into 4 groups with 100 subjects per group, receiving one of the 3 lots of Healive or the comparator vaccine. The vaccination was 2-dose regimen at 0-6 months. The three lots of Healive showed statistically indistinguishable clinical performance with 100% seroconversion rates (SRs) and 3237-3814 mIU/ml geometric mean concentrations (GMCs) 1 month after the second dose.14 The aim of the present analysis is to compare the immunogenicity between Healive and Comparator further for 5 y and
[email protected]
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C. YU ET AL.
predict persistence of protective immunogenicity induced by both vaccines with a suitable statistical model.
The predicted SRs using Model 3 for both groups are shown in Figure 2 and the SRs of Healive were higher than Comparator at all the timepoints until 360 month after the second dose.
Results Participants included in analysis Of 400 children, 375 participants who completed their fullcourse immunization were invited to participate in the followup phase with 283 in Healive and 92 in Comparator (Fig. 1). Demographic characteristics of both groups at baseline in the full analysis set (FAS) are presented in Table 1. There were no statistically significant differences in gender ratio, age, height and weight between 2 groups. Observed immunogenicity of Anti-HAV antibodies over time GMCs and SRs of anti-HAV antibodies in the 2 groups at each timepoint from 1 to 66 month are shown in Table 2. At 1 month after the first dose, GMCs of Healive and Comparator were 29.1 and 20.3 mIU/ml respectively and increased slowly in the following 5 months. At 7 month, i.e. 1 month after dose2, GMCs of both groups reached the peak point (3427.2 mIU/ ml for Healive and 1441.9 mIU/ml for Comparator). Later, there were a sharp decline with 572.0 and 386.0 mIU/ml at 18 month for Healive and Comparator respectively and a relatively slower rate of decline from 30 to 66 month (ranged from 468.7 to 257.1 mIU/ml for Healive and 300.1 to 168.1 mIU/ml for Comparator). The GMCs were significantly higher in Healive than in Comparator at each timepoint from 1 to 66 month (P < 0.01). Similarly significant differences of SRs were found between the 2 groups at 1 month (75.2% for Healive and 50.6% for Comparator) and 6 month (97.5% for Healive and 87.0% for Comparator) (P < 0.01) . Afterwards, the SRs of both groups reached 100% at 7 month and did not decline until 66 month(99.1% for Healive and 97.5% for Comparator). Model results 278 participants in Healive and 92 participants in Comparator were included in the model research with 5 in Healive excluded for reasons of sample contamination and data missing (see model selection section for details). The predicted GMCs and SRs from 7 to 306 month after the first dose using Model 3 are shown in Table 3. GMCs (95% CI) were predicted to 33.0 (24.3-45.0) mIU/mL at 246 month and 16.1 (11.0-23.6) mIU/mL at 306 month for Healive. During this period, 260 month was found to be the farthest timepoint with protective immunogenicity, where the GMC (95% CI) was estimated to 27.9 (20.2-38.7) mIU/mL with a lower limit no less than 20 mIU/mL. (Not listed in Table 3, the same below). In a similar way, the farthest timepoint with protective immunogenicity for Comparator was 209 month where the GMC (95% CI) was estimated to 33.2(20.0-55.2) mIU/mL. With regard to SRs, in order to guarantee a lower limit no less than 80%, it was estimated that the SR (95% CI) was 84.9% (80.1%88.9%) at 157 month for Healive and 89.1% (80.9%-94.7%) at 116 month for Comparator.
Discussion This study was designed to compare GMCs and SRs of antiHAV antibody elicited by the inactivated vaccines Healive and Havrix as comparator vaccine for 5 y post immunization, and then a suitable statistical model was used to predict the persistence of protective immunogenicity for the 2 vaccines. The GMCs were significantly higher in Healive than in Comparator at each timepoint from 1 to 66 month (P < 0.01). The SRs of both groups reached 100% at 7 month and did not decline until 66 month. There were no significant differences of SRs between the 2 groups at each timepoint except 1 and 6 month. Since each company has different antigen dissociation technique and dissociation rate, which is a patent technology and not open to the public, the dose unit of U(Healive) and El. U(Havrix) is different and the antigen content could not be compared directly. However, it does not matter to make comparison of the immunogenicity above and protective immunogenicity persistence between the 2 licensed products which is what is most pertinent to the use of the products in the field and population. Because the advantage of linear mixed models fitting to longitudinal data was recognized by several studies,2,15-19 4 previously used linear mixed models were applied to fit our followup data and Model 3 was confirmed to be a suitable one. Similar to many clinical trials showed,2,20,21 the GMCs declined rapidly in the first 12 months after 2 doses and slowly later, therefore, the timepoint of 18 month after the first dose was used as the chang point in Model 3. Apart from anti-HAV serostatus at 1 month, we also considered the inclusion of other covariates (age and gender), however, it had no statistically significant differences and did not improve goodness of fit. A series of previous trials had explored the protective immunogenicity persistence of Havrix based on statistical models. Van Damme et al.22 assumed a constant basic exponential decline and predicted the persistence of protective immunogenicity for at least 20 y among healthy adults with a 0-1-6 month vaccination schedule. Hammitt et al.23 used a log-linear model of decline in GMC of antibody, and predicted that children would retain protective immunogenicity levels of anti-HAV for more than 22 y with a 0-1-6 month vaccination schedule or for more than 27 y with a 0-1-12 month vaccination schedule. Based on 2 of the longest follow-up studies (participants were vaccinated according to a 0-12 mo and a 0-6 mo schedule, respectively) in adults,24,25 Niel et al.16 reported a duration of protective immunogenicity at least 25 y with a linear mixed model, which was confirmed appropriate to describe the profile of HAV antibody decline phase and it was also applied in our persistence estimation. In our study, the persistence of protective immunogenicity for Havrix was less than 20 y which was shorter compared with the studies mentioned above. ELISA method (Enzyme-Linked Immunosorbent Assay) to measure anti-HAV antibody concentration was adopted and anti-HAV antibody concentration no lower than 20 mIU/mL was considered the indicator of
HUMAN VACCINES & IMMUNOTHERAPEUTICS
2597
Figure 1. Follow-up of subjects in the 2 groups.
seroprotection for all the 4 studies including ours. Considering there are wide statistical bounds around the data in the published and current study, all results could lie within the range of variation of following such cohorts and modeling long-term changes based on a few years of data. There were some limitations to our study as follows. The period of observations was limited to describe the whole profile
of anti-HAV antibody elicited by the vaccines and a longer follow-up study need to be conducted to further adjust and verify the present results. In addition, results from single site might have resulted in selection bias. In conclusion, compared with Havrix, the new preservativefree inactivated hepatitis A vaccine Healive with 0-6 month vaccination schedule showed better immunogenic for 5 y after
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C. YU ET AL.
Table 1. Demographic characteristics of participants. Mean(95%CI) Group
N
M/F
Age(y)
Height(cm)
Weight(kg)
Healive 283 142/141 3.8(3.6-4.0) 100.7(99.2-102.2) 17.2(16.8-17.7) Comparator 92 48/44 3.7(3.4-4.0) 100.6(97.9-103.2) 17.4(16.6-18.2) N, number of subjects; M/F, male/female ratio; 95% CI, 95% Confidence Interval on the mean value.
full-course immunization among children and the persistence of protective immunogenicity was estimated for at least 20 y.
screening blood samples collected before immunization at 0 and 6 month. Anti-HAV antibody concentrations were assessed by microparticle enzyme immunoassay (MEIA) during the study. Both seroconversion and protective immunogenicity were defined as the ability of hepatitis A vaccines to elicit an immune response of at least 20 mIU/mL.12,26 The study was conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines. Study protocols were approved by the Ethics Review Committee of the Changzhou Center for Disease Control and Prevention. Written informed consents were obtained from all participants prior to the performance of the study. The trial was registered at Clinicaltrials. gov (NCT00534885).
Materials and methods Clinical trial methodology The three consecutive production lots of Healive were combined as one group with the consistency of immunogenicity according to regulatory acceptance criteria14 taken into consideration. Therefore, the 400 healthy children were assigned in a 3:1 ratio to receive 2 doses of Healive (0.5 mL/dose) contained 250 U antigen and 0.25 mg alum without preservative or the comparator vaccine Havrix (0.5 mL/dose) contained 720 ELISA units (El.U) antigen and 0.25 mg alum with 2-phenoxyethanol as preservative.Volunteers who completed their full-course immunization were monitored annually for 5 y. Blood samples were collected at 0, 1, 6, 7, 18, 30, 42, 54 and 66 month with
Statistical methods GMCs and SRs of anti-HAV antibody were calculated based on the actual observed data without missing data imputation. Logarithmic transformation (log10) had been made before the calculation of GMC and 95% CI. Student’s t-test or Mann– Whitney U test (for non-normally distributed data) was used to compare GMCs when relevant, and Chi-square test or Fisher’s exact test (when data were sparse) was used to compare SRs. The significance level was 0.05 (2-sided). All data were handled and analyzed using SAS version 9.3 (SAS Institute, Cary, NC).
Table 2. Geometric mean concentrations and seroconversion rates over time in healthy children. Healive
Comparator
P Valuea
Subjects, no SR,%(95% CI) GMC,mIU/ml(95% CI)
278 75.2(69.7-80.1) 29.1(26.5-32.0)
91 50.6(39.9-61.2) 20.3(17.2-24.1)
RESEARCH PAPER
Comparison of immunogenicity and persistence between inactivated hepatitis A vaccine HealiveÒ and HavrixÒ among children: A 5-year follow-up study Chengkai Yua,#, Yufei Songb,#, Yangyang Qia, Chanjuan Lia, Zhiwei Jianga, Chen Lia, Wei Zhanga, Ling Wanga, and Jielai Xiaa a Department of Health Statistics, School of Preventive Medicine, Fourth Military Medical University, Xi’an, Shaanxi, China; bSinovac Biotech, Beijing, China
ABSTRACT
ARTICLE HISTORY
Background: Inactivated vaccines for hepatitis A virus (HAV) infection are widely used in China. Mass vaccination programs drive the need for data on long-term persistence of vaccine-induced protection. Methods: A prospective, randomized, open-label clinical trial was conducted to compare geometric mean concentrations (GMCs) and seroconversion rates (SRs) of anti-HAV antibody elicited by the inactivated vaccines Healive and Havrix for 5 y post immunization, in which 400 healthy children were randomly assigned in a 3:1 ratio to receive 2 doses of Healive or Havrix at 0 and 6 month. Anti-HAV antibody concentration was detected by microparticle enzyme immunoassay (MEIA) during the study. Furthermore, an attempt was made to predict persistence of protective immunogenicity by using a suitable statistical model. Results: The GMCs were significantly higher after vaccination with Healive than after Havrix as comparator vaccine at 1, 6, 7, 18, 30, 42, 54 and 66 month (P < 0.01) with the peak point at 7 month (3427.2 mIU/ml for Healive and 1441.9 mIU/ml for Comparator). Similarly significant differences of SRs were found between the 2 groups at 1 and 6 month (P < 0.01). Afterwards, the SRs of both groups reached 100% at 7 month and did not decline until 66 month(99.1% for Healive and 97.5% for Comparator). A linear mixed model with a change point at 18 month(Model 3) was found to be suitable to predict persistence of protective immunogenicity induced by vaccines. It was estimated that the duration of protection for Healive was at least 20 y with a lower limit of GMC 95% confidence interval (CI) no less than 20 mIU/mL. Conclusions: Compared with Havrix, the new preservative-free inactivated hepatitis A vaccine (Healive) in 2 doses showed better persistence of antibody concentrations for 5 y after full-course immunization among children and the persistence of protective immunogenicity was estimated for at least 20 y.
Received 18 February 2016 Revised 11 May 2016 Accepted 24 May 2016 KEYWORDS
immunogenicity; inactivated hepatitis A vaccine; long term follow-up; persistence of protective immunogenicity
Introduction Hepatitis A which can cause asymptomatic-to-severe illness is a significant endemic and epidemic disease of global importance.1-3 The prevalence of hepatitis A infection varies according to hygienic conditions, being very high in countries where the majority of infections are clinically undetected.4-7 In May, 2013, an outbreak of symptomatic hepatitis A virus (HAV) infections occurred in the USA.8 In Japan, 342 cases of HAV infection had been reported in 2014, which was considered as a nationwide HAV outbreak.9 In China, hepatitis is also a huge public health problem and infection with HAV remains the leading cause of acute viral hepatitis, especially for children and young adults.10 China has long experience using inactivated HAV vaccines.11,12 The review reported by Cui et al.12 demonstrated that inactivated HAV vaccines manufactured in China were immunogenic, effective, and safe. Liu et al.2 conducted a study in the healthy young adults at colleges in Nanchang City, China and found that 1 or 2 doses of inactivated hepatitis A vaccine HealiveÒ (Sinovac Biotech, Beijing, China) induced high rates
CONTACT Ling Wang [email protected]; Jielai Xia # Chengkai Yu and Yufei Song contributed equally to this article. © 2016 Taylor & Francis
of seroconversion (anti-HAV IgG concentration 20 mIU/mL) persisting for at least 36 months. However, mass vaccination programs drive the need for data on long-term persistence of vaccine-induced protection.13 In 2006, a double-blind, randomized and controlled clinical trial was conducted in healthy volunteers aged 1-8 y from Changzhou city, Jiangsu province of China to compare the immunogenicity of anti-HAV antibodies among 3 consecutive production lots of HealiveÒ and HavrixÒ (GlaxoSmithKline Biologicals) as comparator vaccine. Total 400 subjects were randomized into 4 groups with 100 subjects per group, receiving one of the 3 lots of Healive or the comparator vaccine. The vaccination was 2-dose regimen at 0-6 months. The three lots of Healive showed statistically indistinguishable clinical performance with 100% seroconversion rates (SRs) and 3237-3814 mIU/ml geometric mean concentrations (GMCs) 1 month after the second dose.14 The aim of the present analysis is to compare the immunogenicity between Healive and Comparator further for 5 y and
[email protected]
2596
C. YU ET AL.
predict persistence of protective immunogenicity induced by both vaccines with a suitable statistical model.
The predicted SRs using Model 3 for both groups are shown in Figure 2 and the SRs of Healive were higher than Comparator at all the timepoints until 360 month after the second dose.
Results Participants included in analysis Of 400 children, 375 participants who completed their fullcourse immunization were invited to participate in the followup phase with 283 in Healive and 92 in Comparator (Fig. 1). Demographic characteristics of both groups at baseline in the full analysis set (FAS) are presented in Table 1. There were no statistically significant differences in gender ratio, age, height and weight between 2 groups. Observed immunogenicity of Anti-HAV antibodies over time GMCs and SRs of anti-HAV antibodies in the 2 groups at each timepoint from 1 to 66 month are shown in Table 2. At 1 month after the first dose, GMCs of Healive and Comparator were 29.1 and 20.3 mIU/ml respectively and increased slowly in the following 5 months. At 7 month, i.e. 1 month after dose2, GMCs of both groups reached the peak point (3427.2 mIU/ ml for Healive and 1441.9 mIU/ml for Comparator). Later, there were a sharp decline with 572.0 and 386.0 mIU/ml at 18 month for Healive and Comparator respectively and a relatively slower rate of decline from 30 to 66 month (ranged from 468.7 to 257.1 mIU/ml for Healive and 300.1 to 168.1 mIU/ml for Comparator). The GMCs were significantly higher in Healive than in Comparator at each timepoint from 1 to 66 month (P < 0.01). Similarly significant differences of SRs were found between the 2 groups at 1 month (75.2% for Healive and 50.6% for Comparator) and 6 month (97.5% for Healive and 87.0% for Comparator) (P < 0.01) . Afterwards, the SRs of both groups reached 100% at 7 month and did not decline until 66 month(99.1% for Healive and 97.5% for Comparator). Model results 278 participants in Healive and 92 participants in Comparator were included in the model research with 5 in Healive excluded for reasons of sample contamination and data missing (see model selection section for details). The predicted GMCs and SRs from 7 to 306 month after the first dose using Model 3 are shown in Table 3. GMCs (95% CI) were predicted to 33.0 (24.3-45.0) mIU/mL at 246 month and 16.1 (11.0-23.6) mIU/mL at 306 month for Healive. During this period, 260 month was found to be the farthest timepoint with protective immunogenicity, where the GMC (95% CI) was estimated to 27.9 (20.2-38.7) mIU/mL with a lower limit no less than 20 mIU/mL. (Not listed in Table 3, the same below). In a similar way, the farthest timepoint with protective immunogenicity for Comparator was 209 month where the GMC (95% CI) was estimated to 33.2(20.0-55.2) mIU/mL. With regard to SRs, in order to guarantee a lower limit no less than 80%, it was estimated that the SR (95% CI) was 84.9% (80.1%88.9%) at 157 month for Healive and 89.1% (80.9%-94.7%) at 116 month for Comparator.
Discussion This study was designed to compare GMCs and SRs of antiHAV antibody elicited by the inactivated vaccines Healive and Havrix as comparator vaccine for 5 y post immunization, and then a suitable statistical model was used to predict the persistence of protective immunogenicity for the 2 vaccines. The GMCs were significantly higher in Healive than in Comparator at each timepoint from 1 to 66 month (P < 0.01). The SRs of both groups reached 100% at 7 month and did not decline until 66 month. There were no significant differences of SRs between the 2 groups at each timepoint except 1 and 6 month. Since each company has different antigen dissociation technique and dissociation rate, which is a patent technology and not open to the public, the dose unit of U(Healive) and El. U(Havrix) is different and the antigen content could not be compared directly. However, it does not matter to make comparison of the immunogenicity above and protective immunogenicity persistence between the 2 licensed products which is what is most pertinent to the use of the products in the field and population. Because the advantage of linear mixed models fitting to longitudinal data was recognized by several studies,2,15-19 4 previously used linear mixed models were applied to fit our followup data and Model 3 was confirmed to be a suitable one. Similar to many clinical trials showed,2,20,21 the GMCs declined rapidly in the first 12 months after 2 doses and slowly later, therefore, the timepoint of 18 month after the first dose was used as the chang point in Model 3. Apart from anti-HAV serostatus at 1 month, we also considered the inclusion of other covariates (age and gender), however, it had no statistically significant differences and did not improve goodness of fit. A series of previous trials had explored the protective immunogenicity persistence of Havrix based on statistical models. Van Damme et al.22 assumed a constant basic exponential decline and predicted the persistence of protective immunogenicity for at least 20 y among healthy adults with a 0-1-6 month vaccination schedule. Hammitt et al.23 used a log-linear model of decline in GMC of antibody, and predicted that children would retain protective immunogenicity levels of anti-HAV for more than 22 y with a 0-1-6 month vaccination schedule or for more than 27 y with a 0-1-12 month vaccination schedule. Based on 2 of the longest follow-up studies (participants were vaccinated according to a 0-12 mo and a 0-6 mo schedule, respectively) in adults,24,25 Niel et al.16 reported a duration of protective immunogenicity at least 25 y with a linear mixed model, which was confirmed appropriate to describe the profile of HAV antibody decline phase and it was also applied in our persistence estimation. In our study, the persistence of protective immunogenicity for Havrix was less than 20 y which was shorter compared with the studies mentioned above. ELISA method (Enzyme-Linked Immunosorbent Assay) to measure anti-HAV antibody concentration was adopted and anti-HAV antibody concentration no lower than 20 mIU/mL was considered the indicator of
HUMAN VACCINES & IMMUNOTHERAPEUTICS
2597
Figure 1. Follow-up of subjects in the 2 groups.
seroprotection for all the 4 studies including ours. Considering there are wide statistical bounds around the data in the published and current study, all results could lie within the range of variation of following such cohorts and modeling long-term changes based on a few years of data. There were some limitations to our study as follows. The period of observations was limited to describe the whole profile
of anti-HAV antibody elicited by the vaccines and a longer follow-up study need to be conducted to further adjust and verify the present results. In addition, results from single site might have resulted in selection bias. In conclusion, compared with Havrix, the new preservativefree inactivated hepatitis A vaccine Healive with 0-6 month vaccination schedule showed better immunogenic for 5 y after
2598
C. YU ET AL.
Table 1. Demographic characteristics of participants. Mean(95%CI) Group
N
M/F
Age(y)
Height(cm)
Weight(kg)
Healive 283 142/141 3.8(3.6-4.0) 100.7(99.2-102.2) 17.2(16.8-17.7) Comparator 92 48/44 3.7(3.4-4.0) 100.6(97.9-103.2) 17.4(16.6-18.2) N, number of subjects; M/F, male/female ratio; 95% CI, 95% Confidence Interval on the mean value.
full-course immunization among children and the persistence of protective immunogenicity was estimated for at least 20 y.
screening blood samples collected before immunization at 0 and 6 month. Anti-HAV antibody concentrations were assessed by microparticle enzyme immunoassay (MEIA) during the study. Both seroconversion and protective immunogenicity were defined as the ability of hepatitis A vaccines to elicit an immune response of at least 20 mIU/mL.12,26 The study was conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines. Study protocols were approved by the Ethics Review Committee of the Changzhou Center for Disease Control and Prevention. Written informed consents were obtained from all participants prior to the performance of the study. The trial was registered at Clinicaltrials. gov (NCT00534885).
Materials and methods Clinical trial methodology The three consecutive production lots of Healive were combined as one group with the consistency of immunogenicity according to regulatory acceptance criteria14 taken into consideration. Therefore, the 400 healthy children were assigned in a 3:1 ratio to receive 2 doses of Healive (0.5 mL/dose) contained 250 U antigen and 0.25 mg alum without preservative or the comparator vaccine Havrix (0.5 mL/dose) contained 720 ELISA units (El.U) antigen and 0.25 mg alum with 2-phenoxyethanol as preservative.Volunteers who completed their full-course immunization were monitored annually for 5 y. Blood samples were collected at 0, 1, 6, 7, 18, 30, 42, 54 and 66 month with
Statistical methods GMCs and SRs of anti-HAV antibody were calculated based on the actual observed data without missing data imputation. Logarithmic transformation (log10) had been made before the calculation of GMC and 95% CI. Student’s t-test or Mann– Whitney U test (for non-normally distributed data) was used to compare GMCs when relevant, and Chi-square test or Fisher’s exact test (when data were sparse) was used to compare SRs. The significance level was 0.05 (2-sided). All data were handled and analyzed using SAS version 9.3 (SAS Institute, Cary, NC).
Table 2. Geometric mean concentrations and seroconversion rates over time in healthy children. Healive
Comparator
P Valuea
Subjects, no SR,%(95% CI) GMC,mIU/ml(95% CI)
278 75.2(69.7-80.1) 29.1(26.5-32.0)
91 50.6(39.9-61.2) 20.3(17.2-24.1)
