Vaccine 33 (2015) 4093–4099
Contents lists available at ScienceDirect
Vaccine journal homepage: www.elsevier.com/locate/vaccine
Efficacy of antigen dosage on the hepatitis B vaccine response in infants born to hepatitis B-uninfected and hepatitis B-infected mothers Guodong Kang a , Fubao Ma a,∗ , Haiping Chen b , Yunkai Yang b , Shaohong Guo b , Zhiguo Wang a , Xiaofeng Liang c , Li Li c , Fuqiang Cui c , Longhua Zhang d a
Jiangsu Provincial Centre of Disease Control and Prevention, Jiangsu Province, China Beijing Tiantan Biological Products Co., Ltd, Beijing, China c Chinese Centre of Disease Control and Prevention, Beijing, China d Xiangshui County Centre of Disease Control and Prevention, Jiangsu Province, China b
a r t i c l e
i n f o
Article history: Received 2 September 2014 Received in revised form 19 May 2015 Accepted 22 June 2015 Available online 3 July 2015 Keywords: Hepatitis B Vaccine dosage Neonates Safety Immunogenicity Perinatal transmission
a b s t r a c t Objective: To compare the safety and immunogenicity of two dosages of recombinant hepatitis B (HB) vaccine administered to infants born to HB-uninfected and HB-infected mothers. Methods: A phase III, controlled, single-blinded clinical trial was conducted with 506 healthy newborns. The newborns were assigned to three groups based on maternal levels of HB surface antigen (HBsAg) and HB e antigen (HBeAg): Group A, HBsAg negative; Group B, HBsAg positive and HBeAg negative; and Group C, HBsAg positive and HBeAg positive. Three doses of 10 or 5 g recombinant HB vaccine were randomly administered by 1:1 within 24 h after birth, at 1 month and at 6 months. Safety data and preand postvaccination blood samples were collected. Results: A total of 326, 93, and 87 subjects were included in Groups A, B, and C, respectively. Both dosages of HB vaccine were well tolerated by all subjects. The most common injection-site adverse reactions (ARs) and systemic ARs were pain and fever. After 1 month of the third dose, the Group A infants who received the 10 g HB vaccine achieved a higher geometric mean concentration (GMC) of HB surface antibody (anti-HBs) than those who received the 5 g dosage. Maternal anti-HBs serostatus did not influence HB vaccine immunogenicity at either dosage. In contrast, there was no significant difference in the anti-HBs seroconversion rate, GMCs, or estimated vaccine efficacy (EVE) against perinatal transmission between Groups B and C, regardless of dosage. However, the seroconversion rate and EVE of the 5 g HB vaccine was lower in Group C than in Group B. Conclusions: Both dosages of the HB vaccine were well tolerated and elicited a good immune response in infants of Group A, regardless of the maternal anti-HBs serostatus. EVE did not significantly differ between Groups B and C. Clinicaltrails.gov identifier: NCT02152709 © 2015 Elsevier Ltd. All rights reserved.
Abbreviations: AR, adverse reaction; anti-HBs, hepatitis B surface antibody; CDC, centre of disease control and prevention; CLIA, chemiluminescence assay; CSFDA, China state food and drug administration; DMID, diseases of the national institutes of allergy and infectious diseases; GMC, geometric mean concentration; EPI, expanded program on immunization; EVE, estimated vaccine efficacy; JSCDC, Jiangsu provincial centre of disease control and prevention; HB, hepatitis B; HBIg, hepatitis B immunoglobulin; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; NIFDC, national institute of food and drug control, China; sAR, serious adverse reaction; SUSAR, suspected unexpected serious adverse reaction. ∗ Corresponding author at: Department of Expanded Programmed on Immunization of Jiangsu Provincial Centre of Disease Control and Prevention, 172 Jiangsu Road, Nanjing 21009, Jiangsu Province, China. Tel.: +86 25 83759422; fax: +86 25 83759423. E-mail address: [email protected] (F. Ma). http://dx.doi.org/10.1016/j.vaccine.2015.06.081 0264-410X/© 2015 Elsevier Ltd. All rights reserved.
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G. Kang et al. / Vaccine 33 (2015) 4093–4099
1. Introduction Hepatitis B virus (HBV) infection is a global public health problem; more than 2 billion people have been infected with HBV [1,2]. Chronically infected individuals have an increased lifetime risk for cirrhosis and hepatocellular carcinoma [3]. Neonatal hepatitis B (HB) vaccination is the most effective measure for preventing HBV vertically transmitted infection and its progress into chronicity [4,5]. In 2002, China integrated HB vaccination into the national routine expanded program on immunization (EPI) and has also increased efforts to improve the HB vaccination coverage rate for infants [6]. Both yeast-derived (5 g) and Chinese hamster ovary cell (10 g) recombinant HB vaccines are commonly used for EPI in China. Timely vaccination at birth using the correct dosage and full HB booster vaccination is recommended [7]. For newborns from HB-infected mothers, combined universal vaccination with HB immunoglobulin (HBIg) to block perinatal transmission is recommended [8], although the limited availability of HBIg has presented challenges for the vaccination program. As a result, universal HB vaccination alone has been used in some areas of China [9]. Vaccine studies in healthy young children have shown the efficacies of various HB vaccine dosages in eliciting immune responses against HBV [10,11]. However, the impact of increasing the HB vaccine antigen dosage in infants delivered by healthy and HB-infected women has been poorly characterized. Therefore, in this study, we compared the safety and immunogenicity of 10 and 5 g/0.5 ml recombinant HB vaccine in infants born to HB-uninfected and HBinfected mothers. 2. Materials and methods 2.1. Study design This study was designed as a phase III, controlled, randomized, and single-blinded (subject, investigator, and laboratory staff) clinical trial to assess the safety and immunogenicity of two dosages (10 and 5 g) of recombinant HB vaccine in children born to HBuninfected or HB-infected mothers. The study was approved by the China State Food and Drug Administration (CSFDA) and was conducted by investigators from the Jiangsu Provincial Centre of Disease Control and Prevention (JSCDC). Institutional Review Board approval was obtained from the Ethics Committee of the JSCDC. Written informed consent was obtained from the subject’s parents. 2.2. Subjects The study was conducted in Xiangshui County, Jiangsu Province, China. Beginning in 2008, eligible pregnant women who had been tested positive for HB surface antigen (HBsAg) and/or HB virus e antigen (HBeAg) using enzyme-linked immunosorbent assay (ELISA) within 9 months prior to delivery were included. Postpartum subject data were documented, including age, sex, body weight, Apgar scores, medication use, and other health status parameters. Inclusion criteria for subjects included: healthy newborn following a full-term pregnancy (37–42 weeks gestation), body weight ≥2,500 g, Apgar scores ≥7, and axillary temperature ≤37.0 ◦ C. Newborn exclusion criteria included infectious diseases, nervous system damage after birth, congenital malformations, developmental disorders or serious chronic illness, and thrombocytopenia or other coagulation disorders. Newborns were also excluded if immunoglobulin, especially HBIg, was administered during the clinical trial. Venous blood samples were collected from participating women during pregnancy for HBsAg and HBeAg testing at the local Center
for Disease Control and Prevention (CDC). Newborns were assigned to three groups based on maternal HBsAg and HBeAg status: Group A included newborns of HBsAg-negative mothers; Group B included newborns of HBsAg-positive and HBeAg-negative mothers; and Group C included newborns of HBsAg-positive and HBeAg-positive mothers. The newborns were randomized at a ratio of 1:1 to receive three doses of 10 or 5 g HB vaccine within 24 h after birth (date of vaccination was considered Day 1), at 1 month and at 6 months. 2.3. Vaccine Single doses of 10 and 5 g/0.5 ml HB vaccine were produced by recombinant techniques in Saccharomyces cerevisiae at Beijing Tiantan Biological Products, Beijing, China. All vaccines were administered intramuscularly in the deltoid region by qualified nurses. 2.4. Safety Subjects receiving at least one dose of HB vaccination were included in the analysis of adverse reactions (ARs). Newborns and infants were monitored for immediate ARs for at least 30 min after each vaccine administration. Follow-up AR assessments were performed on Days 1, 2, and 3 after administration of each dose by qualified staff at the local CDC. Parents and guardians were instructed to measure daily the axilla temperature with mercury thermometers and asked to report any ARs to qualified local general practitioners. The latter were asked to record any reported ARs within 1 month after each vaccine dose in the vaccination report booklet. ARs were coded and graded according to the guidelines provided by the CSFDA and the Division of Microbiology and Infectious Diseases of the National Institutes of Allergy and Infectious Diseases (DMID) [12]. Solicited injection site ARs included pain, mucocutaneous, induration, erythema, swelling, and local rash at injection site. The solicited systemic ARs included fever, allergy, mental reactions, vomiting, level of activity, convulsion, crying, diarrhea, nausea, and breast-feeding disorders. Unsolicited systemic ARs were collected as well. Serious ARs (sARs) and suspected unexpected serious adverse reactions (SUSARs) were also assessed throughout the study period. Induration, erythema, swelling, and local rash at injection site were categorized as Grade 1 (50 mm). Fever was categorized as Grade 1 (≥37.1 to
Contents lists available at ScienceDirect
Vaccine journal homepage: www.elsevier.com/locate/vaccine
Efficacy of antigen dosage on the hepatitis B vaccine response in infants born to hepatitis B-uninfected and hepatitis B-infected mothers Guodong Kang a , Fubao Ma a,∗ , Haiping Chen b , Yunkai Yang b , Shaohong Guo b , Zhiguo Wang a , Xiaofeng Liang c , Li Li c , Fuqiang Cui c , Longhua Zhang d a
Jiangsu Provincial Centre of Disease Control and Prevention, Jiangsu Province, China Beijing Tiantan Biological Products Co., Ltd, Beijing, China c Chinese Centre of Disease Control and Prevention, Beijing, China d Xiangshui County Centre of Disease Control and Prevention, Jiangsu Province, China b
a r t i c l e
i n f o
Article history: Received 2 September 2014 Received in revised form 19 May 2015 Accepted 22 June 2015 Available online 3 July 2015 Keywords: Hepatitis B Vaccine dosage Neonates Safety Immunogenicity Perinatal transmission
a b s t r a c t Objective: To compare the safety and immunogenicity of two dosages of recombinant hepatitis B (HB) vaccine administered to infants born to HB-uninfected and HB-infected mothers. Methods: A phase III, controlled, single-blinded clinical trial was conducted with 506 healthy newborns. The newborns were assigned to three groups based on maternal levels of HB surface antigen (HBsAg) and HB e antigen (HBeAg): Group A, HBsAg negative; Group B, HBsAg positive and HBeAg negative; and Group C, HBsAg positive and HBeAg positive. Three doses of 10 or 5 g recombinant HB vaccine were randomly administered by 1:1 within 24 h after birth, at 1 month and at 6 months. Safety data and preand postvaccination blood samples were collected. Results: A total of 326, 93, and 87 subjects were included in Groups A, B, and C, respectively. Both dosages of HB vaccine were well tolerated by all subjects. The most common injection-site adverse reactions (ARs) and systemic ARs were pain and fever. After 1 month of the third dose, the Group A infants who received the 10 g HB vaccine achieved a higher geometric mean concentration (GMC) of HB surface antibody (anti-HBs) than those who received the 5 g dosage. Maternal anti-HBs serostatus did not influence HB vaccine immunogenicity at either dosage. In contrast, there was no significant difference in the anti-HBs seroconversion rate, GMCs, or estimated vaccine efficacy (EVE) against perinatal transmission between Groups B and C, regardless of dosage. However, the seroconversion rate and EVE of the 5 g HB vaccine was lower in Group C than in Group B. Conclusions: Both dosages of the HB vaccine were well tolerated and elicited a good immune response in infants of Group A, regardless of the maternal anti-HBs serostatus. EVE did not significantly differ between Groups B and C. Clinicaltrails.gov identifier: NCT02152709 © 2015 Elsevier Ltd. All rights reserved.
Abbreviations: AR, adverse reaction; anti-HBs, hepatitis B surface antibody; CDC, centre of disease control and prevention; CLIA, chemiluminescence assay; CSFDA, China state food and drug administration; DMID, diseases of the national institutes of allergy and infectious diseases; GMC, geometric mean concentration; EPI, expanded program on immunization; EVE, estimated vaccine efficacy; JSCDC, Jiangsu provincial centre of disease control and prevention; HB, hepatitis B; HBIg, hepatitis B immunoglobulin; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; NIFDC, national institute of food and drug control, China; sAR, serious adverse reaction; SUSAR, suspected unexpected serious adverse reaction. ∗ Corresponding author at: Department of Expanded Programmed on Immunization of Jiangsu Provincial Centre of Disease Control and Prevention, 172 Jiangsu Road, Nanjing 21009, Jiangsu Province, China. Tel.: +86 25 83759422; fax: +86 25 83759423. E-mail address: [email protected] (F. Ma). http://dx.doi.org/10.1016/j.vaccine.2015.06.081 0264-410X/© 2015 Elsevier Ltd. All rights reserved.
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G. Kang et al. / Vaccine 33 (2015) 4093–4099
1. Introduction Hepatitis B virus (HBV) infection is a global public health problem; more than 2 billion people have been infected with HBV [1,2]. Chronically infected individuals have an increased lifetime risk for cirrhosis and hepatocellular carcinoma [3]. Neonatal hepatitis B (HB) vaccination is the most effective measure for preventing HBV vertically transmitted infection and its progress into chronicity [4,5]. In 2002, China integrated HB vaccination into the national routine expanded program on immunization (EPI) and has also increased efforts to improve the HB vaccination coverage rate for infants [6]. Both yeast-derived (5 g) and Chinese hamster ovary cell (10 g) recombinant HB vaccines are commonly used for EPI in China. Timely vaccination at birth using the correct dosage and full HB booster vaccination is recommended [7]. For newborns from HB-infected mothers, combined universal vaccination with HB immunoglobulin (HBIg) to block perinatal transmission is recommended [8], although the limited availability of HBIg has presented challenges for the vaccination program. As a result, universal HB vaccination alone has been used in some areas of China [9]. Vaccine studies in healthy young children have shown the efficacies of various HB vaccine dosages in eliciting immune responses against HBV [10,11]. However, the impact of increasing the HB vaccine antigen dosage in infants delivered by healthy and HB-infected women has been poorly characterized. Therefore, in this study, we compared the safety and immunogenicity of 10 and 5 g/0.5 ml recombinant HB vaccine in infants born to HB-uninfected and HBinfected mothers. 2. Materials and methods 2.1. Study design This study was designed as a phase III, controlled, randomized, and single-blinded (subject, investigator, and laboratory staff) clinical trial to assess the safety and immunogenicity of two dosages (10 and 5 g) of recombinant HB vaccine in children born to HBuninfected or HB-infected mothers. The study was approved by the China State Food and Drug Administration (CSFDA) and was conducted by investigators from the Jiangsu Provincial Centre of Disease Control and Prevention (JSCDC). Institutional Review Board approval was obtained from the Ethics Committee of the JSCDC. Written informed consent was obtained from the subject’s parents. 2.2. Subjects The study was conducted in Xiangshui County, Jiangsu Province, China. Beginning in 2008, eligible pregnant women who had been tested positive for HB surface antigen (HBsAg) and/or HB virus e antigen (HBeAg) using enzyme-linked immunosorbent assay (ELISA) within 9 months prior to delivery were included. Postpartum subject data were documented, including age, sex, body weight, Apgar scores, medication use, and other health status parameters. Inclusion criteria for subjects included: healthy newborn following a full-term pregnancy (37–42 weeks gestation), body weight ≥2,500 g, Apgar scores ≥7, and axillary temperature ≤37.0 ◦ C. Newborn exclusion criteria included infectious diseases, nervous system damage after birth, congenital malformations, developmental disorders or serious chronic illness, and thrombocytopenia or other coagulation disorders. Newborns were also excluded if immunoglobulin, especially HBIg, was administered during the clinical trial. Venous blood samples were collected from participating women during pregnancy for HBsAg and HBeAg testing at the local Center
for Disease Control and Prevention (CDC). Newborns were assigned to three groups based on maternal HBsAg and HBeAg status: Group A included newborns of HBsAg-negative mothers; Group B included newborns of HBsAg-positive and HBeAg-negative mothers; and Group C included newborns of HBsAg-positive and HBeAg-positive mothers. The newborns were randomized at a ratio of 1:1 to receive three doses of 10 or 5 g HB vaccine within 24 h after birth (date of vaccination was considered Day 1), at 1 month and at 6 months. 2.3. Vaccine Single doses of 10 and 5 g/0.5 ml HB vaccine were produced by recombinant techniques in Saccharomyces cerevisiae at Beijing Tiantan Biological Products, Beijing, China. All vaccines were administered intramuscularly in the deltoid region by qualified nurses. 2.4. Safety Subjects receiving at least one dose of HB vaccination were included in the analysis of adverse reactions (ARs). Newborns and infants were monitored for immediate ARs for at least 30 min after each vaccine administration. Follow-up AR assessments were performed on Days 1, 2, and 3 after administration of each dose by qualified staff at the local CDC. Parents and guardians were instructed to measure daily the axilla temperature with mercury thermometers and asked to report any ARs to qualified local general practitioners. The latter were asked to record any reported ARs within 1 month after each vaccine dose in the vaccination report booklet. ARs were coded and graded according to the guidelines provided by the CSFDA and the Division of Microbiology and Infectious Diseases of the National Institutes of Allergy and Infectious Diseases (DMID) [12]. Solicited injection site ARs included pain, mucocutaneous, induration, erythema, swelling, and local rash at injection site. The solicited systemic ARs included fever, allergy, mental reactions, vomiting, level of activity, convulsion, crying, diarrhea, nausea, and breast-feeding disorders. Unsolicited systemic ARs were collected as well. Serious ARs (sARs) and suspected unexpected serious adverse reactions (SUSARs) were also assessed throughout the study period. Induration, erythema, swelling, and local rash at injection site were categorized as Grade 1 (50 mm). Fever was categorized as Grade 1 (≥37.1 to
