Elsevier

Vaccine

Volume 30, Issue 39, 24 August 2012, Pages 5708-5713
Vaccine

Association of polymorphisms of cytokine and TLR-2 genes with long-term immunity to hepatitis B in children vaccinated early in life

https://doi.org/10.1016/j.vaccine.2012.07.010Get rights and content

Abstract

Hepatitis B vaccine is effective in preventing hepatitis B virus (HBV) infection. However, 5–10% of vaccinees fail to produce sufficient antibody against hepatitis B surface antigen (anti-HBs). In this study, we investigated the association of genetic polymorphisms with long-term response to hepatitis B vaccine in 301 children who received the vaccine 5–7 years ago. Of them, 86 (28.6%) had anti-HBs <10 mIU/ml (group A) and 215 (71.4%) had anti-HBs ≥10 mIU/ml (group B). While the frequencies of T allele and TT genotype in single nucleotide polymorphisms (SNP) rs2243250 and rs2070874 of interleukin (IL)-4 in group A were higher than those in group B (all P < 0.05 and q < 0.2), the frequency of C allele in SNP rs2243250, rs2070874 and rs2227284 of IL-4 in group B was higher than that in group A (all P < 0.05 and q < 0.2). None of 11 other SNP in IL-2, IL-10, IL-1β, IL-13, IL-12B, tumor necrosis factor-α, and toll-like receptor-2 genes was found to associate with anti-HBs response. SNP rs2070874 was associated with humoral response to hepatitis B vaccine after analyzed by multivariable logistic regression analysis (P = 0.015). The haplotype TT defined by SNP rs2243250 and rs2070874 in IL-4 was associated with the poor humoral response (adjusted P = 0.037). Our findings demonstrate that IL-4 gene polymorphisms may affect the long-term immune response to hepatitis B vaccine.

Highlights

► We study the role of gene polymorphisms in immune response to hepatitis B vaccine. ► The T allele and TT genotype in IL-4 (−590, −33) are associated with poor response. ► The C allele in IL-4 (−590, −33, +2979) is associated with good response. ► Eleven other sites were not associated with the immune response. ► Polymorphisms in IL-4 gene may influence the long-term immune response.

Introduction

Hepatitis B virus (HBV) infection is a worldwide health problem. Hepatitis B vaccine, composed of hepatitis B surface antigen (HBsAg), is effective in preventing HBV infection. Vaccination with three-dose series on a 0-, 1-, 6-month schedule induces long-term protection in most vaccinees for more than two decades [1], [2]. Since the introduction of universal vaccination in infants, chronic HBV infections have been substantially reduced in children [3], [4]. However, the vaccine-induced immunity protection is inadequate in 5–10% vaccinees [5], [6]. Deficiency of enough protective immunity poses the risk of infection with HBV.

Variation in immune response to vaccine is influenced by several factors such as age, gender, smoking and immunologic tolerance [7]. In addition, genetic factor is also considered to be important in the production of vaccine induced immunity [8], [9]. A number of studies about correlations between immune response to hepatitis B vaccine and polymorphisms of human leukocyte antigen [10], [11], [12], [13], [14], [15], [16], [17], immunoregulatory cytokine genes [18], [19], [20], [21], [22], cytokine receptor genes [22], [23], or toll-like receptors (TLR) genes [22] have been reported. These studies mostly grouped the participants based on the peak antibody against hepatitis B surface antigen (anti-HBs) levels, which usually occur 1–2 months after the third vaccine dose. The peak anti-HBs level may indicate the vaccine efficacy, while the duration of hepatitis B vaccine-induced immunity could reflect long-term antibody protection. Recently, the influence of 3 single nucleotide polymorphisms (SNP) in interleukin (IL)-10 and 6 IL-10 genetic haplotypes on immune response to hepatitis B vaccine has been analyzed in 454 students born 20 years ago in Taiwan. This study found that ATA/ACC genotype defined by SNP (rs1800896, rs1800871 and rs1800872) in IL-10 was associated with poor antibody response to hepatitis B vaccine, while ACC/ACC genotype was associated with good response [24]. In the present study, we investigated the association of nucleotide variants of the cytokine genes and TLR-2 gene with the duration of hepatitis B vaccine-induced immunity in 301 healthy children who received three doses vaccination 5–7 years ago.

Section snippets

Subjects

Since 2002, vaccination against hepatitis B has been integrated into the China's Planned Vaccination Program; all newborns in China may receive 3 doses (5 μg HBsAg/dose) charge-free recombinant (yeast) hepatitis B vaccine [3]. The first dose is used in the hospital within 24 h after birth and the second and third doses are administered in the local Children's Immunization Clinic at age of 1 and 6 months respectively. The vaccine, licensed by Merck & Dohme Co. through the technology transfer, is

Characteristics of participants

The overall characteristics of the study subjects are listed in Table 2. The positive rates and median levels of anti-HBs had no statistical difference between boys and girls respectively, indicating no gender difference in response to hepatitis B vaccine. The average age and boy-to-girl ratio were comparable between group A and group B respectively. We also tested the correlation between age and anti-HBs levels using spearman correlation with SPSS program, and found no correlation (correlation

Discussion

Numerous factors influence the immune response to vaccine. In recent years, genetic factors, such as cytokine and TLR genes, are reported to play important roles in regulating the immune response to vaccine. In the present study, the associations between the duration of immune response to hepatitis B vaccine and 14 SNP were examined in 301 healthy children. Out of the 14 SNP, we found the T allele and the TT genotype in SNP rs2243250 and rs2070874 in IL-4, and the A allele in SNP rs2227284 in

Acknowledgments

We thank Dr. Biyun Xu for the excellent statistical analyses. We also thank Ms. Jihong Sun, Ms. Fengxiang He, and members in Family Planning Institutes of Xuzhou, Tongshan, Ganyu, Lianyungang, Sheyang, Baoying, Qidong, Yangzhou, Liuhe, Zhenjiang, Liyang, Wuxi, Wujiang, and Nanjing for blood sampling and assistance in collecting relevant information. This study was supported by Special Grants for Principal Investigators (RC2007005 to YHZ), for Leading Principal Investigators (LJ200628 to YH),

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    These authors contributed equally to this work.

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