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中华实验和临床感染病杂志(电子版) ›› 2022, Vol. 16 ›› Issue (06) : 377 -384. doi: 10.3877/cma.j.issn.1674-1358.2022.06.004

论著

乙型肝炎病毒表面抗原阳性母亲所产婴儿乙肝疫苗免疫无/低应答的影响因素
王彩英1, 何明1, 何树新1, 刘玉环1, 杨洪玲1, 易为1(), 庞琳1,()   
  1. 1. 100015 北京,首都医科大学附属北京地坛医院儿科
  • 收稿日期:2022-04-11 出版日期:2022-12-15
  • 通信作者: 易为, 庞琳
  • 基金资助:
    "十三五"重大专项(No. 2018ZX10715005-003-005); 北京市市属医院科研培育计划(No. PX2018080); 首都临床特色应用研究(No. Z131107002213161)

Influencing factors of non- or low-response to hepatitis B vaccine immunity in infants of mothers with hepatitis B virus surface antigen positive

Caiying Wang1, Ming He1, Shuxin He1, Yuhuan Liu1, Hongling Yang1, Lin Pang1,()   

  1. 1. Department of Pediatrics, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
  • Received:2022-04-11 Published:2022-12-15
  • Corresponding author: Lin Pang
引用本文:

王彩英, 何明, 何树新, 刘玉环, 杨洪玲, 易为, 庞琳. 乙型肝炎病毒表面抗原阳性母亲所产婴儿乙肝疫苗免疫无/低应答的影响因素[J/OL]. 中华实验和临床感染病杂志(电子版), 2022, 16(06): 377-384.

Caiying Wang, Ming He, Shuxin He, Yuhuan Liu, Hongling Yang, Lin Pang. Influencing factors of non- or low-response to hepatitis B vaccine immunity in infants of mothers with hepatitis B virus surface antigen positive[J/OL]. Chinese Journal of Experimental and Clinical Infectious Diseases(Electronic Edition), 2022, 16(06): 377-384.

目的

研究乙型肝炎病毒(HBV)表面抗原(HBsAg)阳性孕母所产婴儿发生乙肝疫苗免疫无/低应答的影响因素,为HBV感染母婴阻断随访工作提供临床依据。

方法

本研究为回顾性对照研究,选取2018年12至2020年6月于首都医科大学附属北京地坛医院门诊全程接种乙肝疫苗后1个月,接受HBV母婴阻断随访的766例婴儿为研究对象,根据婴儿HBV表面抗体(hepatitis B surface antibody,HBsAb)水平,将乙肝疫苗免疫应答分为3个层次,即乙肝疫苗免疫无应答(HBsAb < 10 mIU/ml)(7例)、乙肝疫苗免疫低应答(HBsAb:10~99 mIU/ml)(72例)和正常免疫应答(HBsAb ≥ 100 mIU/ml)(687例),共79例婴儿存在乙肝疫苗免疫无/低应答,为研究组,按照1︰2的比例,在正常免疫应答的婴儿中采用随机数表法随机选择158例作为对照组。比较研究组和对照组婴儿在出生史、喂养史、出生时乙肝免疫球蛋白接种剂量以及母亲分娩前HBV DNA载量、HBV标志物、孕期抗病毒指标等差异。两组间正态分布的计量资料比较采用独立样本t检验,非正态分布的计量资料的比较采用非参数检验,率的比较采用Pearson卡方检验、连续性校正卡方检验或Fisher’s确切概率法。将有统计意义的因素纳入多因素Logistic回归分析HBsAg阳性孕母婴儿发生乙肝疫苗免疫无/低应答的影响因素。

结果

入组婴儿共237例,其中女102例(43.04%)、男135例(56.96%),早产儿19例(8.02%),低出生体重儿25例(10.55%),孕母孕28周时HBV DNA ≥ 104 IU/ml者114例(48.10%),61例(25.74%)孕期服用抗病毒药物,分娩前HBV DNA ≥ 104 IU/ml者79例(33.33%),分娩前e抗原(HBeAg)阳性者121例(51.05%)。79例乙肝疫苗免疫无/低应答的婴儿全程接种乙肝疫苗后HBsAb水平为[44.66(20.42,70.42)]mIU/ml,158例正常应答的婴儿HBsAb水平为[848.50(344.23,1 000)]mIU/ml。与对照组相比,研究组早产儿(17.72% vs. 3.16%:χ2 = 15.13、P < 0.001)、低出生体重儿(21.52% vs. 5.06%:χ2 = 20.56、P < 0.001)、未及时添加辅食的婴儿(34.18% vs. 18.99%:χ2 = 6.65、P = 0.01)占比显著升高,其母亲孕28周HBV DNA ≥ 104 IU/ml且服用抗病毒药物者的比率显著降低(27.03% vs. 66.23%:χ2 = 15.44、P < 0.001),而分娩前HBV DNA ≥ 104 IU/ml比率高于对照组(41.77% vs. 29.11%:χ2 = 4.21、P = 0.04);研究组婴儿母亲的HBeAg水平低于对照组[0.37(0.29,891.47)vs. 1.56 (0.32,1 325.68):Z =-2.08、P = 0.04],HBV e抗体(HBeAb)阳性率高于对照组(56.96% vs. 43.04%:χ2 = 4.09、P = 0.04),分娩前HBV DNA ≥ 104 IU/ml同时HBeAg(-)/HBeAb(+)比率高于对照组(13.92% vs. 5.7%:χ2 = 4.61、P = 0.03)。研究组中1例婴儿7月龄发现乙肝疫苗免疫无应答(HBsAb:4.60~6.21 mIU/ml),同时发现HBsAg阳性(0.08~0.34 IU/ml),不排除出生后感染HBV。对以上可能影响婴儿发生乙肝疫苗无/低应答的因素行多因素Logistic回归分析,发现早产儿、低出生体重儿发生乙肝疫苗免疫无/低应答的风险分别为足月适于胎龄儿的3.84和2.82倍(OR = 3.84、P = 0.027、95%CI:1.16~12.69,OR = 2.82,P = 0.046、95%CI:1.02~7.80),分娩前HBV高病毒载量(HBV DNA ≥ 104 IU/ml)孕母婴儿发生免疫无/低应答的风险为孕母低病毒载量的3.15倍(OR = 3.15、P = 0.002、95%CI:1.53~6.48),而分娩前HBeAg水平较高孕母(HBeAg≥ 1 500 S/CO)婴儿发生无/低应答的风险为HBeAg水平较低孕母所产婴儿的0.35倍(OR = 0.35、P = 0.038、95%CI:0.13~0.94)。

结论

早产、低出生体重以及母亲分娩前高病毒载量均为HBsAg阳性孕母所产婴儿发生乙肝疫苗免疫无/低应答的危险因素,而孕母分娩前高水平HBeAg可能是其所产婴儿发生无/低应答的保护因素。

Objective

To investigate the influencing factors of non- or low-response in infants of mothers with hepatitis B virus (HBV) surface antigen (HBsAg) positive after hepatitis B vaccine immunity, and to provide clinical guidance for mother-to-child HBV transmission blocking.

Methods

This was a retrospective case-control study. Total of 766 infants of HBsAg positive mothers who had completed an immunization program of three-dose hepatitis B vaccines, collected in Pediatric Clinic of Beijing Ditan Hospital, Capital Medical University from December 2018 to June 2020, were recruited, and according to the level of HBV surface antibody (HBsAb), they were divided into non-response (HBsAb < 10 mIU/ml, 7 cases), low-response (HBsAb: 10-99 mIU/ml, 72 cases) and normal-response (HBsAb ≥ 100 mIU/ml, 687 cases) to hepatitis B vaccination. Total of 79 infants with non- or low-response to hepatitis B vaccine were collected as study group, and 158 infants who were randomly selected by random digital table method in proportion of 1︰2 from normal-response infants, were collected as control group. History of birth and feeding, the dosage of hepatitis B immune globulin at birth, antepartum HBV DNA and HBV markers, and antiviral therapy in gestation of their mothers were compared between the two groups, respectively. The measometric data of normal distribution were analyzed by independent sample t-test, while measometric data of non-normal distribution were analyzed by nonparametric tests, and comparison of rates were analyzed by Pearson Chi-squared test, Chi-square test for continuity correction and the Fisher’s exact probability method. Statistically significant factors were included in multivariate Logistic regression analysis of the influencing factors of non- or low-response to hepatitis B vaccine immunization in infants of mothers with HBsAg positive.

Results

Total of 237 infants were recruited, including 102 (43.04%) female, 135 (56.96%) male; 19 (8.02%) premature babies, 25 (10.55%) low birthweight babies. There were 114 (48.10%) infants of their mothers with HBV DNA ≥ 104 IU/ml at 28-week gestation, and 61 (25.74%) cases among them received antiviral therapy, while 79 (33.33%) mothers had antepartum HBV DNA ≥ 104 IU/ml, and 121 (51.05%) cases with positive HBeAg. HBsAb level of 79 infants of non- or low-response was [44.66 (20.42, 70.42)] mIU/ml, which was [848.50 (344.23, 1 000)] mIU/ml in 158 infants of normal response. Compared with the control group, the rates of premature babies (17.72% vs. 3.16%: χ2 = 15.13, P < 0.001), low birthweight babies (21.52% vs. 5.06%: χ2 = 20.56, P < 0.001) and babies without seasonable administration of supplementary food (34.18% vs. 18.99%: χ2 = 6.65, P = 0.01) were signficantly higher; the rate of their mothers who had HBV DNA ≥ 104 IU/ml at 28-week gestation and received antiviral therapy was lower (27.03% vs. 66.23%: χ2 = 15.44, P < 0.001), and the rate of the mothers who had antepartum HBV DNA ≥ 104 IU/ml was significantly higher compared with the control group (41.77% vs. 29.11%: χ2 = 4.21, P = 0.04); while the HBeAg level of the mothers was significantly lower in the study group [0.37 (0.29, 891.47) vs. 1.56 (0.32, 1 325.68): Z =-2.08, P = 0.04]. The rates of the mothers who had positive HBV e antibody (HBeAb), and those who had both antepartum HBV DNA ≥ 104 IU/ml and HBeAg(-)/HBeAb(+) were higher in the study group (56.96% vs. 43.04%: χ2 = 4.09, P = 0.04; 13.92% vs. 5.7%: χ2 = 4.61, P = 0.03). In the study group, one infant was found to be HBsAg positive (0.08-0.34 IU/ml), meanwhile, the level of HBsAb was 4.60-6.21 mIU/ml, who was thought infected with HBV after birth. Logistic regression analysis found that the risks of non- or low-response to hepatitis B vaccine in premature or low birthweight babies were 3.84 and 2.82 times of that in appropriate for gestational age term babies, respectively (OR = 3.84, P = 0.027, 95%CI: 1.16-12.69; OR = 2.82, P = 0.046, 95%CI: 1.02-7.80), and the risk in babies of mothers with high antepartum viral load in serum (HBV DNA ≥ 104 IU/ml) was 3.15 times of that in babies of mothers with low antepartum viral load (OR = 3.15, P = 0.002, 95%CI: 1.53-6.48), while the risk in babies of mothers with high antepartum level of HBeAg (HBeAg ≥ 1 500 S/CO) was 0.35 times of that in babies of mothers with low level of HBeAg (OR = 0.35, P = 0.038, 95%CI: 0.13-0.94).

Conclusions

Premature, low birthweight infants and high antepartum viral load in mothers’ serum were the risk factors of non- or low-response to hepatitis B vaccine immunity in infants of mothers with HBsAg positive, but high antepartum level of HBeAg was a protective factor.

表1 研究组和对照组孕母所产婴儿的基本资料[例(%)]
表2 研究组和对照组孕母HBV感染及孕期治疗指标
指标 合计(237例) 研究组(79例) 对照组(158例) 统计量 P
年龄(± s,岁) 29.67 ± 4.06 30.04 ± 4.08 29.46 ± 4.05 t = 0.82 0.41
分娩前HBV DNA [例(%)]          
  ≥ 104 IU/ml 79(33.33) 33(41.77) 46(29.11) χ2 = 4.21a 0.04
  < 104 IU/ml 158(66.67) 46(58.23) 112(70.89)    
孕28周HBV DNA [例(%)]          
  ≥ 104 IU/ml 114(48.10) 37(46.84) 77(48.73) χ2 = 0.08a 0.78
  < 104 IU/ml 123(51.90) 42(53.16) 81(51.27)    
孕28周HBV DNA≥ 104 IU/ml治疗[例(%)]          
  服用抗病毒药物 61(53.51)* 10(27.03)# 51(66.23)& χ2 = 15.44a < 0.001
  未服用抗病毒药物 53(46.49)* 27(72.97)# 26(33.77)&    
HBsAg [例(%)]          
  HBsAg> 250 IU/ml 207(87.34) 70(88.61) 137(86.71) χ2 = 0.17a 0.68
  HBsAg ≤ 250 IU/ml 30(12.66) 9(11.39) 21(13.29)    
HBsAb水平[M(P25,P75),mIU/ml] 0.22(0.06,0.49) 0.22(0.03,0.48) 0.22(0.07,0.49) Z =-0.46 0.64
HBsAb定性[例(%)]          
  HBsAb(+) 3(1.27) 0(0.00) 3(1.90) χ2 = 0.38b 0.54
  HBsAb(-) 234(98.73) 79(100.00) 155(98.10)    
  HBeAg水平[M(P25,P75),S/CO] 1.19(0.31,1287.04) 0.37(0.29,891.47) 1.56(0.32,1 325.68) Z =-2.08 0.04
HBeAg [例(%)]          
  HBeAg(+) 121(51.05) 37(46.84) 84(53.16) χ2 = 0.84a 0.36
  HBeAg(-) 116(48.95) 42(53.16) 74(46.84)    
  HBeAb水平[M(P25,P75),S/CO] 1.28(0.01,46.37) 0.09(0.01,36.31) 1.36(0.01,48.79) Z =-1.66 0.10
HBeAb [例(%)]          
  HBeAb(+) 113(48.09) 45(56.96) 68(43.04) χ2 = 0.09a 0.04
  HBeAb(-) 122(51.91) 32(40.51) 90(56.96)    
HBcAb水平[M(P25,P75),S/CO] 10.04(9.05,10.61) 9.80(9.09,10.56) 10.07(9.05,10.64) Z =-0.93 0.35
HBcAb [例(%)]          
  HBcAb(+) 236(99.58) 79(100.00) 157(99.37) c 1.00
  HBcAb(-) 1(0.42) 0(0.00) 1(0.63)    
分娩前HBeAg(-)/HBeAb(+)且HBV DNA ≥ 104 IU/ml [例(%)]          
  20(8.44) 11(13.92)   χ2 = 4.61a  
  217(91.56) 68(86.08)     0.03
表3 HBsAg阳性母亲婴儿发生乙肝疫苗免疫无/低应答影响因素的多因素Logistic回归分析
表4 一例HBsAg阳性婴儿乙肝免疫应答及母亲HBV DNA载量
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