Losonsky G A, Wasserman S S, Stephens I, Mahoney F, Armstrong P, Gumpper K, Dulkerian S, West D J, Gewolb I H
Center for Vaccine Development, Division of Pediatric Infectious Diseases and Tropical Pediatrics, Department of Pediatrics, University of Maryland, Health Science Facility, Baltimore, MD 21201, USA.
Pediatrics. 1999 Feb;103(2):E14. doi: 10.1542/peds.103.2.e14.
Current American Academy of Pediatrics and United States Public Health Service Immunization Practices Advisory Committee recommendations for hepatitis B immunization in premature infants weighing <2 kg at birth born to hepatitis B surface antigen (HBSAg)-negative mothers are to delay the initiation of vaccination until such infants reach 2 kg or until 2 months of age. This proposal to delay vaccination at birth in these low-risk infants was based on limited studies not conducted in the United States. We sought to reassess current recommendations to delay administration of hepatitis B vaccine in low-risk premature infants by determining the immunogenicity of early hepatitis B vaccination in a US population and identifying variables associated with poor immunogenicity.
A total of 148 infants <37 weeks' gestation born to mothers negative for HBSAg were recruited at birth and stratified to three birth weight groups: <1000 g, 1000 to 1500 g, and >1500 g. Recombinant hepatitis B vaccine was administered within the first week of life, at 1 to 2 months of age, and at 6 to 7 months of age. Serum obtained at birth and after the second and third doses of vaccine was tested for antibody to HBSAg. Variables associated with poor response were sought prospectively by collecting demographic and clinical data.
A total of 118 subjects (83%) completed the study. Postsecond dose sera were available for 117 infants and postthird dose sera were available for 112 infants. The seroprotection rate (attaining >/=10 mIU/mL HBS antibody) after two doses was low (25%) regardless of birth weight; infants weighing <1000 g at birth had the poorest response (11%). The seroprotection response rate after three doses of vaccine increased with birth weight; infants weighing </=1500 g at birth (groups 1 and 2) had lower rates of response (52% and 68%, respectively) than did infants weighing >1500 g at birth (group 3; 84% response rate). The seroprotection response rate of group 3 infants after three doses of vaccine, although low, could not be differentiated from the response rates reported for full-term infants using 95% confidence intervals. Of all infants who did not achieve protective levels of antibody after three doses of vaccine, 96% (26/27) weighed <1700 g at birth. The geometric mean HBS antibody levels in responders were 88 and 386 mIU/mL after two and three doses, respectively. Of 36 children with a birth weight >1500 g, 33 (91%) achieved levels of HBS antibody >100 mIU/mL after three doses of vaccine, compared with 25/35 (71%) of infants with birth weight <1500 g. Using logistic regression analysis, nonresponders were more likely than were responders to have been treated with steroids (26% vs 9%) and to have had a low birth weight (1037 g vs 1455 g). In addition, the seroresponse rate of black infants was more likely than that of white infants to be associated with poor weight gain (falling off 2 percentile ranks in weight) in the first 6 months of life: 22% of black and 60% of white children who failed to gain weight adequately responded to vaccination, compared with 92% of black and 70% of white children who were growing adequately. Of interest, the only infant with a birth weight of >1700 g who did not make protective levels of specific antibody after three doses of vaccine was 2300 g at birth, but had inadequate weight gain in the first 6 months of life.
This study supports current recommendations of the American Academy of Pediatrics and the Centers for Disease Control and Prevention for delaying the initiation of hepatitis B immunization beyond the first week of life for premature infants at low risk for hepatitis B infection, particularly in newborns weighing <1700 g at birth. In addition, we have identified variables other than birth weight that were associated with an inadequate immune response to early hepatitis B vaccination in premature infants, such as poor weight gain in the first 6 months of life
美国儿科学会和美国公共卫生服务免疫实践咨询委员会目前针对出生时体重<2 kg且母亲乙肝表面抗原（HBSAg）阴性的早产儿乙肝免疫接种的建议是，将疫苗接种起始时间推迟至此类婴儿体重达到2 kg或至2月龄。在这些低风险婴儿出生时推迟接种疫苗的这一建议是基于在美国未开展的有限研究。我们试图通过确定美国人群中早期乙肝疫苗接种的免疫原性并识别与免疫原性不佳相关的变量，来重新评估目前针对低风险早产儿推迟接种乙肝疫苗的建议。
共招募了148例孕周<37周且母亲HBSAg阴性的婴儿，出生时将其分为三个出生体重组：<1000 g、1000至1500 g和>1500 g。重组乙肝疫苗在出生后第一周内、1至2月龄以及6至7月龄时接种。采集出生时以及第二剂和第三剂疫苗接种后获得的血清，检测抗HBSAg抗体。通过收集人口统计学和临床数据前瞻性地寻找与反应不佳相关的变量。
共有118名受试者（83%）完成了研究。117例婴儿可获得第二剂疫苗接种后的血清，112例婴儿可获得第三剂疫苗接种后的血清。两剂疫苗接种后血清保护率（抗-HBS抗体达到≥10 mIU/mL）较低（25%），无论出生体重如何；出生时体重<1000 g的婴儿反应最差（11%）。三剂疫苗接种后的血清保护反应率随出生体重增加而升高；出生时体重≤1500 g的婴儿（第1组和第2组）反应率较低（分别为52%和68%），低于出生时体重 >1500 g的婴儿（第3组；反应率为84%）。第3组婴儿三剂疫苗接种后的血清保护反应率虽然较低，但使用95%置信区间无法与足月儿报告的反应率区分开来。在所有三剂疫苗接种后未达到抗体保护水平的婴儿中，96%（26/27）出生时体重<1700 g。反应者两剂和三剂疫苗接种后的抗-HBS抗体几何平均水平分别为88和386 mIU/mL。在36例出生体重>1500 g的儿童中，33例（91%）三剂疫苗接种后抗-HBS抗体水平>100 mIU/mL，而出生体重<1500 g 的婴儿中这一比例为25/35（71%）。使用逻辑回归分析，无反应者比反应者更有可能接受过类固醇治疗（26%对9%）且出生体重较低（1037 g对1455 g）。此外，黑人婴儿的血清反应率比白人婴儿更有可能与出生后头6个月体重增加不佳（体重下降2个百分位）相关：体重增加不足的黑人儿童中有22%、白人儿童中有60%对疫苗接种有反应，而体重增长正常的黑人儿童中有92%、白人儿童中有70%对疫苗接种有反应。有趣的是，唯一一名出生体重>1700 g但三剂疫苗接种后未产生特异性抗体保护水平的婴儿出生时体重为2300 g，但在出生后头六个月体重增加不足。
本研究支持美国儿科学会和疾病控制与预防中心目前的建议，即对于乙肝感染低风险的早产儿，将乙肝免疫接种起始时间推迟至出生后第一周之后，尤其是出生时体重<1700 g的新生儿。此外，我们还确定了除出生体重外，与早产儿早期乙肝疫苗接种免疫反应不足相关的变量，如出生后头6个月体重增加不佳。
