Qu Chunfeng, Chen Taoyang, Fan Chunsun, Zhan Qimin, Wang Yuting, Lu Jianhua, Lu Ling-ling, Ni Zhengping, Huang Fei, Yao Hongyu, Zhu Jian, Fan Jian, Zhu Yuanrong, Wu Zhiyuan, Liu Guoting, Gao Wenhong, Zang Mengya, Wang Dongmei, Dai Min, Hsia Chu Chieh, Zhang Yawei, Sun Zongtang
State Key Lab of Molecular Oncology, Cancer Institute/Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
Qidong Liver Cancer Institute, Qidong, Jiangsu Province, China.
PLoS Med. 2014 Dec 30;11(12):e1001774. doi: 10.1371/journal.pmed.1001774. eCollection 2014 Dec.
Neonatal hepatitis B vaccination has been implemented worldwide to prevent hepatitis B virus (HBV) infections. Its long-term protective efficacy on primary liver cancer (PLC) and other liver diseases has not been fully examined.
The Qidong Hepatitis B Intervention Study, a population-based, cluster randomized, controlled trial between 1985 and 1990 in Qidong, China, included 39,292 newborns who were randomly assigned to the vaccination group in which 38,366 participants completed the HBV vaccination series and 34,441 newborns who were randomly assigned to the control group in which the participants received neither a vaccine nor a placebo. However, 23,368 (67.8%) participants in the control group received catch-up vaccination at age 10-14 years. By December 2013, a total of 3,895 (10.2%) in the vaccination group and 3,898 (11.3%) in the control group were lost to follow-up. Information on PLC incidence and liver disease mortality were collected through linkage of all remaining cohort members to a well-established population-based tumor registry until December 31, 2013. Two cross-sectional surveys on HBV surface antigen (HBsAg) seroprevalence were conducted in 1996-2000 and 2008-2012. The participation rates of the two surveys were 57.5% (21,770) and 50.7% (17,204) in the vaccination group and 36.3% (12,184) and 58.6% (17,395) in the control group, respectively. Using intention-to-treat analysis, we found that the incidence rate of PLC and the mortality rates of severe end-stage liver diseases and infant fulminant hepatitis were significantly lower in the vaccination group than the control group with efficacies of 84% (95% CI 23%-97%), 70% (95% CI 15%-89%), and 69% (95% CI 34%-85%), respectively. The estimated efficacy of catch-up vaccination on HBsAg seroprevalence in early adulthood was 21% (95% CI 10%-30%), substantially weaker than that of the neonatal vaccination (72%, 95% CI 68%-75%). Receiving a booster at age 10-14 years decreased HBsAg seroprevalence if participants were born to HBsAg-positive mothers (hazard ratio [HR] = 0.68, 95% CI 0.47-0.97). Limitations to consider in interpreting the study results include the small number of individuals with PLC, participants lost to follow-up, and the large proportion of participants who did not provide serum samples at follow-up.
Neonatal HBV vaccination was found to significantly decrease HBsAg seroprevalence in childhood through young adulthood and subsequently reduce the risk of PLC and other liver diseases in young adults in rural China. The findings underscore the importance of neonatal HBV vaccination. Our results also suggest that an adolescence booster should be considered in individuals born to HBsAg-positive mothers and who have completed the HBV neonatal vaccination series. Please see later in the article for the Editors' Summary.
全球已实施新生儿乙肝疫苗接种以预防乙肝病毒（HBV）感染。其对原发性肝癌（PLC）和其他肝脏疾病的长期保护效果尚未得到充分研究。
启东乙肝干预研究是1985年至1990年在中国启东开展的一项基于人群的整群随机对照试验，纳入39292名新生儿，他们被随机分配至疫苗接种组，其中38366名参与者完成了乙肝疫苗全程接种；另有34441名新生儿被随机分配至对照组，该组参与者既未接种疫苗也未接受安慰剂。然而，对照组中有23368名（67.8%）参与者在10至14岁时接受了补种疫苗。截至2013年12月，疫苗接种组共有3895名（10.2%）参与者失访，对照组有3898名（11.3%）参与者失访。通过将所有剩余队列成员与一个成熟的基于人群的肿瘤登记处进行关联，收集了PLC发病率和肝脏疾病死亡率的信息，直至2013年12月31日。在1996 - 2000年和2008 - 2012年进行了两次关于HBV表面抗原（HBsAg）血清流行率的横断面调查。疫苗接种组两次调查的参与率分别为57.5%（21770名）和50.7%（17204名），对照组分别为36.3%（12184名）和58.6%（17395名）。采用意向性分析，我们发现疫苗接种组的PLC发病率、严重终末期肝病和婴儿暴发性肝炎的死亡率显著低于对照组，有效率分别为84%（95%CI 23% - 97%）、70%（95%CI 15% - 89%）和69%（95%CI 34% - 85%）。补种疫苗对成年早期HBsAg血清流行率的估计有效率为21%（95%CI 10% - 30%），远低于新生儿疫苗接种的有效率（72%，95%CI 68% - 75%）。如果参与者的母亲为HBsAg阳性，在10至14岁时接种加强针可降低HBsAg血清流行率（风险比[HR] = 0.68，95%CI 0.47 - 0.97）。解释研究结果时需考虑的局限性包括PLC患者数量较少、参与者失访以及随访时未提供血清样本的参与者比例较大。
研究发现，新生儿乙肝疫苗接种可显著降低儿童期至青年期的HBsAg血清流行率，进而降低中国农村青年患PLC和其他肝脏疾病的风险。这些发现强调了新生儿乙肝疫苗接种的重要性。我们的结果还表明，对于母亲为HBsAg阳性且已完成新生儿乙肝疫苗全程接种的个体，应考虑在青春期接种加强针。请参阅本文后面的编辑总结。
