The Chinese Centre for Disease Control and Prevention (CDC) reported that the coverage of three-dose vaccination before age 1 year was 83-99.53% between 2001 and 2017. According to our previous serosurvey, the proportion of seroprotection in 1–14 years old children was 46.03–72.29%, and the rate of anti-HBs < 10 mIU/ml in children ranged from 3.33–25.79% in all age groups. The data were comparable with the CDC survey data of the HBV seroprevalence among different age groups in China.
Hepatitis B vaccine is one of the safest immunizations to prevent HBV infection and reduce the future risk of liver cancer. In this study, all children had completed three-birth-dose HepB. We analyzed their immune response to HepB booster after neonatal immunization. We mainly focused on two questions: whether there is protective immune response in children without anti-HBs (titer < 10mIU/mL); whether or not need a dose of HepB booster in children.
This is the first study to show that protective immunity from neonatal immunization in children persists long on account of the complementary presence of HBV-specific humoral and T-cellular immune response. A detectable T-cell response to HBsAg (85.71%) was also found in anti-HBs negative children (< 10mIU/mL) when measured HBsAg-specific INF-γ, which suggest that protection lasts long. In the study group of Wang RX et al, most anti-HBs negative vaccinees showed positivity in HBsAg specific immune cells response. Leuridan et al demonstrated the activation of immune cells in vaccinees based on cell proliferative response. Long-lasting cellular immunity was also proved by detection of the secretion of cytokines by Th1 and Th2 lymphocytes after HBsAg stimulation. These results confirmed T cell immunity persists long regardless of anti-HBs, which is consistent with our views. In addition, HBsAg-specific T Cell responses showed a trend for an initial increase and then a decrease with age while anti-HBs titers were opposite. After birth, children can mount an immune response against pathogens, but adaptive immune responses are relatively weak and narrowly focused in neonates resulting in T cell hypo-responsiveness. In younger children, HBV-specific T cells are defective and not able to secrete enough IFN‐γ but gradually improves with age. Before and after HepB booster, the tendency of changes in anti-HBs titer is opposed to HBsAg-specific T Cell response in each age group of children. In vaccine development, determining the balance between humoral and cellular response is the key challenge. The complementary existence between protective antibody responses and T-cell responses is important to the persistence of protection from vaccine. So, there is no need to worry about the decline in anti-HBs in population. It is precisely because of this dynamic balance that screening for HBsAg-specific T Cell immunity is not recommended for the general population. The routine screening for anti-HBs in vaccinees is sufficient to evaluate the protection afforded by HepB.
One dose of HepB booster is efficient enough. All individuals who had received an HepB booster demonstrated protective anti-HBs and enhanced HBsAg-specific T cell responses at 4 weeks post-booster. We found that humoral and T cellular immune response to Hepatitis B vaccine booster depended on the pre-booster anti-HBs titer. Only 56.25% of children with pre-booster anti-HBs < 10mIU/ml demonstrated anti-HBs ≥ 1000mIU/mL at 4 weeks post-vaccination. Those with pre-booster anti-HBs < 10mIU/ml were less likely to produce more anti-HBs compared to anti-HBs= [10,100) mIU/ml. Equally, the intensity of T-cellular immunoreactivity post-booster also depended on the pre-booster anti-HBs titer. After booster, the quantity of HBsAg-specific IFN-γ–producing T cells in children with pre-booster anti-HBs= [10,100) mIU/ml significantly increased compared to anti-HBs < 10mIU/ml. This phenomenon has been observed in other previous studies. Therefore, a series of 3-dose of HepB at 0, 1 and 6 months and the long-term immunity obtained by vaccine are of seminal importance.
Although immune memory for HepB exist persistently in children, HepB booster is recommended to children without anti-HBs in the endemic areas due to the increasing risk of exposure to HBV. Currently, although the available evidence does not provide a compelling basis for recommending a booster dose of Hepatitis B vaccine[6, 24] and chronic HBV infection rarely occurs after primary immunization even when anti-HBs is lower than 10 mIU/mL[6, 25]. However, according to our previous study, the prevalence of HBsAg and anti-HBc began to rise significantly in the 11–16-year-old children compared with 1-10-year-old children (from 0.46–1.40% and from 5.69–7.8% respectively). This may suggest that the risk of exposure to hepatitis B virus is increased in > 10 years old children, and more attention should be paid to this age group, and HepB booster should be conducted to reduce the risk of breakthrough infection. Some individuals with anti-HBs < 10mIU/ml who are at high risk of HBV exposure will require only one HepB booster to achieve protective anti-HBs. Hepatitis B vaccine has been continuously optimized since it was launched in 1986. The immunization strategy of HepB in China has been continuously improved and its safety has been confirmed. Furthermore, serosurvey shows that the prevalence of HBV is significantly reduced[2–4, 26], which is closely related to hepatitis B vaccination, which further proves that vaccination against hepatitis B is an economic and effective means to prevent and control hepatitis B.
In addition to T cellular immune response, B cells also participate in HBV vaccine response by generating a protective level of anti-HBs. Our results demonstrated that total B cells including some antibody-secreting cells decreased dramatically after booster. Furthermore, reductions in plasmablasts, memory B cells and unswitched memory B cells were observed in individuals, especially in children with pre-booster anti-HBs= [10,100) mIU/ml. After vaccination, there is rapid activation of circulating memory cells to terminally differentiate into low-affinity plasma or formation of germinal centers, which mediate further proliferation and selection for antigen binding later[28, 29]. In this study, there was a decline in memory B cells, unswitched memory B cells and plasmablasts appearing in the peripheral blood post-booster. But subjects did show an increase in anti-HBs in the blood, so they must have produced antibody-secreting cells at some time before blood collection which may be high-affinity.
In conclusion, this study had comprehensively analyzed humoral and cellular immune response to Hepatitis B vaccine booster in children before and after neonatal immunization. Protection from primary HBV immunization persists long on account of the complementary presence of HBV-specific humoral and T-cellular immune response. In addition, we demonstrated that one dose of HepB booster is efficient enough to produce protective anti-HBs and enhance HBsAg-specific T cell responses. As the most economical and effective way, HepB booster immunization could be recommended to children without anti-HBs in the endemic areas to prevent HBV infection.