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Qu et al. Etiological prevention of liver cancer

period when HBV vaccine was not available in any rural chronic liver diseases, including liver cancer and chronic
areas of China. The neonates in the control group did liver failure, was significantly lower in the neonatal
not receive the HBV vaccine at birth, and the neonates vaccination group than in the control group (HR = 0.30,
in the vaccination group received the three-dose 95% CI: 0.11-0.85), and the efficacy was 70% (95% CI:
plasma-derived HB vaccine, which were manufactured 15-89%) [33] . The study population was still young and
and donated by the Merck Company through the WHO. incidence and deaths were very low. Remarkably, in
The first dose (5 μg) of HBV vaccine was administered the QHBIS participants, no differences in liver cancer
within 24 h after birth, followed by two doses (5 μg/dose) incidence and mortality of chronic liver failure were
at 1 and 6 months of age, respectively [18,33] . Due to the observed by age 30 years between the individuals who
shortage of hepatitis B immunoglobulin (HBIG), all the received and those who did not receive the catch-up
newborns were given the vaccine only regardless of vaccination [33] . These results further addressed the
their maternal HBsAg status. The protocol can be found importance of HBV vaccination on neonates in highly
via https://doi.org/10.1371/journal.pmed.1001774.s003. HBV endemic regions.

During that time, it was considered ethically justifiable Risk factors related to vaccination failures in
(to have neonates in a control group that did not receive children and HBV vaccination guideline by
the HBV vaccine) given that the plasma-derived HBV Chinese Center for Disease Control
vaccine and recombinant vaccine was not universally HBV vaccination has been recommended universally
available in China. However, in June 2000, the Qidong for prevention of HBV infection and liver diseases. As
Center for Disease Control and Prevention (CDC) of 2012, 183 (94%) of the 193 member states have
issued a Notification (File No. 2000-010) regarding initiated a HBV vaccination program, with an average
HBV catch-up vaccination and booster (https://doi. of 79% for the third dose vaccine coverage in infants
org/10.1371/journal.pmed.1001774.s004). Children born worldwide (www.who.int/mediacentre/factsheets/fs378/
in 1986-1990 and randomized into the control group of en). Current data from different areas demonstrated
QHBIS received 3 doses of recombinant HBV vaccine that vaccination is very efficacious in decreasing the
at age 10-14 years, and those in the vaccination group HBsAg seroprevalence in children and in preventing
received 1 dose of recombinant HBV vaccine at age 10- the devastating complications of HBV infection in young
14 years [33] . adults [32,33,55-57] .

This cohort provides us a unique opportunity to The vaccination failure in children was found mainly due
examine the efficacy of HBV vaccination administered to being born to HBeAg-positive HBsAg carrier mothers,
at different ages against liver cancer and other liver the mother-to-child transmission (MTCT) [23,58-60] . It
diseases. To reflect the real world situation of HBV had been reported that the protective efficacy of HBV
vaccination, participants who were involved in the pilot vaccination was enhanced by co-administration of HBIG
study were no longer included in our analysis [33,54] . The among the neonates who were born to HBsAg-positive
30-year follow-up study demonstrated that more than mothers. Current recommendations strongly suggest
72% efficacy of neonatal vaccination against chronic screening pregnant women, and adding on HBIG to the
HBV infection in adulthood was achieved. However, newborns if the mother is positive for HBsAg, regardless
when catch-up HBV vaccination was administered to of the HBeAg status [23] . For neonates born to the HBeAg-
the control group at age 10-14, the protection efficacy positive HBsAg carrier mothers, another important issue
was only 21% (95% CI: 10-30%), substantially weaker affecting the efficacy of HBV vaccination is the timely
compared to neonatal vaccination, and highlighting the birth dose of the vaccine. The delay in this initial dose
crucial importance of HBV vaccination on neonates showed an increased risk of infection in children [61] .
against chronic HBV infection in highly HBV endemic Premature gestation ages or low birth weights also
regions [33] . affected the vaccination efficacy [6,63] . The administration
of a recombinant HBV vaccine shortly after birth is less
Using brain tumor as the negative control, the incidence immunogenic in preterm infants weighing < 1,800 g
rates between the vaccination group (0.52/10 ) and the at birth than in full term infants. Therefore, it was
5
control group (0.71/10 ) were similar. However, liver suggested that the first dose of the vaccine in HBsAg-
5
cancer cases were only diagnosed in the control group negative mother’s infants weighing < 2,000 g might be
when the participants reached 20 years or older. The administrated until they reached 2,000 g, or alternatively,
incidence rate in the vaccination group was 0.71/10 5 until one month old [23] .
person-year, and it was 1.41/10 person-year in the
5
control group. The protective efficacy was 84% against Based on the practices and experiences conducted in
HBV-related liver cancer development in young adults different areas, the National Health and Family Planning
< 30 years. The mortality rate of severe end-stage Commission of the People’s Republic of China issued
232 Hepatoma Research ¦ Volume 3 ¦ October 25, 2017