By the end of 2015, 185 countries had implemented universal vaccination against hepatitis B in all newborn infants to prevent hepatitis B virus (HBV) infection. Whether a booster dose of hepatitis B vaccine is required in adolescence or young adulthood remains controversial, although booster vaccination is generally considered unnecessary, even when hepatitis B surface antibody (anti-HBs) levels decline to <10 mIU/ml (
Gara et al., 2015
, Bruce et al., 2016
). A recent editorial in the International Journal of Infectious Diseases (Carmody, 2017
) referred to an article by Wang et al. published in Vaccine (Wang et al., 2017
), and pointed out that it is time to re-evaluate the effect of the adolescent booster of hepatitis B vaccine. The author of the editorial considered that children of hepatitis B surface antigen (HBsAg)-positive mothers are less protected from HBV infection in young adulthood with the neonatal three-dose series of hepatitis B vaccine, and that a booster dose in early adolescence would be beneficial for these children.Indeed, based only on the data presented in the article by
Wang et al., 2017
, booster vaccination does appear to be required. Wang et al. reported that, of 9786 participants who received neonatal vaccination and were HBsAg-negative in childhood (10–11 years old, 1996–2000), 50 (0.51%) were identified with chronic HBV infection in young adulthood (23–28 years old, 2010–2014). Based on the mother’s HBsAg status, 28 (2.99%) of 936 uninfected children born to HBsAg-positive mothers and 22 (0.25%) of 8850 uninfected children born to HBsAg-negative mothers became HBV carriers in young adulthood. Among these 936 uninfected children born to HBsAg-positive mothers, 12 (2.12%) of 566 children with positive anti-HBs and 16 (4.32%) of 370 children with negative anti-HBs became carriers in young adulthood. Furthermore, the authors assessed the effect of booster vaccination at 10–11 years old on HBV infection status at 23–28 years old. The results showed that the HBsAg prevalence in young adults born to HBsAg-negative mothers had no significant difference in the following four subgroups: anti-HBs-positive with a booster (9/3965, 0.23%), anti-HBs-positive without a booster (1/1012, 0.10%), anti-HBs-negative with a booster (7/2736, 0.26%), anti-HBs-negative without a booster (5/1138, 0.44%). Among young adults born to HBsAg-positive mothers, the HBsAg prevalence in the above four subgroups was 2.01% (9/447), 2.52% (3/119), 3.09% (8/259), and 7.21% (8/111), respectively; the prevalence in adults who were anti-HBs-negative and did not receive a booster in childhood was significantly higher than that in any other subgroup.However, because several critical issues in the study by
Wang et al., 2017
are not clearly described and some results are obviously exceptional, I consider that the clinical implications of this study are obscure in the assessment of the effect of the adolescent hepatitis B booster vaccine.First, whether the two surveys (2010–2014 and 1996–2000, respectively) included the same participants is questionable. The authors mentioned that 9786 vaccinated individuals were tested both in childhood (10–11 years old, 1996–2000) and young adulthood (23–28 years old, 2010–2014), but the statement that “a total of 6132 and 6067 individuals had stored serum samples for 10–11 year time-point and 23–28 year time-point respectively” raises the question of whether these samples collected in the two surveys were from the same subjects. Only for those who were tested both in childhood and in adulthood may the hepatitis B serological marker results be reliably compared.
Based on a closely related article by the same authors (
Qu et al., 2014
), the study initially included a total of 38 366 vaccinated infants during 1985–1990, and two cross-sectional surveys were conducted in 1996–2000 and 2008–2012, respectively, which correspond to the same survey periods in the article by Wang et al., 2017
. The HBsAg prevalence was 2.16% (470/21 770) in children during 1996–2000 and 1.83% (315/17 207) in young adults during 2008–2012. It is also unknown whether the two surveys included the same participants, since only 56.7% (21 770/38 366) and 50.7% (17 207/33 947) were tested in the first and second surveys, respectively. Based on the report of Wang et al., 2017
, 0.51% (50/9786) of uninfected children in 1996–2000 caught a new infection and became carriers before the second survey. Logically, one may assume that the young adults would have a higher HBV prevalence due to the newly developed chronic infection after childhood, but the actual prevalence was reduced (from 2.16% to 1.83%); the authors attributed the lower prevalence in young adults to the natural clearance of HBsAg (Qu et al., 2014
). If the de novo HBsAg prevalence of 0.51% occurred after 2000 (Wang et al., 2017
) and the HBsAg-positive rate of 1.83% in the young adults during 2008–2012 (Qu et al., 2014
) truly reflects the prevalence, it means that only 1.32% (1.83% minus 0.51%) HBsAg prevalence in the young adults (2008–2012) was derived from childhood (1996–2000). Based on these results, one may calculate the cumulated HBsAg clearance rate between childhood and young adulthood in this population: as high as 38.9% ((2.16%–1.32%)/2.16%) of chronic HBV infections spontaneously cleared HBsAg. This is an exceptionally high clearance rate (annual ∼2.6%) in adolescents and young adults. The clearance of HBsAg in childhood and adolescence seldom occurs. A Japanese study showed that none of 548 children diagnosed with chronic HBV infection under 15 years of age underwent HBsAg clearance during 7.8 years of follow-up (Takano et al., 2017
). Of 349 HBV-infected children identified at a mean age of 8.4 years in Taiwan, only 12.0% spontaneously cleared HBsAg during 20.6 years of follow-up, with an annual rate of 0.58% and a cumulated HBsAg clearance rate of 7.62% between the ages of 10 and 25 years (Chiu et al., 2014
).Therefore, without the guarantee of the same participants having been investigated in the two surveys, the HBsAg prevalence acquired in the two surveys just reflects the overall HBV carrier rates in this population, but cannot be used to calculate the clearance rate (
Qu et al., 2014
), as well as the prevalence of newly developed chronic HBV infection (Wang et al., 2017
).Second, Wang et al. reported that 2.12% (12/566) of uninfected children who were anti-HBs-positive were found to be HBV carriers in young adulthood, and even in anti-HBs-positive children who received a booster, 2.0% became carriers (
Wang et al., 2017
). These findings indicate that chronic breakthrough infection in the presence of anti-HBs occurred frequently, which is very unusual. Indeed, chronic HBV infection in the offspring of HBsAg-positive mothers, particularly those with high HBV DNA levels or positive for hepatitis B e antigen (HBeAg), may occur even after passive (hepatitis B immunoglobulin, HBIG) and active (hepatitis B vaccine) immunoprophylaxis; however, the infection usually occurs perinatally. Established chronic breakthrough infection in the presence of anti-HBs rarely occurs, except for infection with mutant virus.Lu et al., in a study from Taiwan, reported that during 15 years of observation, one (1.3%) of 78 vaccinated children of HBsAg- and HBeAg-positive mothers (genotype B) was diagnosed as an HBV carrier (mixed genotypes B and C, no mutation) at 15 years of age; the child was HBsAg-negative at 7 years old, indicating that infection occurred between the ages of 7 and 15 years. However, it is unknown whether the child was infected in the presence or absence of anti-HBs, since his anti-HBs was only 21 mIU/ml at 1.5 years old (
Lu et al., 2004
). In Thailand, none of 87 vaccinated infants of HBsAg-positive mothers became HBV carriers during 20 years of follow-up (Poovorawan et al., 2011
). A 30-year prospective observational study performed in Hong Kong that initially enrolled 1086 infants born to HBsAg-positive mothers and vaccinated after birth, showed that none of the tested participants had a chronic infection after 3 years of age, although the proportion of anti-HBs ≥10 mIU/ml declined from 91.2% at year 1 to 37.4% at year 30 (Lin and Wong, 2013
). Not until 2009 was a case of genuine acute hepatitis B reported; this occurred in a vaccinated homosexual man who was positive for anti-HBs (Boot et al., 2009
).Third, the finding that as high as 10% (5/50) of children who were negative for HBsAg and positive for hepatitis B core antibody (anti-HBc) became HBsAg carriers in young adulthood is also exceptional. Whether these anti-HBc-positive children were also anti-HBs-positive is not known, as the authors did not mention this (
Wang et al., 2017
); if positive, it should be nearly impossible to acquire a novel HBV infection except mutant virus. The authors used occult HBV infection (OBI) to explain the result (Shahmoradi et al., 2012
), but OBI is extremely low in infants of HBsAg-positive mothers (Liu et al., 2014
), and most of the reported OBI cases in vaccinated infants or children result from occult cross-contamination (Zhou, 2016
). Actually, the same authors reported this high proportion of OBI in vaccinated children from the same area (Xu et al., 2010
), but more than half of the OBI was caused by cross-contamination, as evidenced by 51.2% of isolates with an identical HBV sequence; this is impossible in different individuals except if they were infected with the same virus. Additionally, anti-HBc positivity in the absence of HBsAg usually indicates a resolved infection, with or without the existence of virus in the liver. Reactivation of HBV in such subjects is rarely seen in those who are immunocompetent, especially in young subjects.Fourth, Wang et al. reported that only 82 (34.17%) of the 240 anti-HBc-positive children remained anti-HBc-positive in young adulthood (
Wang et al., 2017
), indicating that as high as 66% of anti-HBc positivity turned out to be negative during approximately 15 years. This is against the general notion that anti-HBc, once produced by natural HBV infection, is usually maintained for decades, and even life-long (Seeff et al., 1987
). Although false-positive results may occur in the detection of anti-HBc, the reagents from Roche Diagnostics GmbH used in a Cobas e-601 system (Wang et al., 2017
) would be unlikely to have so high a false-positive rate. Thus, one may raise the question of whether the samples were from the same subjects or the samples were mismatched in the two surveys.Fifth, close contact between mother and child usually occurs during infancy and young childhood and this contact decreases as the child grows up. More importantly, approximately 10% of the fathers of these children born to HBsAg-negative mothers were also HBsAg-positive, since the HBsAg prevalence in the mothers was approximately 9.6% (
Wang et al., 2017
) and Chinese males have a relatively higher HBsAg prevalence than Chinese females (Liang et al., 2009
). Children at the age of 10–11 years and in adolescence actually have comparable contact with their mothers and fathers. However, the study by Wang et al., 2017
showed that the adolescent booster vaccination appeared to be beneficial for children of HBsAg-positive mothers, but not for children of HBsAg-negative mothers. It is difficult to find an explanation for these results.Last, it should also be stressed that neonatal vaccination reported in the study by
Wang et al., 2017
was not verified based on the vaccination cards, but on whether the birth place was located in ‘vaccination towns’ (Qu et al., 2014
). In real-life practice, even though the ‘vaccination towns’ were assigned, it would still be difficult to vaccinate all infants in the towns because of preterm birth, neonatal illness, maternal fear of the adverse effects associated with the vaccine, and other factors. Indeed, the same authors reported an HBsAg prevalence of 2.16% in the vaccinated children from the same area during 1996–2000 (Qu et al., 2014
). However, recent surveys have shown that the HBsAg prevalence in children born after the implementation of universal hepatitis B vaccination in China is 0.35–1.0% (Liang et al., 2009
, Yonghao et al., 2015
, Lin et al., 2016
). Although the relatively higher HBsAg prevalence may be explained in part by the unavailability of HBIG for infants of HBsAg-positive mothers (Wang et al., 2017
), studies have shown that the hepatitis B vaccine alone has comparable protective efficacy to the combination of HBIG and vaccine in infants born to HBsAg-positive but HBeAg-negative mothers (Yang et al., 2003
, Chen et al., 2012
, Lu et al., 2017
). Together, these results suggest that the vaccination might have been suboptimal in the study population. Additionally, the anti-HBs response after the primary vaccination was not presented, and the non-response to vaccination and loss of detectable anti-HBs in the children were not distinguished, which makes the interpretation of the results more complicated.In brief, numerous investigations have demonstrated that a full primary vaccination course with three doses of hepatitis B vaccine may provide long-term protection against chronic HBV infection (
Gara et al., 2015
, Bruce et al., 2016
, FitzSimons et al., 2013
, European Consensus Group on Hepatitis B Immunity, 2000
, Van Damme, 2016
). To date, no convincing data have been documented to support the necessity of a booster dose of hepatitis B vaccine in children or adolescents vaccinated successfully. Care should be taken when interpreting exceptional data, such as those found in the article by Wang et al., which are difficult to explain logically. Whether a booster dose of hepatitis B vaccine in adolescents is necessary for those high-risk individuals with anti-HBs <10 mIU/ml requires further investigation.Funding
This work was supported by the Jiangsu Provincial Department of Health (H201537), the Science and Technology Department of Jiangsu Province (BK20161105), and the National Natural Science Foundation of China (81672002). The funders had no role in the study design, data collection, analysis, and interpretation, writing, or submission of the article.
Conflict of interest
No conflict of interest to declare.
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Article info
Publication history
Published online: November 11, 2017
Received:
July 19,
2017
Corresponding Editor: Eskild Petersen, Aarhus, DenmarkIdentification
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© 2017 The Author. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases.
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- Response to Letter to the Editor re ‘Be cautious for exceptional results in evaluating the effect of adolescent booster of hepatitis B vaccine’International Journal of Infectious DiseasesVol. 66
- PreviewIn 1982, two plasma-derived hepatitis B vaccines, which were prepared from plasma of chronic HBsAg carriers from France and the United States, were licensed. From Jan 30 to Feb 4, 1983 a WHO Scientific Group meeting was convened on the discussion of HBV vaccination for prevention of primary liver cancer (Zuckerman et al., 1983). Millions of the first-generation plasma-derived vaccines have been administrated in neonates, infants, children and adults and the effectiveness and safety records are excellent.
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