Significance and anamnestic response in isolated hepatitis B core antibody-positive individuals 18 years after neonatal hepatitis B virus vaccination in Taiwan

Abstract

Aim

To investigate the significance of isolated hepatitis B core antibody (anti-HBc) and to analyze the response to hepatitis B virus (HBV) booster vaccination in young adults with isolated anti-HBc who had been fully vaccinated with HBV vaccine as infants.

Materials and methods

We screened 1734 new university entrants who had been fully vaccinated against HBV in infancy for the presence of hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti-HBs), and anti-HBc upon university entry. Results positive for isolated anti-HBc were reconfirmed by testing for the presence of HBsAg and anti-HBc once more, and further evaluated for anti-HCV, anti-HIV, and HBV DNA status 6 months later. Students were also offered HBV booster vaccinations at that time. Geometric mean titers (GMT) of anti-HBs after one booster dose of HBV were compared between students with isolated anti-HBc and students with HBV naïve status.

Results

The overall prevalence of isolated anti-HBc in our student cohort was 1.2% (21 of 1734). No evidence of occult HBV infection was observed. A “booster” anamnestic response (anti-HBs titer ≥10 mIU/mL) was noted in 95% (20 of 21) of subjects with isolated anti-HBc. After re-measurement of anti-HBc, 13 (62%) of the 21 subjects with isolated anti-HBc were reclassified as having resolved HBV infection with a loss of anti-HBs. In the remaining 8 subjects (38%), isolated anti-HBc was determined to be false positive. The HBV status of these 8 subjects was HBV naïve due to the waning-off effect of anti-HBs of the neonatal HBV vaccination. There was no significant difference in anamnestic response to a single HBV booster dose of vaccine between students with isolated anti-HBc (n = 13) and those with HBV naïve (n = 323) status (GMT 50.6 vs 47.7 mIU/mL, P = 0.90).

Conclusion

The presence of isolated anti-HBc 18 years after HBV vaccination can be attributed to post-HBV infection with a loss of anti-HBs and to a decline in anti-HBs elicited by vaccine. A single HBV booster dose of vaccine is recommended for subjects with isolated anti-HBc who were fully vaccinated with HBV vaccine as infants. This finding needs to be replicated in further studies with larger cohorts.

Introduction

Hepatitis B core antibodies (anti-HBc) against hepatitis B core antigen peptides develop in response to acute hepatitis B virus (HBV) infection. Core antibodies typically persist for life, regardless of whether the infection resolves or remains chronic [1]. Therefore, anti-HBc acts as a serum marker for evidence of HBV infection. Testing for the presence of anti-HBc is recommended as a screening test for HBV infection prior to HBV vaccination in endemic areas [2].

In asymptomatic populations, anti-HBc positive individuals, that is, subjects with previous natural HBV infection, can be classified into three groups according to the presence or absence of hepatitis B surface antigen (HBsAg) and hepatitis B surface antibody (anti-HBs): (1) subjects with HBV immunity through natural infection (anti-HBc positivity, anti-HBs positivity, and HBsAg negativity); (2) subjects with chronic HBV infection (HBsAg positivity); or, (3) subjects with isolated anti-HBc (anti-HBc positivity, anti-HBs negativity, and HBsAg negativity) [3].

The prevalence of isolated anti-HBc in different populations ranges from 0.1% to 20%, depending upon whether HBV is endemic in a particular region [4], [5], [6], [7], [8], [9]. In areas with low endemicity, such as most parts of Europe and the United States, the prevalence of isolated anti-HBc is about 1%–4% of the population [4]. In contrast, in endemic countries such as those in South East Asia and sub-Saharan Africa, the prevalence of isolated anti-HBc is much higher [10], [11]. Prior to the introduction of the universal HBV vaccination program in 1984, the prevalence of isolated anti-HBc in the adult population in Taiwan was 15%. In addition, Chan et al. reported that majority of their adult subjects (>75%) with isolated anti-HBc had evidence of previous infection with HBV [5]. Although the prevalence of HBV infection has decreased markedly in Taiwan since the introduction of the neonatal HBV vaccination program, infection still remains endemic to the area [12], [13], [14], [15], [16], [17], [18], [19].

Isolated anti-HBc seropositivity may result from (1) resolved HBV infection with waning titers of anti-HBs (type I); (2) a false positive anti-HBc result (type II); (3) occult chronic HBV infection with undetectable HBsAg (type III); or, (4) the presence of anti-HBc during the “window period” following acute HBV infection, when antigenemia with HBsAg has resolved and anti-HBs has not yet developed (type IV). The possibility of isolated anti-HBc reactivity being due to the anti-HBc window period, however, is highly unlikely with current sensitive HBsAg assays [5], [20].

The clinical approach to the evaluation and management of isolated anti-HBc depends on the clinical situation. For subjects who are at risk for HBV infection, such as individuals living in areas that are endemic for HBV infection, some experts suggest vaccination with a complete HBV immunization series while others suggest that total anti-HBc testing be repeated. If the repeat test result is negative, suggesting a false-positive result in the initial test, patients are recommended to receive a complete HBV immunization series. If the repeat anti-HBc test result is positive, the patient most likely has resolved HBV infection with waning anti-HBs titers. There is a lack of consensus regarding whether these patients should receive HBV vaccination. The options for these patients include (1) not vaccinating, (2) administering one dose and then checking the anti-HBs titers to see whether there is a “booster” anamnestic response (anti-HBs titer greater than 10 mIU/mL), or (3) administering a complete vaccination series. Hence, whether patients with isolated anti-HBc require vaccination against HBV remains controversial.

The purposes of this study are to investigate the significance of isolated anti-HBc and to analyze the response to HBV booster vaccination in young adults with isolated anti-HBc who had been fully vaccinated with HBV vaccine in infancy.