Hepatitis B virus (HBV) is a leading cause of acute or chronic hepatitis, and HBV infection continues to be a serious public health problem due to its high prevalence and association with chronic liver disease including cirrhosis and hepatocellular carcinoma. Vaccination is important because no complete cure for HBV infection exists, other than conservative treatment [1]. With the availability of low-cost, unrestricted production of recombinant vaccines, vaccination in all age groups, including newborns, is expected to eradicate hepatitis B infection [2]. In Korea, the hepatitis B vaccine has finally been included in the National Mandatory Vaccination program since 1995 and the vaccination rate has reached 95% [3]. In the 1980s, the overall positive rate of hepatitis B surface antigen (HBsAg) in Korea was approximately 7.25%, which decreased to 4.38% in 2001 and 3.7% in 2005 after vaccination was initiated [4]. In a study conducted in 2008, the overall HBsAg seropositivity rate was found to have decreased to 2% [5].

After the hepatitis B vaccine was included in the National Expanded Program on Immunization in Korea, all infants have been eligible for the basic course of HBV immunization, including 3 consecutive inoculations at 0, 1, and 6 months after birth [6]. The preventive effect of the hepatitis B vaccine as protection against infection is defined on the basis of the concentration of antibodies against hepatitis B surface antigen (anti-HBs) being ≥10 mIU/mL. The anti-HBs seropositivity rate is known to be ≥95% after 3 serial doses of HBV vaccination during infancy. However, 5%–15% of normal adults are reported to fail to produce anti-HBs after 3 inoculations, and there have been a few cases of HBV infection in such nonresponders, although with mild clinical courses [1].

Responses to hepatitis B vaccine vary among vaccine responders and vaccine-induced anti-HBs levels may progressively decrease, as shown in several studies [7-10]. The factors associated with immunogenicity of the hepatitis B vaccine in healthy individuals include the number of injections, site of injection, type of vaccine, use of adjuvant materials, and storage conditions of vaccines [11]. It is also known that characteristics and health status of subjects such as immunosuppression, hemodialysis, female gender, older age, obesity, smoking, and drinking are associated with decreased antibody formation [1]. In particular, there have been studies in adults showing that a reduction in the rate of anti-HBs production is related to obesity [1,12-14]. However, there is a lack of studies addressing antiHBs production or retention in obese children after HBV vaccination in Korea, even though the obesity rate is gradually increasing among the population, especially in children and adolescents.

The present study investigated whether BMI affects anti-HBs seropositivity in healthy children who received 3 serial doses of vaccination in infancy.

The Advisory Committee on Immunization, World Health Organization, and the international group of hepatitis experts have defined the preventive effect of the hepatitis B vaccine as the presence of anti-HBs concentration ≥10 mIU/mL, representing protection against infection [7]. The rate of protective anti-HBs formation is known to be 16%–40% after the first inoculation and 80%–95% after the second inoculation. The third inoculation is performed as the booster, raising the antibody production rate to 98%–100% [16]. However, there are many cases in which negative or low anti-HBs levels are found in healthy children. The highest concentration of anti-HBs level is known to be attained between 1 and 3 months after the last inoculation and subsequently, the anti-HBs level begins to decrease. The decrease in anti-HBs level is rapid after 1 to 2 years, but then slows down gradually [16]. In the present study, the seropositivity rate was found to be 79.7% at 3 years after vaccination, 57.7% after 5 years, 51.7% after 7 years, and 44.7% after 10 years. This is consistent with previous studies showing a statistically significant decrease in anti-HBs seropositivity rate with increasing age (Table 2).

It is known that the immune status of an individual is an important factor influencing antibody production. In addition, some studies have reported that several host factors in healthy individuals such as sex, age, obesity, smoking, and drinking are significantly related to immunogenicity of the hepatitis B vaccine [1]. In particular, obesity can be a notable risk factor for failure to produce anti-HBs, and it has been on the rise in both adults and children. In our study, we found significant differences in mean BMI values between seronegative and seropositive subjects (Table 3). Further, there was a significant relationship association between anti-HBs titer and BMI z score with age and sex adjusted (Table 4). These are similar to results of previous studies in Iran, Turkey, China, and Belgium involving adults [11]. This finding indicates a trend of decreasing anti-HBs with increasing BMI, beyond the simple fact that obese individuals (BMI≥25 kg/m²) are significantly more likely to be nonresponders as reported in previous studies on adults [1,12,17]. In the present study as well, nonresponders accounted for 72% (18 of 25) of the group with BMI≥23 kg/m² and 100% (3 of 3) of the group with BMI≥25 kg/m². Other previous studies on adults have reported vaccine deposition into gluteal fat as a risk factor among obese people [1,12,18-20]. In the present study, however, injection site was not found to be a risk factor associated with obesity because all subjects were injected in the thigh or the deltoid muscle during the neonatal period.

There have been several previous studies reporting poor vaccineinduced immune responses in obese individuals against influenza/ pH1N1, tetanus, or rabies [21-23], and those reporting the effect of obesity on immune responses [24], but the data were not of sufficient detail [25]. The mechanism via which obesity reduces antibody production is not clear, and it can be assumed that the relationship between obesity, inflammation, and vaccine immunogenicity is more complex than anticipated. It is currently a matter of discussion whether obesity should be regarded as a state of low-grade chronic inflammation which inhibits antibody production [26], or whether dietary intake leading to obesity affects the gut leading to bacterial translocation and altered levels of immune activation [17]. Even if we cannot fully establish the mechanism currently, it is important to note that the proportion of obese individuals is increasing globally, particularly among adolescents.

Several studies have revealed that in individuals with the maximal anti-HBs level≥10 mIU/mL after a 3 serial dose vaccination, the anamnestic response rapidly elevates the anti-HBs level to a protective level upon further exposure to the virus and maintains such immune system memory for at least 15 years [7,9,10]. However, there is no clear evidence that normal responders continue to have an anamnestic response for more than 15 years. Further, the immune system memory status in individuals is unknown unless the maximum antibody level after vaccination is tested, which is not done in most cases [7]. Due to the above reasons, there is no precise consensus on the necessity or scheduling of revaccination, and there have been no claims that booster doses are unnecessary. However, if obesity directly affects the immune system outcome, the possibility that the anamnestic response does not occur in obese nonresponders should be considered. Therefore, further studies on the anamnestic response in obese nonresponders are needed. In addition, booster vaccination based on BMI or a range of vaccination dose based on body weight can be considered.

This study is the first in Korea to report the association between BMI and anti-HBs seropositivity in healthy children. This study also has strengths in that it offers some considerations in the interpretation of anti-HBs in children.

The present study does have some limitations. First, the study was limited to the Gyeonggi area and may not represent all regions. Second, we could not evaluate whether the anti-HBs-negative subjects were nonresponders from the beginning, or were initial responders who lost anti-HBs production. Third, height and weight values were obtained via parental questionnaires, and the accuracy of the BMI may have been low. Fourth, because samples with antiHBs≥1,000 mIU/mL were recorded as 1,000 mIU/mL, the results of anti-HBs titer analysis considering it as a continuous variable may have been affected.

In conclusion, our results indicate that BMI may be a factor potentially affecting anti-HBs titer in healthy children. Our findings also revealed a significant correlation between anti-HBs titer and BMI in children and adolescents, beyond the simple observation that obese people are unlikely to respond to the hepatitis B vaccine.