Patients with IBD are at increased risk of infectious disease raised from the nature of disease, immunosuppressive agents such as biologics and immunomodulators, and procedures including endoscopy, transfusion, and surgery, which are frequently required during treatment [1,2]. Infectious diseases often lead to higher morbidities and mortalities in IBD patients who are generally in an immune-suppressed status. Therefore, effective vaccinations against these diseases should be administered.

HBV infection has been reported to cause fulminant or fatal hepatitis by opportunistic infection or reactivation of HBV in IBD patients, but is preventable with a vaccine [3-6]. The American College of Gastroenterology (ACG) clinical guidelines recommend HBV vaccination for every IBD patient lacking HBV immunity with non-immunization regardless of immunosuppression status, especially before the start of anti-tumour necrosis factor (anti-TNF) therapy [7]. Since anti-HBs levels decline over time [8], ACG guidelines also recommend a regular check of anti-HBs titer to confirm immunity [7]. A booster vaccination or a new vaccination series is recommended for patients with insufficient protective antibody concentrations [7].

As a part of the National Immunization Program, all neonates have received a universal HBV vaccine since 1995 in Korea, regardless of maternal HBsAg status [9]. With the implementation of the national vaccination program, HBsAg prevalence has decreased from 10% in the 1980s [10] to 2.9% in 2013 [11]. However, it has been reported that the decline of HBV infection is limited to the younger population whereas the prevalence of HBV infection in the middle-aged and elderly populations has remained unchanged [9]. HBV infection is still the leading cause of chronic liver disease, including chronic hepatitis, cirrhosis, and hepatocellular carcinoma [12]. Therefore, it is important to monitor the status of HBV immunity and vaccinate IBD patients who lack HBV immunity.

In this study, we aimed to assess the following: (1) the HBV immune status in patients with IBD; (2) the response to a booster HBV vaccination in patients who had previous completed a 3-dose vaccination series or the response to a 3-dose HBV vaccination series in patients with incomplete or an unknown vaccination history; (3) the predictive factors for an effective HBV vaccine response; (4) the response to a new complete vaccination series (revaccination) in patients who had shown no response to a booster vaccination; and (5) the factors associated with compliance to the recommended vaccination schedule.

This study is the first to prospectively analyze HBV vaccine response in patients with IBD in Korea, an intermediate endemic area for HBV. We found that 26% of IBD patients did not have immunity to HBV, 49% of patients had maintained immunogenicity against HBV from a prior vaccination, and 25% of patients had prior or present HBV infection. In regard to the vaccination response, 70.5% of patients obtained an optimal response from the booster vaccination, and 89.7% of patients acquired an optimal response from the full vaccination series.

HBV vaccination is an effective method for reducing infection and related serious complications, including cirrhosis or hepatocellular carcinoma. In Korea, HBV vaccination prevalence has exceeded 99% since 1990 [17], which has resulted in dramatic decreases of HBsAg seropositive rates (2.9% in the general population) [11] and HBcAb seropositive rates (10.6% in adults younger than 30 years) [17]. The non-immunity rate for HBV in the general population is reported as 19.7% [18].

Compared to the general population in Korea, our study showed that IBD patients have higher risk of HBV infection and suboptimal response to HBV vaccination. Among the patients who did not have immunity, only 55% had a history of the complete vaccination series, whereas the other patients had not completed the vaccination series or the vaccination history was unknown. Recent Korean studies [19] reported an HBV vaccination rate of 52.6% in IBD patients, which is higher than other vaccination rate, such as measles-mumps-rubella (42.2%), influenza (37.5%), varicella (34.9%), and hepatitis A (15.6%). However, this rate still falls short. The primary reason given for not receiving a vaccination was “not knowing the existence or necessity of vaccine.” The low rate of HBV vaccination in IBD patients is worrisome because an endogenous immunosuppressive state arising from altered immunity and an exogenous immunocompromised state due to immunosuppressive drugs can increase the risk of opportunistic infections [19].

Generally among healthy individuals, a 3-dose vaccination induces a 90% to 95% protective antibody concentration [20]. Although antibody concentration wanes over time after the primary immunization, the protection can persist for at least two decades [21]. Moreover, protection against disease could persist even after the disappearance of anti-HBs antibodies in individuals with an intact immune system [22]. Therefore, further vaccination is usually not recommended in individuals with full response to the complete vaccination series [21].

However, IBD patients have shown diminished vaccine response in the range of 33% to 76% [23] due to aberrant Th1/Th2 immune response, which led to disturbance of cytokine secretion and ineffective vaccine response, as well as concurrent use of immunosuppressive therapy [18]. In addition, low initial antibody level was also correlated with decreased antibody persistence [24]. Thus, 2017 ACG clinical guidelines recommend testing for HBV serologic markers and to vaccinate non-immune patients, particular before anti-TNF treatment [7]. For patients with suboptimal antibody concentration, a single dose booster vaccine should be considered, and if the response is not optimal, a full vaccination series is recommended [7]. Booster vaccinations are known to increase antibody levels rapidly by triggering memory B cells, which have been sensitized by the primary vaccine to proliferate and differentiate [22].

Based on this guideline, we evaluated the response of HBV vaccination in 2 groups classified by prior complete vaccine experience, namely the booster group and the full vaccination group. As expected, the response rates in both groups was lower than the levels within the general population, 70.5% versus 88% [24] for booster group and, 89.7% versus 90% to 95% [20] for full vaccination group, respectively. Young age was a significantly positive predictive factor for optimal vaccine response, whereas prior complete vaccination was a significantly negative factor. Disease type, duration, activity, and type of treatment at the time of vaccination were not significant factors.

Age has been known to have an inverse correlation with vaccine response [25-27]. Immunosenescence, an aging process of the immune system including thymic involution, changes in cytokine production/distribution, and changes in the quality or quantity of the lymphocyte population results in poor response to vaccination [28,29]. Based on our results, it is necessary to evaluate the immunogenicity for HBV at the diagnosis of IBD [30] and to minimize the time to vaccination.

Based on the immunologic principles of vaccinations, a positive relationship between a prior complete vaccination and vaccine response would be reasonable. However, our result showed a negative relationship. This negative relationship should be further analyzed based on the time of the primary vaccination and the serum titers of antibodies after primary vaccination, because there could be patients who failed to respond to the primary vaccination. Nearly 5% of individuals have been reported to show blunted immune response to vaccination [31]. However, nearly none of the patients in our study could recall that information.

Another explanation for this negative relationship could arise from the study design. We considered patients who were uncertain of a previous vaccination as a vaccine naïve group. Thus, some of these patients could have had a previous complete vaccination series. However, if we compare HBV vaccination rates from another Korean study, which reported a 52.6% rate, this kind of recall bias would be negligible. Fortunately, 77.2% of patients with a suboptimal response to the booster vaccine responded to an additional full series vaccine. Thus, a full series vaccination should be administered if the booster vaccination fails. Also, physicians should pay strict attention to this population of patients since a complete vaccination history is associated with poor compliance.

Immunosuppressive therapy, including conventional immunosuppressants such as corticosteroids or azathioprine, and biologics are closely related to suboptimal vaccine response [32,33]. The most recent American study also reported that exposure to anti-TNF, especially infliximab was associated with decreased antibody response [34] in IBD patients. However, in our study, there was no statistically significant association between the type of treatment and vaccine response although 70% of patients were under immunosuppressive therapy. These inconsistent results could be explained by different study design between 2 studies. Although the American study included relatively large number of patients, this study included patients with and without documented vaccination history which has significant influence on vaccine response as well as medication. In addition, the lack of an association between the treatment modality and response could be due to the mild disease activity of a majority of patients in our study. Therefore, we still have to monitor the negative influence of immunosuppressive agents carefully, especially the effects of anti-TNF agents on vaccine response, and consider appropriate vaccinations for non-immune patients before starting anti-TNF therapies [7,35,36].

This study has several limitations. First, as a single-center study, our subjects did not necessarily represent the characteristics of the general Korean IBD patient population. Second, we considered patients “not knowing about the vaccination” as non-vaccinated individuals. Some patients who had completed the vaccination, but could not recall having been vaccinated might be assigned to the full vaccination group. However, since the Korean National Immunization Program had started in 1995 and due to the relatively young age of enrolled patients, recall bias might not have significantly influenced the results. Despite these limitations, this study is valuable in terms of evaluating the status of immunogenicity against HBV in IBD patients within an intermediate endemic area and the vaccine response in subgroups classified as booster and vaccine naïve groups.

In conclusion, this study confirmed that IBD patients who are more susceptible to HBV infection have suboptimal response to an HBV vaccination. Thus, it is necessary to evaluate the immunogenicity to HBV at the diagnosis of IBD, and a vaccine schedule should be created as soon as possible. Considering that a previous complete HBV vaccination series is associated with suboptimal response and poor compliance, serum-HBV titers should be thoroughly evaluated in these patients, and, if negative, an additional 3-dose vaccination should be administered.