Response to HBV vaccination in CD children and adolescents compared to healthy subjects.
Abstract
Celiac disease (CD) is an immune-mediated systemic disorder elicited by gluten and related prolamins in genetically susceptible individuals, characterized by the presence of a variable combination of gluten-dependent clinical manifestations, CD-specific antibodies, HLA-DQ2 and HLA-DQ8 haplotypes, and enteropathy. Hepatitis B virus (HBV) infection is an important global public health problem that can cause chronic liver disease, and it is associated to a high risk of death from cirrhosis and hepatocellular carcinoma. Since 1982, a safe and effective HBV vaccine has been available, and recommendation for HBV vaccination has been extended to all infants to achieve protection against HBV infection. HBV vaccination is highly effective in eliciting a sustained immune response in immune-competent individuals. However, research papers have suggested that celiac patients may have low rate of protective antibodies after HBV vaccination. The failure of CD subjects to respond to HBV vaccination has great importance for public health policies as the nonresponders could be regarded as a reservoir for HBV. The aim of our work is to revise and to discuss the scarce literature on this field in order to provide clinical practice guidelines to establish the best surveillance program of response to HBV vaccine in CD pediatric patient.
Keywords
- celiac disease
- children
- hepatitis B vaccine
- HLA
- gluten-free diet
1. Introduction
Celiac disease (CD) is an immune-mediated systemic disorder elicited by gluten and related prolamins in genetically susceptible individuals, characterized by the presence of a variable combination of gluten-dependent clinical manifestations, CD-specific antibodies, HLA-DQ2 and HLA-DQ8 haplotypes, and enteropathy. Genetic, immunological, and environmental factors therefore appear to be responsible for the disease. HLA-DQ2 is present in 90%–95% of patients with CD, whereas 5% carry the HLA-DQ8 haplotype and the remaining 5% at least one of the two DQ2 alleles [1, 2]. The prevalence of CD is high in the European and North American population (1%), reaching 10%–15% in patients who have first-degree relatives with this disease [1, 2].
HLA system has a fundamental role in identifying the antigens inoculated with the vaccines and in the production of specific antibodies [3, 4], and some HLA phenotypes seem to be predictive of a less effective immunological response [5].
In particular, the immunogenic peptides in the hepatitis B (HBV) vaccine determine the protective immune response to the virus through the HLA-DR and DQ molecules [6, 7], with the DR3-DQ2 and DR7-DQ2 haplotypes generally having a lower response rate [7–10].
HBV infection is one of the major causes of chronic liver disease, associated with a high risk of death from cirrhosis and hepatocellular carcinoma, and therefore represents an important global public health problem [11, 12]. To prevent it, since 1982, a safe and effective hepatitis B vaccine has been available. The one currently in use is a recombinant vaccine that contains HBV surface antigen (HBsAg) and causes the production of specific antibodies (anti-HBs) that protect against the infection [13]. Many epidemiologic studies have been conducted to determine the efficacy of the vaccine. A positive immune response to the vaccine is defined as the development of HBV anti-HBs at a titer of >10 mIU/mL, after a complete and appropriate immunization schedule, measured preferably 1–3 months after the last vaccine administration [14, 15]. The optimum response, conferring seroprotection against HBV infection, is defined as an anti-HBs titer ≥100 IU/l [14, 15]. Subjects that develop an anti-HBs titer between 10 and 100 IU/ml are referred to as “poor responders.” Vaccinated subjects with an anti-HBs titer <10 mIU/ml after completion of primary vaccine series are called “nonresponders” [16]. HBV vaccination is very effective, showing a sustained immune response in immune-competent individuals: the antibody response has been found to occur in more than 90% of the healthy subjects vaccinated with the standard dose regimen of 20 μg HBV vaccine given at 0, 1, and 6 months of intervals [17, 18]. However, among healthy immunocompetent subjects, approximately 4–10% do not produce protective levels of anti-HBs after immunization [19] depending on age, male gender, obesity, inappropriate vaccine storage conditions, route of administration, smoking, drug abuse, state of immunosuppression, and presence of specific HLA haplotypes.
2. Responses to vaccinations in celiac children
Data concerning antibody response of patients with CD to vaccine are scanty. Most studies in this field are addressed to HBV vaccination response, while fewer works are available about the immunological response to other vaccinations.
Several research papers have suggested that celiac patients may have low rate of protective antibodies after vaccinations such as HBV. The failure of CD subjects to respond to HBV vaccination has great importance for public health policies as the nonresponders could be regarded as a reservoir for HBV [20]. The studies that have addressed the relation between CD and HBV vaccination in children are summarized in Table 1 [21–29]. In the earliest report involving 26 celiac patients aged 9.2 ± 4.6 years and 18 age-matched controls, receiving the full complement of childhood vaccination (HBV, tetanus, rubella,
Author/references | Year | Country | Study design | Patient population and sample size | Vaccine | (%) of nonresponders | HLA |
---|---|---|---|---|---|---|---|
Park et al. [21] | 2007 | Japan | Prospective | 26 (mean age 9.2 ± 4.6 years) untreated CD vs 18 (mean age 10.4 ± 3.8) controls | HBV | 53.9% vs 11.1%; | NA |
Nemeset al. [22] | 2008 | Finland | Prospective | 22 (mean age 8.8 years) treated CD prospectively immunized; 27 (mean age 16.7 years) untreated CD; 79 (mean age 16.7 years) treated CD vs 113 (mean age 16.1 years) controls | HBV | 0.5% 74.0% 38.6% vs 24.8%; | Group 1 (22 treated CD): HLA DQ2 Group 2 (53/106 treated and untreated CD): 51: HLA DQ2 2: HLA DQ8 |
Leonardi et al. [26] | 2009 | Italy | Retrospective | 60 (mean age 9.32 years) treated CD vs 60 (mean age 10.1 years) controls | HBV | 50% vs 11.6%; | 15/60: 13 HLA-DQ2 2 HLA-DQ8 |
Ertem et al. [23] | 2010 | Turkey | Retrospective Prospective | 40 vaccinated (mean age 12.4 ± 5.4 years) treated CD vs 54 (mean age 9.8 ± 3.6 years) controls 28 prospectively vaccinated treated CD | HBV | 32.5% vs 14.8%; 3.6% | 37.5% CD 23.8% controls: HLA DRB1*03 21% CD 2.4% controls: HLA DRB1*07 55% CD 14.6% controls: HLA DQB1*02 30% CD 47.6% controls: HLA DQB1*03 |
Ertekin et al. [25] | 2011 | Turkey | Retrospective | 52 (mean age 10.7 ± 4 years) CD vs 20 (mean age 10.7 ± 4 years) controls | HBV | 38.5% vs 10%; | NA |
Balamtekin et al.[24] | 2011 | Turkey | Retrospective | 64 (mean age 4.69 ± 2.31 years) treated and untreated CD vs 49 (mean age 5.45 ± 2.92 years) controls | HBV | 21.9% vs 4.1%; | NA |
Urganci and Kalyoncu [28] | 2013 | Turkey | Prospective | 30 (mean age 6.15 ± 4.1 years) treated and untreated CD vs 50 (8.13 ± 1.7 years) controls | HBV | 30% vs 10%; | NA |
Leonardi et al. [27] | 2011 | Italy | Retrospective | 66 (mean age 8.34 ± 3.47 years) CD vs 50 (mean age 7.58 ± 3.51 years) controls | HBV | 53% vs 16%; | NA |
Leonardi et al. [29] | 2015 | Italy | Prospective | 30 (mean age 6 years) CD/DMT1 vs 100 (mean age 13.6 years) DMT1 vs 60 (mean age 8.6 years) CD | HBV | 53.3% vs 38.2% vs 50%; | NA |
3. Pathogenetic role of HLA system in vaccination unresponsiveness in celiac disease
The mechanism for hepatitis B vaccination failure in patients with CD is not clear. A few hypotheses have been proposed. Multiple candidate genes influence the ability to respond to the recombinant HBV vaccine [9, 30–32]. HLA is believed to contribute significantly to the genetic susceptibility immune response variations to the vaccine [33]. Poor or nonresponsiveness to HBV vaccine has been associated with HLA-DQ2, DR3, and DR7 alleles, which are also associated with CD [9, 10, 34]. In particular, HLA genotype DQ2, found in 90–95% of celiac patients, may have a fundamental role in the predisposition to a weaker immunization to recombinant hepatitis B vaccine in these patients. The HLA is coded by the major histocompatibility complex (MHC) group of genes located on chromosome 6 in the human genome, and they are essential for determining the specificity of an individual’s immune response [35]. There are three classes of HLA: HLA class I, HLA class II, and HLA class III. Among them, HLA class II molecules have the task of presenting antigens to the T lymphocytes from outside the cell. Antibody-producing B cells are then stimulated to produce specific antibodies by these antigens [36]. HLA-DQ2 haplotype would be responsible for the failure of induction of the Th2 response needed to promote the differentiation of B cells and the formation of memory B cells necessary for immunization.
Defective or insufficient HBsAg-specific T-helper cells, inadequate T-helper 1, and T-helper 2 cytokine production [37–39], or diminished expression of cell contact signal between activated T and B cells, like CD40L [40] may also be responsible for the lack of response to HBsAg [41, 42]. On this regard, interleukin genotypes (IL10, IL12, IL18) were associated with the anti-HBs antibody development in response to HBsAg in hemodialysis patients [43, 44]. Chen et al. in 2011 found that serum anti-HBsAg response to HBV vaccine in healthy population was closely related to four specific single-nucleotide polymorphism (SNPs) in the IL4, IL4RA, IL13, and Toll-like receptor (TLR2) genes and suggested that variation in these structures may influence the duration and intensity of HBV vaccine-induced immune response [45].
Other studies suggested that compliance with a GFD is responsible for the response to the hepatitis B vaccine in patients with CD. Several studies have hypothesized gluten intake as a cause of failed immunity upon vaccination. Gluten may be implicated because both HBsAg protein fragments and gliadin peptides bind to HLA-DQ2 molecules and induce proliferation of T lymphocytes. Defective antibody production may result from competition between the proteins [22, 23].
4. New approaches in hepatitis B vaccination in celiac children
Inadequate response to HBV immunization in CD patients represent a public health concern because the group of nonresponder patients could act as an HBV infection reservoir. For this reason, response to HBV vaccine should be investigated in children with CD. To protect this population and to achieve the goal of universal protection, new immunization strategies were proposed for CD: the first one is the use of booster and/or higher doses of HBV vaccine by intramuscular (IM) route, and the second one addresses on the use of intradermal route (ID). The studies that have addressed new immunization strategies in CD are summarized in Table 2 [22, 23, 46, 47].
Author/references | Year | Country | Study design | Patient population and sample size | VAC Ag | Type of vaccine | Route | Number of booster doses | % Seroconversion |
---|---|---|---|---|---|---|---|---|---|
Nemes et al. [22] | 2008 | Finland | Prospective | 37 (mean age 16.7 years) nonresponders CD on GFD | HBV | Recombinant | IM | 1 | 97.3% |
Ertem et al. [23] | 2010 | Turkey | Prospective | 28 (12.4 ± 5.4 years) nonresponders CD | HBV | Recombinant | IM | Three doses of HBV vaccine | 96.4% |
Leonardi et al. [46] | 2010 | Italy | Prospective | 20 nonresponders CD to IM vaccination | HBV | Recombinant | ID | 4 | 90% |
Leonardi et al. [47] | 2012 | Italy | Prospective Randomized | 58 (mean age 9.8 ± 6.2 years) nonresponders CD | HBV | Recombinant | 30 ID vs 28 IM | 3 | After first dose: ID:76.7% vs IM: 78.6% After third dose: ID: 90% vs IM: 96.4% High responders (anti-HBs >1000 IU/l): ID: 40% IM: 7%; |
Nemes et al. administered intramuscularly to 37 nonresponder CD children on GFD, the booster dose of 20 μg of recombinant HBV vaccine, and found that 36 out 37 (97.3%) showed seroconversion 4 weeks after vaccination. However, success with the booster vaccination after controlled GFD suggests that disease activity may play a primary role in vaccination failure [22]. Few studies that exist about HBV vaccine administered by ID route in CD patients unresponsive to IM recombinant vaccine. Leonardi et al. revaccinated 20 CD children and adolescents with a 2 μg dose of recombinant intradermal HBV vaccine. After 4 weeks they found that 15 out 20 patients (75%) showed a protective titer of anti-HBs [22, 23].
Subsequently, Leonardi et al. conducted a prospective, randomized study on 58 CD patients, vaccinated in the first year of life, without protective HBV antibodies as demonstrated by blood analysis. They performed in all patients randomly an HBV vaccination booster dose by ID or IM route. In 30 CD children, a 2 μg dose of recombinant HBV vaccine was administered by the ID route, while 28 CD patients received by IM route 10 μg dose of the same vaccine. Four weeks after every booster dose, 90% of ID patients and 96.4% of IM subjects showed a protective anti-HBs titer after a third booster dose. The authors concluded that both routes are effective in revaccinating CD patients; however, the ID route seems to produce a significantly higher percentage of higher responders [47].
Data suggest that the ID route offers greater immunogenicity due to direct delivery of antigen to the skin immune system, using even lower doses of antigen than IM route [47]. Moreover, the presence of a skin reaction on the site of the intradermal injection could represent a less expensive strategy to test serum anti-HBs response after the booster dose [48]. Economic studies suggest that the substantial cost-saving benefits could be achieved using a fraction of the IM dose via an ID route [48, 49].
5. Conclusions
The available literature shows that HBV vaccine response is lower in celiac subjects compared with healthy ones. Some authors hypothesize that the failure to respond to HBV vaccination is related to specific HLA association, whereas others argue that exposure to gluten at the time of vaccination may play an important role in unresponsiveness to the HBV vaccine. Therefore, nonresponsiveness to the HBV vaccination in CD patients represents a serious public health problem because of the large diffusion of CD that affects about 1% of the European population. Consequently, new vaccination strategies have been proposed to achieve full protection in this context, including the administration of booster doses of HBV vaccine by the intramuscular or the intradermal route. An evaluation of the response to HBV vaccine should be considered as a routine assessment in children newly diagnosed with CD who were previously vaccinated for HBV. Whenever unresponsiveness occurs, certain measures must be taken into account, such as revaccination utilizing ID route, which offers a potentially greater immunogenicity than the IM one, even using lower doses, due to the direct delivery of antigen to the skin immune system. Moreover, the revaccination should be done after the decrease of specific antibodies, which usually occurs after about 1 year of GFD, seen as some studies support GFD as crucial to vaccine responsiveness. More randomized controlled studies with a prospective design are needed for CD patients in order to clarify this topic.
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