Journal of Pediatric Gastroenterology & Nutrition:
Original Article: Hepatology and Nutrition
Immunogenicity of Hepatitis A Vaccine in Children With Celiac Disease
Sari, Sinan*; Dalgic, Buket*; Basturk, Bilkay†; Gonen, Sevim‡; Soylemezoglu, Oguz‡
*Department of Pediatric Gastroenterology
†Department of Immunology
‡Department of Pediatric Nephrology, Gazi University Faculty of Medicine, Ankara, Turkey.
Address correspondence and reprint requests to Sinan Sari, MD, Gazi Üniversitesi Tıp Fakültesi, 1. Kat, Besevler, Ankara 06500, Turkey (e-mail: firstname.lastname@example.org).
Received 31 January, 2011
Accepted 4 May, 2011
The authors report no conflicts of interest.
Objectives: The response to hepatitis A vaccine has not been studied in children with celiac disease (CD). The aim of the present study was to evaluate the immunogenicity of an inactivated hepatitis A virus (HAV) vaccine and the effect of the human leukocyte antigen (HLA) type on immunogenicity in children with CD.
Patients and Methods: Thirty-three patients with CD and 62 healthy controls were enrolled in the study. Inactivated HAV vaccine (Havrix; GlaxoSmithKline Biologicals, Rixensart, Belgium) containing 720 enzyme-linked immunosorbent assay units of alum-adsorbed hepatitis A antigen was administered intramuscularly in a 2-dose schedule at 0 and 6 months. Seroconversion rates and antibody titers of HAV were measured at 1 and 7 months.
Results: At 1 month, seroconversion rates were 78.8% and 77.4% and geometric mean titers were 50.7 and 49.9 mIU/mL in the CD and control groups, respectively (P > 0.05). At 7 months, seroconversion rates were 97% and 98.4% and geometric mean titers were 138.5 and 133 mIU/mL in the CD and control groups, respectively (P > 0.05). The most frequent HLA types were HLA-DQ2, -DR3, and -DR7 alleles in patients with CD and HLA-DQ3, -DQ6, -DR11, and -DR14 in the controls. There was no association between HLA alleles and antibody titers of hepatitis A vaccine.
Conclusion: Children with CD have a good immune response to hepatitis A vaccine, similar to healthy controls.
Hepatitis A virus (HAV) infection is a worldwide health problem and is one of the most important causes of fulminant hepatic failure in developing and developed countries (1). With improvement in economic and living conditions, the age of HAV infection is shifting from early childhood to adolescence and adulthood. This epidemiological shift has led to an increased incidence of symptomatic disease, including acute liver failure (2). Vaccination is an effective and safe tool for the prevention of HAV infection, along with improvement in sanitary conditions (3). The protective efficacy of vaccine is 95% to 100% in preventing clinical HAV infection (4). In developed countries with low endemicity of hepatitis A and high rates of disease in specific high-risk populations, vaccination of these populations against hepatitis A is recommended by the World Health Organization. Although hepatitis A immunization is recommended routinely to all children in the United States, in Turkey, high-risk groups (eg, people with chronic liver disease and health professionals) and people who come in contact with acute hepatitis A are being immunized (5). Besides many environmental factors, a significant proportion of the variation in individual humoral immune response to vaccination appears to be genetic. The association between human leukocyte antigen (HLA) and the development of immunity to vaccines has been investigated in healthy populations and specific disease groups (6).
Celiac disease (CD) is characterized by gluten-associated inflammatory destruction of the small bowel in genetically susceptible individuals (7). HLA and non-HLA genes in association with gluten and additional environmental factors are involved in CD pathogenesis (8). Major histocompatibility complex haplotypes B8, DR3, and DQ2 are most strongly associated with CD (9). Recent studies have confirmed that patients with CD have a poorer response to hepatitis B vaccine than do healthy controls, and HLA-DQ2 is considered the most important genetic factor for unresponsiveness to hepatitis B vaccine (10–15).
The efficacy of hepatitis A vaccine has been investigated in patients with hepatitis C, autoimmune hepatitis, inflammatory bowel disease (IBD), and Down syndrome (16–18); however, the efficacy of hepatitis A vaccine in CD has not been established. The present study was conducted to examine the immunogenicity of hepatitis A vaccine in children with CD.
PATIENTS AND METHODS
From January 2005 to December 2009, 33 children (18 girls and 15 boys; mean age 8.4 ± 3.6 years; range 1.5–17 years) with biopsy-proven CD were enrolled in the study. The diagnosis of CD was based on anti–tissue transglutaminase positivity and typical histopathological findings of small intestinal biopsies, according to a modified Marsh classification (19). The control group comprised 62 healthy children (33 girls and 29 boys, mean age 8.7 ± 2.2 years, range 1–12 years) with negative serological tests for CD. Parents of all of the patients gave written, informed consent before enrollment. The study protocol was approved by the ethics committee at Gazi University Faculty of Medicine. Children younger than 12 months and those with allergy to any vaccine component, chronic disease, congenital or acquired immunodeficiency, history of HAV infection, or previous administration of hepatitis A vaccine were excluded. The children were screened for prior exposure to HAV using commercially available assays for HAV. All of the HAV antibody–negative patients were offered hepatitis A vaccine after screening.
For each patient, a blood sample was taken and genomic DNA was extracted. All of the samples were analyzed for HLA-DRB1 and -DQB1 alleles by reverse transcriptase-polymerase chain reaction sequence-specific oligonucleotide (SSO) reverse hybridization on microbead arrays (Luminex Technology, Luminex Corporation, Austin, TX) after locus-specific amplification of genomic DNA samples using LabType RSSO2B reagents (One Lambda, Ingen, Chilly Mazarin, France). This assay provided results at an intermediate level (groups of alleles), with assignment of the 4-digit allele in some cases.
Inactivated hepatitis A vaccine (Havrix, GlaxoSmithKline Biologicals, Rixensart, Belgium) containing 720 enzyme-linked immunosorbent assay units of alum-adsorbed hepatitis A antigen per 0.5 mL dose was given intramuscularly in the deltoid muscle in 2 doses at 0 and 6 months. Postvaccination antibody against HAV at 1 and 7 months was tested with AxSYM HAVAB 2.0 (Abbott Laboratories, Wiesbaden, Germany), a microparticle enzyme immunoassay. An antibody concentration of >20 mIU/mL was considered protective (seropositivity).
Geometric mean titers (GMTs) of anti-HAV antibodies were calculated by taking the antilog of the mean of the log-transformed titers for each sampling time. Student t test was used to compare continuous variables including age, standard deviation score (SDS) for weight and height, body mass index (BMI), and GMT between groups. The χ2 test was used for categorical variables. The correlation among age, SDS for weight and height, BMI, and GMT was evaluated by Pearson test. A P value <0.05 was considered significant. Statistical analyses were performed with SPSS for Windows, version 17.0 (SPSS Inc, Chicago, IL).
Demographic characteristics of both groups are shown in Table 1. Although there was no difference with respect to sex, age, and BMI between the CD and control groups, SDS for height and weight was significantly lower in the CD group.
The proportion of children in each group who responded to vaccination is shown in Table 2. After the first and second doses of hepatitis A vaccination, the rates of positivity for anti-HAV antibody were 78.8% and 77.4% at 1 month and 97% and 98.4% at 7 months in children with CD and the control group, respectively. GMTs of anti-HAV antibody were similar in both groups at 1 and 7 months. The GMT of anti-HAV antibody in children with CD at 1 month was 50.72 mIU/mL (95% confidence interval [CI] 38.16–67.41) compared with 49.85 mIU/mL (95% CI 34.67–71.68) in the control group. At 7 months, the GMT of anti-HAV antibody in children with CD was 138.46 mIU/mL (95% CI 114.03–168.13) compared with 132.96 mIU/mL (95% CI 94.87–186.32) in the control group (Table 3).
The frequencies of HLA-DQ2, -DR3, and -DR7 alleles were significantly higher in the patients with CD compared with the control group, whereas HLA-DQ3, -DQ6, -DR11, and -DR14 alleles were significantly more frequent in the control group (Table 4). There was no association between HLA alleles and vaccine antibody titers.
As a result of improved living conditions and subsequent changes in hepatitis A epidemiology, the disease burden is increasing in many regions of the world (20). Basic management of hepatitis A consists of active vaccination. The effectiveness of the vaccine has been evaluated in different populations of healthy children (4,21,22). Seroconversion rates have reached 100% in healthy children after 12 months of age (23–25). Although rare, primary failure of hepatitis A vaccination may be linked to the inability of some individuals to mount a specific immune response to the vaccine components. There is scant information about the response to hepatitis A vaccination in different pediatric disease groups. Hepatitis A vaccination is effective in children with cancer, IBD, chronic liver disease, and Down syndrome (16,17,26,27). The response to hepatitis A vaccination in patients with decompensated cirrhosis and in liver-transplant recipients is lower than that in the healthy population (28,29). The immunogenicity of hepatitis A vaccine in children with CD has not been studied previously.
The humoral response to a vaccine is determined by a number of factors, including age, sex, race, quality and quantity of vaccine antigens, number of doses administered, and route of immunization (30). There is a strong genetic component to variations in the immune response to the vaccine. It is believed that the HLA region contributes significantly to genetic susceptibility to variations in vaccine immune responses. The HLA-DRB1*03 allele is associated with poor response to hepatitis B and measles vaccines (30).
In CD, poor response to immunization was first described with hepatitis B vaccine by Noh et al (12), and this was supported by subsequent studies (10–15). It is thought that patients with CD who are characterized by unresponsiveness to hepatitis B vaccine may have failure of induction of the TH2 response that is needed for B-cell differentiation and formation of memory B cells that are needed for immunization. This lack of TH2 response is associated with the particular HLA genotype of the individuals with poor vaccine response and CD (12).
In the present study, children with CD had a good response to inactivated hepatitis A vaccine, with 97% seroconversion after 2 doses and an antibody GMT comparable to that of healthy control children. Similarly, Ferreira et al (17) have demonstrated a good response to hepatitis A vaccination in children with Down syndrome. Radzikowski et al (16) have found that hepatitis A vaccine is immunogenic and safe in pediatric patients with IBD. Our results demonstrated no association between HLA alleles and antibody response to hepatitis A vaccine. A similar antibody response to hepatitis A vaccine between children with and without CD could explain the minimal role of HLA in hepatitis A vaccine immunogenicity. A vaccination study in twins by Höhler et al (31) showed that a questionable effect was noted for the HAV-specific response on contrary to hepatitis B vaccination. Also, many nongenetic factors, including age, sex, smoking, BMI, liver failure, zinc deficiency, maternal antibody level, and physical activity may affect the response to hepatitis A immunization (28,31–36). We did not find any association between antibody titers and age, sex, SDS for weight and height, and BMI.
To the best of our knowledge, this is the first study to evaluate the immunogenicity of hepatitis A vaccine and the effect of HLA type on immunogenicity in children with CD. In contrast to hepatitis B vaccine response in children with CD, our study showed that hepatitis A vaccine was greatly immunogenic in children with CD. Routine HAV immunization protocol for healthy children could be efficiently used in children with CD. Also, no association between HLA alleles and antibody response to hepatitis A vaccine was found, and we suggest that HLA alleles have a questionable effect on the HAV-specific response in children with CD.
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celiac disease; hepatitis A vaccine; immunization
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