See “Vaccinations in Celiac Disease” by Rostami and Rostami Nejad on page 341.
Celiac disease (CD) is an immune-mediated disease, characterized by villous atrophy of the proximal small intestine and malabsorption (1). Human leukocyte antigen (HLA) and non-HLA genes also play a role besides gluten and additional environmental factors in CD pathogenesis (2).
The hepatitis A and B vaccines are both efficacious and safe. The administration of 2 doses of hepatitis A vaccine, given 6 months apart, induces 100% seropositivity in healthy individuals (3–5). The standard 3-dose regimen of hepatitis B vaccines, with the second and third doses being given 1 and 6 months after the initial dose, elicits protective serum titers of anti-HBs (greater than 10 IU/L) in 95% to 99% of healthy infants, children, and young adults (6,7).
The immunogenicity of hepatitis B vaccine in patients with CD has been investigated and found reduced in patients with CD (8–14). HLA phenotype DQ2 is considered the most important genetic marker for unresponsiveness to hepatitis B vaccine (9). Because CD is also strongly associated with the same haplotype, it was suggested that CD may be associated with unresponsiveness or hyporesponsiveness to the hepatitis B virus (HBV) vaccine (8,9). In contrast to hepatitis B vaccine, hepatitis A vaccine was found greatly immunogenic in children with CD (15).
In the present study, the rate of response to the hepatitis A and B vaccines, duration of protection against hepatitis A virus (HAV) and HBV, and the incidence of acute HAV or HBV infections during follow-up were determined in pediatric patients with CD and compared with healthy children.
Thirty children with CD diagnosed and followed up between 1999 and 2011 at Division of Pediatric Gastroenterology of Sisli Etfal Training and Research Hospital (Istanbul, Turkey), and 50 healthy age-, sex-, and body mass index–matched controls were evaluated prospectively. The patients and controls who had been vaccinated previously against HAV and HBV and had coexisting disease such as immunodeficiencies, autoimmune disorders including type 1 diabetes mellitus, autoimmune hepatitis, or thyroiditis were excluded. The controls were recruited from healthy children attending our pediatric clinics.
Baseline hepatitis B surface antigen (HBsAg), antibody to hepatitis B surface antigen (anti-HBs), total antibody to hepatitis B core antigen (anti-HBc), anti-HAV immunoglobulin (Ig)G and IgM were examined in all patients and controls. The diagnosis of CD was based on ESPGHAN criteria (16). The histopathological changes of small intestinal biopsies were graded according to a modified Marsh classification (17). Control subjects were also tested for the presence of anti-gliadin antibody, anti-endomysial antibody, and anti-tissue transglutaminase antibody. Informed consents were obtained from all of the parents before the procedures.
When the patients and the controls were susceptible to HAV defined as a negative total HAV antibody, 2 doses of hepatitis A vaccine (720 ELISA units, in 0.5 mL, Havrix, GlaxoSmithKline Biologicals, Rixensart, Belgium) were given 6 months apart intramuscularly into the deltoid muscle. When they were not immune for HBV, 3 doses of hepatitis B vaccine (20 μg, in 0.5 mL, Genhevac B, Sanofi Pasteur Diagnostic, France) were administered at months 0, 1, and 6 intramuscularly. None received the combined hepatitis A/B vaccine. Postvaccination serologic and virologic evaluation was performed 1 month after the last dose of vaccine. Seroconversion was considered if anti-HBs levels were above ≥10 mIU/mL and anti-HAV IgG was positive. Children were followed by testing anti-HAV antibodies, anti-HBs, and anti-HBc titers 1 month after the last dose of vaccinations, 1 month after the booster dose given to cases who did not respond to primary vaccination, and once every year during 7-year follow-up period. The booster dose was administered during a gluten-free diet (GFD). Dietary compliance and CD activity were monitored by measurement of antibodies against transglutaminase and endomysium. No validated questionnaire was used to assess dietary compliance.
Statistical analysis was performed using SPSS 11.0 software (SPSS Inc, Chicago, IL). Results were expressed as means ± standard deviation for quantitative variables and proportions for categorical variables, and percentage with 95% confidence interval (CI) was used to describe the prevalence. The analysis was conducted using Fisher exact test, χ2 test, and analysis of variance to analyze qualitative variables. P values of <0.05 were considered statistically significant.
The age of patients ranged from 1 to 15 years (mean 6.15 ± 4.1), and male:female ratio was 0.87. None of the patients was vaccinated against HAV and HBV before the diagnosis of CD. The control group consisted of 50 healthy children (17 girls and 33 boys, mean age 8.13 ± 1.7 years, range 1–17 years) with negative serological tests for CD.
Among 30 patients who had antibody testing, 14 (46.6%) had natural immunity for hepatitis A, and 16 (53.3%) were susceptible to HAV. Fifteen (30%) of the controls had natural immunity for hepatitis A. All patients and controls were negative for HBsAg, anti-HBc, and anti-HBs before vaccination. Thirty patients without evidence of earlier exposure to hepatitis B received hepatitis B vaccine, whereas 16 (53.3%) of them negative for HAV antibodies received hepatitis A vaccine. All of the controls were vaccinated against HBV and 70% against HAV. The baseline demographic and clinical characteristics of the cases are shown in Table 1.
No severe adverse reactions or allergy to vaccine components were reported after any dose of the vaccines. Local adverse effects (erythema, pain at injection side, induration) were mild and systemic side effects such as flu-like syndrome and fever occured several days following vaccines in only 3% of the cases in each group.
Twelve patients and 35 controls became positive for anti-HAV antibodies 1 month after hepatitis A vaccination (75% vs 100%, respectively; 95% CI 0.47–0.92, P = 0.007). Seventy percent of the patients and 90% of the controls were anti-HBs–positive 1 month after the last dose of the vaccine (95% CI 0.74–0.90, P = 0.03). The anti-HBs–positive and –negative patients did not differ significantly in age, sex, weight, height, and compliance to GFD (P > 0.05) (Table 2).
Those with anti-HBs <10 mIU/mL received a booster dose and 3 of them became anti-HBs–positive afterward (Table 3). Only 4 (13.3%; 95% CI 0.05–0.34) patient did not develop seroprotection against both HAV and HBV and also did not give response to the booster dose. Healthy nonresponders to primary vaccination had achieved 60% (3/5) rate of seroconversion after a single booster. Nine anti-HBs–negative patients with CD received a booster during a controlled GFD, and only 3 (33.3%) seroconverted. When compared with CD nonresponders (6/9), the difference was not statistically significant (95% CI 0.46–0.99, P = 0.58).
Overall seroconversion rates after booster dose were 96% in controls and 80% in patients with CD (95% CI 0.04–0.18, P = 0.04). All of the patients and controls except nonresponders had seroprotective titers of anti-HBs and anti-HAV IgG 7 years after the administration of last doses of vaccines. The sustained response rates were also similar in hepatitis A and B vaccination in both groups (P > 0.05). None of the patients, even nonresponders, became infected with HBV and HAV during follow-up period. All cases are still negative for anti-HAV IgM, HbsAg, and anti-HBc.
Approximately 4% to 10% of healthy individuals do not develop an adequate immune response against the hepatitis B vaccine after the primary vaccination series (18,19), and as reported in previous studies, nonresponsiveness was higher in patients with certain chronic illnesses such as chronic liver disease, uremia, inflammatory bowel disease, and CD (8–14,20–23).
It has been reported that HLA-II haplotypes and homozygosis for alleles HLA-B8, DR3, and DQ2 were significantly associated with hepatitis B vaccine nonresponse (24). There is a strong genetic predisposition to CD, associated with haplotypes DQ8 and most specifically with DQ2 (1,9,25,26). The exact pathogenesis of unresponsiveness to hepatitis B vaccine in patients with CD remains unknown. Park et al (12) demonstrated that 53.9% of children with CD did not respond to standard vaccination regimen for HBV; however, the response to other vaccines was not impaired, supporting the role of HLA haplotypes in responding to hepatitis B vaccine. In our study, the response rate of patients with CD to hepatitis B vaccination was found to be significantly lower than that of healthy individuals (70% vs 90%, 95% CI 0.74–0.90, P = 0.03) similarly as reported in previous studies (8–14). The limitation of our study is that HLA haplotypes were not be checked in controls; thus, the response rate could not be compared between the HLA-DQ2–positive and –negative controls and patients with CD.
It was postulated that vaccine nonresponse may not be permanent and compliance to treatment with GFD may improve the immune response to HBV vaccine in celiac children. Leonardi et al (9) demonstrated that the patients with CD who were immunized prospectively during a treatment with GFD developed protective immunity with similar success as healthy individuals. As reported in the study conducted by Ertem et al (11), we found that the response to hepatitis B vaccine in children with CD who were compliant with GFD was not different from that in healthy control group (P = 0.42). We observed a difference in compliance with GFD between responders and nonresponders that only 33.3% noncompliant patients responded to vaccination when compared with 55.5% who did not respond, but it was not significant (P = 0.82).
Zingone et al (27) studied seroprotective levels of anti-HBs during 11 years after primary immunization and a booster dose of vaccine and found that responses were lower in patients with CD compared with healthy individuals. Also in our study, the lower response rates were detected in patients with CD during 7-year follow-up.
Hepatitis A vaccine has been reported to be efficacious in healthy individuals and also in children with cancer, chronic liver disease, and inflammatory bowel disease (28–31). The completion of the 2-dose vaccine induces 100% seropositivity (4,5), and nonresponse is extremely rare (32). Similarly to the study reported by Sari et al (15) in which the response rate to hepatitis A vaccine in children with CD was 78.8% at 1 month and 97% at 7 months, it was found to be 75% at 1 month in our study but did not change during 7-year follow-up period.
In conclusion, we established the low immunologic response of hepatitis A and B vaccines in pediatric patients with CD similarly as reported in the literature. Further studies with larger study groups and longer duration of follow-up are required to clarify, in addition to antibody persistence, if hepatitis A and B vaccinations also induce immune memory that could maintain antibody production and confer lifelong immunity in children with CD.
1. van Heel DA, West J. Recent advances in coeliac disease. Gut
2. Plenge RM. Unlocking the pathogenesis of celiac disease
. Nat Genet
3. Bian GL, Ma R, Dong HJ, et al. Long-term clinical observation of the immunogenicity of inactivated hepatitis A vaccine
in children. Vaccine
4. Bell BP. Hepatitis A vaccine
. Semin Pediatr Infect Dis
5. Schmidtke P, Habermehl P, Knuf M, et al. Cell mediated and antibody immune response to inactivated hepatitis A vaccine
6. Assad S, Francis A. Over a decade of experience with a yeast recombinant hepatitis B vaccine
7. Venters C, Graham W, Cassidy W. Recombivax-HB: perspectives past, present and future. Expert Rev Vaccines
8. Noh KW, Poland GA, Murray JA. Hepatitis B nonresponse and celiac disease
. Am J Gastroenterol
9. Leonardi S, Spina M, Spicuzza L, et al. Hepatitis B vaccination failure in celiac disease
: is there a need to reassess current immunization
10. Nemes E, Lefler E, Szegedi L, et al. Gluten intake interferes with the humoral immune response to recombinant hepatitis B vaccine
in patients with celiac disease
11. Ertem D, Gonen I, Tanidir C, et al. The response to hepatitis B vaccine
: does it differ in celiac disease
? Eur J Gastroenterol Hepatol
12. Park SD, Markowitz J, Pettei M, et al. Failure to respond to hepatitis B vaccine
in children with celiac disease
. J Pediatr Gastroenterol Nutr
13. Balamtekin M, Uslu N, Baysoy G, et al. Responsiveness of children with celiac disease
to different hepatitis B vaccination protocols. Turk J Gastroenterol
14. Ahishali E, Boztas G, Akyuz F, et al. Response to hepatitis B vaccination in patients with celiac disease
. Dig Dis Sci
15. Sari S, Dalgic B, Basturk B, et al. Immunogenicity of hepatitis A vaccine
in children with celiac disease
16. Revised criteria for diagnosis of coeliac disease. Report of Working Group of European Society of Paediatric Gastroenterology and Nutrition. Arch Dis Child
17. Rostami K, Kerckhaert J, Tiemessen R, et al. Sensitivity of antiendomysium and antigliadin antibodies in untreated celiac disease
: disappointing in clinical practice. Am J Gastroenterol
18. Alper CA. The human immune response to hepatitis B surface antigen. Exp Clin Immunogenet
19. Coates T, Wilson R, Patrick G, et al. Hepatitis B vaccines: assessment of the seroprotective efficacy of two recombinant DNA vaccines. Clin Ther
20. Wiedmann M, Libert UG, Oesen U, et al. Decreased immunogenicity of recombinant hepatitis B vaccine
in chronic hepatitis C. Hepatology
21. Kalyoncu D, Urganci N. Response to hepatitis A and B vaccination in patients with chronic hepatitis C: 8-year follow-up. Paediatr Int Child Health
22. Stachowski J, Barth C, Pollok M, et al. Defective antigen presentation by monocytes in ESRD patients not responding to hepatitis B vaccination: impaired HBsAg internalization and expression of ICAM-1 and HLA-DR/la molecules. Mediators Inflamm
23. Gisbert JP, Chaparro M, Esteve M. Review article: prevention and management of hepatitis B and C infection in patients with inflammatory bowel disease. Aliment Pharmacol Ther
24. Wang C, Tang J, Song W, et al. HLA and cytokine gene polymorphisms are independently associated with responses to hepatitis B vaccination. Hepatology
25. Lundin KEA, Scott H, Fausa O, et al. T cells from the small intestinal mucosa of a DR4, DQ7/DR4, DQ8 celiac disease
patient preferentially recognize gliadin when presented by DQ8. Hum Immunol
26. Quarsten H, McAdam SN, Jensen T, et al. Staining of celiac disease
-relevant T cells by peptide-DQ2 multimers. J Immunol
27. Zingone F, Morisco F, Zanetti A, et al. Long-term antibody persistence and immune memory to hepatitis B vaccination in adult celiac patients vaccinated as adolescents. Vaccine
28. Radzikowski A, Banaszkiewicz A, Łazowska-Przeorek I, et al. Immunogenicity of hepatitis A vaccine
in pediatric patients with inflammatory bowel disease. Inflamm Bowel Dis
29. Ferreira CT, da Silveira TR, Vieira SM, et al. Immunogenicity and safety of hepatitis A vaccine
in children with chronic liver disease. J Pediatr Gastroenterol Nutr
30. Koksal Y, Yalcin B, Aydin GB, et al. Immunogenicity of hepatitis A vaccine
in children with cancer. Pediatr Hematol Oncol
31. Fioredda F, Plebani A, Hanau G, et al. Reimmunisation schedule in leukaemic children after intensive chemotherapy: a possible strategy. Eur J Haematol
32. Garner-Spitzer E, Kundi M, Rendi-Wagner P, et al. Correlation between humoral and cellular immune responses and the expression of the hepatitis A receptors HAVcr-1 on T cells after hepatitis A re-vaccination in high and low-responder vaccinees. Vaccine