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.
1. Yeung LT, Roberts EA. Current issues in the management of paediatric viral hepatitis. Liver Int
2. Fiore AE, Wasley A, Bell BP. Prevention of hepatitis A through active or passive immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep
3. Craig AS, Schaffner W. Prevention of hepatitis A with the hepatitis A vaccine. N Engl J Med
4. Bian GL, Ma R, Dong HJ, et al. Long-term clinical observation of the immunogenicity of inactivated hepatitis A vaccine in children. Vaccine
5. Hepatitis A vaccines. Wkly Epidemiol Rec
6. Ovsyannikova IG, Dhiman N, Jacobson RM, et al. Human leukocyte antigen polymorphisms: variable humoral immune responses to viral vaccines. Exp Rev Vaccines
7. King AL, Ciclitira PJ. Celiac disease: strongly heritable, oligogenic, but genetically complex. Mol Genet Metab
8. Plenge RM. Unlocking the pathogenesis of celiac disease. Nat Genet
9. Sollid LM, Thorsby E. HLA susceptibility genes in celiac disease: genetic mapping and role in pathogenesis. Gastroenterology
10. Ertem D, Gonen I, Tanidir C, et al. The response to hepatitis B vaccine: does it differ in celiac disease? Eur J Gastroenterol Hepatol
11. Park SD, Markowitz J, Pettei M, et al. Failure to respond to hepatitis B vaccine in children with celiac disease. J Pediatr Gastroenterol Nutr
12. Noh KW, Poland GA, Murray JA. Hepatitis B vaccine nonresponse and celiac disease. Am J Gastroenterol
13. 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. Pediatrics
14. Leonardi S, Spina M, Spicuzza L, et al. Hepatitis B vaccination failure in celiac disease: is there a need to reassess current immunization strategies? Vaccine
15. Ahishali E, Boztas G, Akyuz F, et al. Response to hepatitis B vaccination in patients with celiac disease. Dig Dis Sci
16. Radzikowski A, Banaszkiewicz A, Lazowska-Przeorek I, et al. Immunogenecity of hepatitis A vaccine in pediatric patients with inflammatory bowel disease. Inflamm Bowel Dis
17. Ferreira CT, Leite JC, Taniguchi A, et al. Immunogenicity and safety of an inactivated hepatitis A vaccine in children with Down syndrome. J Pediatr Gastroenterol Nutr
18. Keeffe EB, Iwarson S, McMahon BJ, et al. Safety and immunogenicity of hepatitis A vaccine in patients with chronic liver disease. Hepatology
19. Marsh MN. Gluten, major histocompatibility complex, and the small intestine. A molecular and immunobiologic approach to the spectrum of gluten sensitivity (‘celiac sprue’). Gastroenterology
20. Karakayali H, Ekici Y, Ozcay F, et al. Pediatric liver transplantation for acute liver failure. Transplant Proc
21. Kurugol Z, Mutlubas F, Ozacar T. A two-dose schedule for combined hepatitis A and B vaccination in children aged 6–15 years. Vaccine
22. Lopez EL, Contrini MM, Xifro MC, et al. Hepatitis A vaccination of Argentinean infants: comparison of two vaccination schedules. Vaccine
23. Werzberger A, Mensch B, Kuter B, et al. A controlled trial of a formalin-inactivated hepatitis A vaccine in healthy children. N Engl J Med
24. Bell BP, Negus S, Fiore AE, et al. Immunogenicity of an inactivated hepatitis A vaccine in infants and young children. Pediatr Infect Dis J
25. Marshall H, Nolan T, Diez Domingo J, et al. Long-term (5-year) antibody persistence following two- and three-dose regimens of a combined hepatitis A and B vaccine in children aged 1–11 years. Vaccine
26. Koksal Y, Yalcin B, Aydin GB, et al. Immunogenicity of hepatitis A vaccine in children with cancer. Pediatr Hematol Oncol
27. 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
28. Arguedas MR, Johnson A, Eloubeidi MA, et al. Immunogenicity of hepatitis A vaccination in decompensated cirrhotic patients. Hepatology
29. Arslan M, Wiesner RH, Poterucha JJ, et al. Safety and efficacy of hepatitis A vaccination in liver transplantation recipients. Transplantation
30. Van Loveren H, Van Amsterdam JG, Vandebriel RJ, et al. Vaccine-induced antibody responses as parameters of the influence of endogenous and environmental factors. Environ Health Perspect
31. Hohler T, Reuss E, Evers N, et al. Differential genetic determination of immune responsiveness to hepatitis B surface antigen and to hepatitis A virus: a vaccination study in twins. Lancet
32. Launay O, Grabar S, Gordien E, et al. Immunological efficacy of a three-dose schedule of hepatitis A vaccine in HIV-infected adults: HEPAVAC study. J Acquir Immune Defic Syndr
33. Reuman PD, Kubilis P, Hurni W, et al. The effect of age and weight on the response to formalin inactivated, alum-adjuvanted hepatitis A vaccine in healthy adults. Vaccine
34. Ozgenc F, Aksu G, Kirkpinar F, et al. The influence of marginal zinc deficient diet on post-vaccination immune response against hepatitis B in rats. Hepatol Res
35. Letson GW, Shapiro CN, Kuehn D, et al. Effect of maternal antibody on immunogenicity of hepatitis A vaccine in infants. J Pediatr
36. Orr N, Klement E, Gillis D, et al. Long-term immunity in young adults after a single dose of inactivated hepatitis A vaccines. Vaccine