Surface protein mutations in chronic hepatitis B patients who received hepatitis B vaccine therapy

Document Type: Original Article

Authors

1 Hepatitis B Molecular Laboratory, Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran

2 Digestive Disease Research Center, Shariati Hospital, Tehran, Iran

3 Department of Epidemiology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran

4 Keyvan Virology Laboratory, Tehran, Iran

5 Imam Khomeini Hospital, Tehran, Iran

6 Baqiyatallah Research Center for Gastroenterology and Liver Disease, Tehran, Iran

7 Robert-Koch-Haus Virchowstr.179.45147, Essen, Germany

Abstract

Objective (s):The aim of this study was to determine the correlation between vaccine therapy and appearance of mutations in hepatitis B surface antigen (HBsAg)-positive chronic hepatitis B virus (HBV) patients.
Materials and Methods: 16 patients received the HBV vaccine and another 16 individuals from the control group did not. The surface gene was amplified and directly sequenced from samples prior to vaccination and six months after the third dose.
Results:Only one patient lost HBsAg. 48 and 44 amino acid mutations were found before and after vaccine therapy in the vaccine group respectively, 51 of which (55.4%) occurred in immune epitopes: 5 were in B cell, 21 in T helper (Th), and 25 in cytotoxic T-lymphocyte (CTL) epitopes. In the control group, 35 and 41 amino acid substitutions were found before and after therapy, respectively. 32 (42%) of 76 amino acid changes occurred within immune epitopes. There were no differences in age, gender, and duration of chronicity in both patient and control groups in terms of the frequency and the patterns of mutations.
Conclusion: In chronic carriers who already had HBsAg variants selected by the host-immune response, any immune stimulation by the vaccine had no effect on the chronic state of these patients or selected any remarkable escape mutants. Newer strategies should be considered based on third generation or the use of DNA vaccines or new adjuvants.

Keywords


1.   Fontaine H, Thiers V, Pol S. Hepatitis B virus genotypic resistance to lamivudine. Ann Intern Med. 1999;131:716-717.

2.   Zoulim F, Trepo C. New antiviral agents for the therapy of chronic hepatitis B virus infection. Intervirology. 1999;42:125-144.

3.   Bidgoli SA, Daryani NE, Motamedi M, Miri A, Poorsamimi P. Evaluation of possible risk factors of lamivudine resistance in chronic hepatitis b patients: a retrospective study in Iran. Hepat Mon 2009; 9:171-179.

4.   Pol S, Driss F, Michel ML, Nalpas B, Berthelot P, Brechot C. Specific vaccine therapy in chronic hepatitis B infection. Lancet 1994; 344:342.

5.   Pol S, Michel ML, Brechot C. Immune therapy of hepatitis B virus chronic infection. Hepatology 2000; 31:548-549.

6.   Daryani NE, Nassiri-Toosi M, Rashidi A, Khodarahmi I. Immunogenicity of recombinant hepatitis B virus vaccine in patients with and without chronic hepatitis C virus infection: a case-control study. World J Gastroenterol 2007;13:294-8.

7.   Palmovic D, Crnjakovic-Palmovic J. Vaccination against hepatitis B: results of the analysis of 2000 population members in Croatia. Eur J Epidemiol 1994; 10:541-547.

8.   Pata C, Yazar A, Konca K, Bilgic G, Eskandari G, Ozturk C. The effect of recombinant hepatitis B vaccine therapy in chronic hepatitis B infection. Turk J Gastroenterol 2002;13:6-10.

9.   Weinstein T, Chagnac A, Boaz M, Ori Y, Herman M, Zevin D, et al. Improved immunogenicity of a novel third-generation recombinant hepatitis B vaccine in patients with end-stage renal disease. Nephron Clin Pract 2004;97:c67-72.

10. Boni C, Penna A, Bertoletti A, Lamonaca V, Rapti I, Missale G, et al. Transient restoration of anti-viral T cell responses induced by lamivudine therapy in chronic hepatitis B. J Hepatol 2003; 39:595-605.

11. Boni C, Penna A, Ogg GS, Bertoletti A, Pilli M, Cavallo C, et al. Lamivudine treatment can overcome cytotoxic T-cell hyporesponsiveness in chronic hepatitis B: new perspectives for immune therapy. Hepatology 2001; 33:963-971.

12. Inchauspe G, Michel ML. Vaccines and immunotherapies against hepatitis B and hepatitis C viruses. J Viral Hepat 2007; 14:97-103.

13. Brown SE, Howard CR, Zuckerman AJ, Steward MW. Affinity of antibody responses in man to hepatitis B vaccine determined with synthetic peptides. Lancet 1984; 2:184-187.

14. Carman WF, Zanetti AR, Karayiannis P, Waters J, Manzillo G, Tanzi E, et al. Vaccine-induced escape mutant of hepatitis B virus. Lancet 1990; 336:325-329.

15. Hsu HY, Chang MH, Liaw SH, Ni YH, Chen HL. Changes of hepatitis B surface antigen variants in carrier children before and after universal vaccination in Taiwan. Hepatology 1999; 30:1312-1317.

16. Huang X, Lu D, Ji G, Sun Y, Ma L, Chen Z, et al. Hepatitis B virus (HBV) vaccine-induced escape mutants of HBV S gene among children from Qidong area, China. Virus Res 2004;99:63-68.

17. Cooreman MP, Leroux-Roels G, Paulij WP. Vaccine- and hepatitis B immune globulin-induced escape mutations of hepatitis B virus surface antigen. J Biomed Sci 2001; 8:237-47.

18. Carman WF, Thursz M, Hadziyannis S, McIntyre G, Colman K, Gioustoz A, et al. Hepatitis B e antigen negative chronic active hepatitis: hepatitis B virus core mutations occur predominantly in known antigenic determinants. J Viral Hepat 1995; 2:77-84.

19. Ijaz S, Torre F, Tedder RS, Williams R, Naoumov NV. Novel immunoassay for the detection of hepatitis B surface 'escape' mutants and its application in liver transplant recipients. J Med Virol 2001; 63:210-216.

20. Yamamoto K, Horikita M, Tsuda F, Itoh K, Akahane Y, Yotsumoto S, et al. Naturally occurring escape mutants of hepatitis B virus with various mutations in the S gene in carriers seropositive for antibody to hepatitis B surface antigen. J Virol 1994; 68:2671-2676.

21. Waters JA, Kennedy M, Voet P, Hauser P, Petre J, Carman W, et al. Loss of the common "A" determinant of hepatitis B surface antigen by a vaccine-induced escape mutant. J Clin Inves 1992; 90:2543-2547.

22. Barnaba V, Franco A, Paroli M, Benvenuto R, De Petrillo G, Burgio VL, et al. Selective expansion of cytotoxic T lymphocytes with a CD4+CD56+ surface phenotype and a T helper type 1 profile of cytokine secretion in the liver of patients chronically infected with Hepatitis B virus. J Immunol 1994; 152:3074-3087.

23. Ducos J, Bianchi-Mondain AM, Pageaux G, Conge AM, Poncet R, Vendrell JP, et al. Hepatitis B virus (HBV)-specific in vitro antibody production by peripheral blood mononuclear cells (PBMC) after vaccination by recombinant hepatitis B surface antigen (rHBsAg). Clin Exp immunol 1996; 103:15-18.

24. Honorati MC, Dolzani P, Mariani E, Piacentini A, Lisignoli G, Ferrari C, et al. Epitope specificity of Th0/Th2 CD4+ T-lymphocyte clones induced by vaccination with rHBsAg vaccine. Gastroenterology 1997;112:2017-2027.

25. Mancini-Bourgine M, Fontaine H, Brechot C, Pol S, Michel ML. Immunogenicity of a hepatitis B DNA vaccine administered to chronic HBV carriers. Vaccine 2006; 24:4482-4489.

26. Jazayeri SM, Basuni AA, Sran N, Gish R, Cooksley G, Locarnini S, et al. HBV core sequence: definition of genotype-specific variability and correlation with geographical origin. J Viral Hepat 2004; 11:488-501.

27. Chen WN, Oon CJ. Mutation "hot spot" in HLA class I-restricted T cell epitope on hepatitis B surface antigen in chronic carriers and hepatocellular carcinoma. Biochem Biophys Res Commun 1999; 262:757-761.

28. Chong-Jin O, Wei Ning C, Shiuan K, Gek Keow L. Identification of hepatitis B surface antigen variants with alterations outside the "a" determinant in immunized Singapore infants. J Infect Dis 1999;179:259-263.

29. Khakoo SI, Ling R, Scott I, Dodi AI, Harrison TJ, Dusheiko GM, et al. Cytotoxic T lymphocyte responses and CTL epitope escape mutation in HBsAg, anti-HBe positive individuals. Gut. 2000; 47:137-143.

30. Liu CJ, Kao JH, Shau WY, Chen PJ, Lai MY, Chen DS. Naturally occurring hepatitis B surface gene variants in chronic hepatitis B virus infection: correlation with viral serotypes and clinical stages of liver disease. J Med Virol 2002; 68:50-59.

31. Song BC, Kim SH, Kim H, Ying YH, Kim HJ, Kim YJ, et al. Prevalence of naturally occurring surface antigen variants of hepatitis B virus in Korean patients infected chronically. J Med Virol. 2005; 76:194-202.

32. Chisari FV. Hepatitis B virus transgenic mice: models of viral immunobiology and pathogenesis. Curr Top Microbiol Immunol 1996; 206:149-173.

33. Chisari FV. Rous-Whipple Award Lecture. Viruses, immunity, and cancer: lessons from hepatitis B. Am J Pathol 2000;156:1117-1132.

34. Carman WF, Boner W, Fattovich G, Colman K, Dornan ES, Thursz M, et al. Hepatitis B virus core protein mutations are concentrated in B cell epitopes in progressive disease and in T helper cell epitopes during clinical remission. J Infect Dis 1997; 175:1093-1100.

35. Ferrari C, Penna A, Bertoletti A, Valli A, Antoni AD, Giuberti T, et al. Cellular immune response to hepatitis B virus-encoded antigens in acute and chronic hepatitis B virus infection. J Immunol 1990; 145:3442-3449.

36. Hosono S, Tai PC, Wang W, Ambrose M, Hwang DG, Yuan TT, et al. Core antigen mutations of human hepatitis B virus in hepatomas accumulate in MHC class II-restricted T cell epitopes. Virology. 1995; 212:151-162.

37. Jazayeri SM, Dornan ES, Boner W, Fattovich G, Hadziyannis S, Carman WF. Intracellular distribution of hepatitis B virus core protein expressed in vitro depends on the sequence of the isolate and the serologic pattern. J Infect Dis 2004; 189:1634-1645.

38.          Rehermann B, Pasquinelli C, Mosier SM, Chisari FV. Hepatitis B virus (HBV) sequence variation of cytotoxic T lymphocyte epitopes is not common in patients with chronic HBV infection. J Clin Invest 1995; 96:1527-1534.