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Hepatitis B vaccination: an alternative (re)view

Hepatitis B vaccination: an alternative (re)view. Geert Leroux-Roels Center for Vaccinology Ghent University and Hospital. Overview of the presentation. the virus the infection the immune response the HBV vaccine: HBsAg non-response to HBsAg strategies to overcome non-response

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Hepatitis B vaccination: an alternative (re)view

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  1. Hepatitis B vaccination:an alternative (re)view Geert Leroux-Roels Center for Vaccinology Ghent University and Hospital

  2. Overview of the presentation • the virus • the infection • the immune response • the HBV vaccine: HBsAg • non-response to HBsAg • strategies to overcome non-response • immune memory

  3. HBV genome organization

  4. Reverse transcription P protein Capsid protein ER/IC e Golgi cap RNA pregenome RNA ccc-DNA Precore, L, M, S + X proteins The HBV infectious cycle ( ( (

  5. Viral clearance without destruction of infected cells during acute HBV infection Luca Guidotti et al. Science 284:825- 829, 1999 Infectious serum containing ~ 5x107 genome equivalents of HBV (ayw) from transgenic mice 2 healthy chimps developed typical acute,self-limited HBV infections documented with - serological - virological - histopathological - molecular analyses on serum specimens and liver biopsies that were obtained weekly

  6. HBsAg a-HBs HBeAg a-HBe a-HBc %HBcAg+ hepatocytes Serum HBV-DNA sALT 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 CD3 CD8 CD4 Based on Guidotti et al. Science 284:825, 1999

  7. a-HBe Y B cell Y a-HBc a-HBs Y Th2>Th1 cytokines Lysis Hepatocyte CD8+ CTL CD4+ Th cell TNF-a IFN-g IFN-g APC The adaptive immune response to HBV

  8. The Hepatitis B vaccine : choice of the immunogen • A 1 minute boil of MS2 serum (HBV) destroyed infectivity, but left immunogenicity • HBsAg is an envelope protein • recovery of acute HBV infection is characterized by HBsAg/anti-HBs seroconversion • passively acquired anti-HBs protects individuals from infection with HBV

  9. Envelope proteins of HBV and HBV vaccines

  10. HBsAg vaccine is effective in preventing HBV infection despite the fact that : • Anti-HBs is not strictly a ‘neutralizing’ antibody, since HBsAg is probably not the receptor-binding element of HBV • HBsAg is a poor immunogen • HBsAg has anti-inflammatory qualities

  11. HBV preS1 preS2 Hepatocyte Glyceraldehyde-3-P dehydrogenase IgA receptor Interleukin 6 Asialoglycoprotein receptor Transferrin receptor Polymerized-albumin-receptor Fibronectin HBV - Hepatocyte interactions(1)

  12. HBV HBsAg Hepatocyte Annexin V Apolipoprotein H CD14 HBV - Hepatocyte interactions(2) Lipids play an important role in these interactions Neurath et al. Virology 1994;204:475 Vanlandschoot et al. unpublished

  13. d/y 122 K Molecular structure of the major hydrophilic region of HBsAg a

  14. Y Y Y mF T Mechanisms of action of anti-HBs ? HBV Y Liver Rapid clearance of infection Prevent cell entry Y Anti-HBs Uptake via FcR Improve T cell response Improve antigen presentation

  15. HBsAg is a poor immunogen VAX = 20 µg SL* in PBS

  16. HBsAg is ‘special’ • Produced by HBV-infected hepatocytes • Circulates in serum of chronic HBV patients at 50-300 µg/ml • HBsAg contains 30% lipids • HBsAg binds to CD14 expressing cells • monocytes, macrophages • suppresses inflammatory responses

  17. B B B B B ISO CD3 CD19 CD14 FSC SA-PE b-rHBsAg + SA-PE Interaction between HBsAg and CD14+ cells CD14 CD14 CD14 Cell SA-PE

  18. HBsAg binds to monocytes andsuppresses their activation by LPS LBP HBsAg LPS - TNFa, IL1, .. Monocyte/mF

  19. Host factors determining response to HB vaccines • Gender • Age • Concomitant illness • Genetic factor - MHC

  20. Immunogen Strain H-2 Specific antibody titer (1/dilution) S PreS2 PreS1 HBsAg (S) B10.D2 d 81,920 0 0 B10.S s 0 0 0 B10.M f 0 0 0 PreS2 + S B10.D2 d 40,960 10,240 0 B10.S s 1,280 10,240 0 B10.M f 0 0 0 PreS1 + PreS2 B10.D2 d 81,920 5,120 640 + S B10.S s 5,120 10,240 1,280 B10.M f 10,240 1,280 10,240 Milich et al. J. Immunol. 1986;137:315 Influence of H-2 genotype on the humoral immune response to HBsAg particles of different compositions

  21. GOOD RESPONSE is associated with DRB1*010- DR5 DPB1*040- DQB1*0301 DQB1*0501 NON/POOR RESPONSE is associated with DRB1*07 DPB1*1101 DQB1*020- Response to HB vaccine:multiple HLA genes are involved Desombere et al. Tissue Antigens 1998;51:593-604

  22. Antibody production requires cooperation between macrophages, T cells and B cells Peptide fragment of antigen HLA DP, DQ, DR TCR Non-response resides at the level of APC-TCR interaction

  23. Strategies to overcome nonresponsiveness • Add preS-epitopes to HBsAg vaccine • Change vaccine carrier • DNA vaccines • HBcAg as carrier • More immunogenic adjuvants • Give additional vaccine doses

  24. Immunogen Strain H-2 Specific antibody titer (1/dilution) S PreS2 PreS1 HBsAg (S) B10.D2 d 81,920 0 0 B10.S s 0 0 0 B10.M f 0 0 0 PreS2 + S B10.D2 d 40,960 10,240 0 B10.S s 1,280 10,240 0 B10.M f 0 0 0 PreS1 + PreS2 B10.D2 d 81,920 5,120 640 + S B10.S s 5,120 10,240 1,280 B10.M f 10,240 1,280 10,240 Milich et al. J. Immunol. 1986;137:315 Influence of H-2 genotype on the humoral immune response to HBsAg particles of different compositions

  25. HBV envelope proteins and S-L* 1 126 175 400 preS1 preS2 HBsAg 12 52 175 400 S-L* 133-145

  26. Antibody response to HBsAg following administration of three additional doses of Engerix-B or S-L* in poor responders Month 0 1 2 3 Seroprotection rate (%) Engerix-B (n=18) 0 83 89 89 S-L* (n=14) 0 57 71 93 Geometric mean titer ( mIU/ml) Engerix-B (n=18) 3.4 241 385 540 S-L* (n=14) 3.7 26 65 198 Leroux-Roels et al. Vaccine 1997;15:1732-6

  27. Persistence of immunity • Level of anti-HBs declines after vaccination • How long does protection last ? • Is booster immunization needed ? • Very few breakthrough infections occur • Vaccination induces immune memory

  28. Persistence of anti-HBs Combined hepatitis A/B vaccine versus Engerix-B (schedule : 0-1-6 months) 10000 1000 100 GMTs in mIU/ml (log scale) Twinrix (B) Engerix-B 10 1 -6 0 6 12 18 24 30 36 42 48 54 60 66 TIMING (in months)

  29. Persistence of immunity • Levels of anti-HAV and anti-HBs decline after vaccination • How long does protection last ? • Is booster immunization needed ? • Very few breakthrough infections occur • Vaccination induces immune memory

  30. Demonstration of CMI towards HAVMethods - Subjects (1) • Subjects enrolled in this project were recruited from 2 follow-up studies of long-term antibody persistence after the administration of 2 doses of 1440 EU HAV vaccine • study HAV-112 : 0-12 month scheme • study HAV-123 : 0-6 month scheme • anti-HAV titers were measured on months 24, 36, 48, 60 and 72

  31. Demonstration of CMI towards HAVMethods - Subjects (2) • Based on the anti-HAV titers measured on month 60, two groups were defined Group H anti-HAV > 200 U/L n=20 Group L anti-HAV < 200 U/L n=16 • At month 72 blood was drawn to measure antibodies and HAV-specific cell mediated immune responses

  32. RESULTS 15/20 18/20

  33. RESULTS 4/16 6/16

  34. Center for Vaccinology Agnes Vandeputte Ali Farhoudi Andrea Verwulgen Annick Willems Arsène-Hélène Batens Cao Tinghua Frédéric Clement Freya Van Houtte Isabelle Desombere Lieve Van Crombrugge Lieven Verhoye Peter Vanlandschoot Philip Meuleman Sophia Steyaert Sybil Couvent Yvonne Gijbels

  35. Recommendations of the European Consensus Group in Hepatitis B Immunity • No boosters for immunocompetent individuals who have responded to a primary course • in certain risk groups boosters may be used to provide reassurance of protective immunity • for immunocompromised patients regular testing for anti-HBs and booster injections when titer falls below 10mIU/ml are recommended • non-responders to a primary course should continue to be studied • long-term monitoring should continue Lancet 2000;355:561-5

  36. ResultsBinding Reactivity of Human anti-HBsAg mAb with Wild-type and Mutant HBsAg 1600 1400 1200 1000 800 A450 nm 600 Cut-off 320 400 200 0 A128V S136T T148A Y134F G130N S154E M133T D144H G145A R122K K160R Q129R G145R K141W wt ayw3 Wild-type and mutant HBsAg

  37. HBsAg vaccine escape variants • Point mutations in the second ‘a’ loop, notably at amino acids 144 and 145, alter antigenicity dramatically • these mutations confer escape characteristics to HBV under pressure mediated by rHBsAg-induced antibodies

  38. Will escape variants ever become important ? Model simulation representing the worse case scenario with a highly infectious variant and a non-cross-reactive vaccine Wilson et al. J.Viral Hepat. 1998;5(suppl2):25-30

  39. T and B cell responses during acute and chronic HBV infections

  40. Vaccination induces memory In vivo antibody production In vitro lymphoproliferation • in vivo humoral and in vitro anti-HBs responses are closely correlated • booster responses reveal the immune memory Leroux-Roels et al. Vaccine 1994;12:812-8

  41. Y Y Y Y Y CD8+ CTL CD4+ Th cell NK APC NKT cells The principal actors B cell Hepatocyte

  42. Strategies to overcome nonresponsiveness • Add preS-epitopes to HBsAg vaccine • Change vaccine carrier • DNA vaccines • HBcAg as carrier • More immunogenic adjuvants • Give additional vaccine doses

  43. 1 Engerix-B 4 S-L* 4 7 2 Evolution of anti-HBs in response to three additional vaccine doses given to 18 subjects with a poor response to 4 doses of HB vaccine 2 Leroux-Roels et al. Vaccine 1997;15:1732-6

  44. Severe combined immunodeficient mousePrkdcscid/Prkdcscid (SCID) • autosomal recessive mutation in mice • severe deficiency in mature lymphocytes • virtual absence of lypmhoid cells in the thymus, spleen, lymph nodes and gut • no Ab production, no DTH response, no graft rejection • innate immune system is intact

  45. In vivo exposure to a recall antigen activates Ag-specificB cell clones Depraetere et al. J Immunol 2001;166:2929

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