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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 nonresponse • immune memory HBV genome organization The HBV infectious cycle Reverse transcription P protein Capsid protein ER/IC e Golgi cap RNA pregenome RNA ccc-DNA Precore, L, M, S + X proteins 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 HBsAg a-HBs HBeAg a-HBe a-HBc 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 %HBcAg+ hepatocytes Serum HBV-DNA sALT 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 The adaptive immune response to HBV a-HBe a-HBc a-HBs B cell Th2>Th1 cytokines Lysis Hepatocyte CD8+ CTL CD4+ Th cell TNF-a IFN-g IFN-g APC 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 Envelope proteins of HBV and HBV vaccines 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 HBV - Hepatocyte interactions (1) HBV Hepatocyte • preS1 • Glyceraldehyde-3-P dehydrogenase • IgA receptor • Interleukin 6 • Asialoglycoprotein receptor • preS2 • Transferrin receptor • Polymerized-albumin-receptor • Fibronectin HBV - Hepatocyte interactions HBV Hepatocyte • HBsAg • Annexin V • Apolipoprotein H • CD14 (2) Lipids play an important role in these interactions Neurath et al. Virology 1994;204:475 Vanlandschoot et al. unpublished Molecular structure of the major hydrophilic region of HBsAg d/y K a 122 Mechanisms of action of anti-HBs ? HBV Y Prevent cell entry Rapid clearance of infection Liver Anti-HBs Uptake via FcR Y mF T Improve antigen presentation Improve T cell response HBsAg is a poor immunogen Anti-HBs VAX 1 VAX2 VAX 3 Subject Day 0 W2 W4 W6 W8 16 <1 <1 <1 <1 <1 17 <1 <1 <1 <1 <1 18 <1 <1 <1 <1 <1 19 <1 <1 <1 <1 <1 20 <1 <1 3 6 5 21 2 <1 2 4 8 22 <1 <1 <1 <1 <1 23 <1 <1 <1 <1 <1 24 <1 <1 <1 <1 <1 25 <1 <1 <1 <1 <1 26 <1 <1 <1 <1 <1 27 <1 <1 <1 <1 <1 28 <1 <1 <1 <1 <1 29 <1 <1 <1 <1 <1 30 <1 <1 <1 <1 <1 VAX = 20 µg SL* in PBS VAX4 W16 <1 10 <1 <1 16 36 <1 <1 <1 2 <1 <1 <1 11 2 VAX5 W18 <1 33 <1 <1 850 132 <1 <1 117 7 8 4 <1 28 7 W20 2 300 <1 1 1420 1250 <1 <1 1410 28 14 102 7 58 66 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 Interaction between HBsAg and CD14+ cells ISO CD14 CD3 CD14 Cell CD19 B B B B B SA-PE CD14 FSC SA-PE b-rHBsAg + SA-PE CD14 HBsAg binds to monocytes and suppresses their activation by LPS LBP HBsAg LPS Monocyte/mF TNFa, IL1, .. Host factors determining response to HB vaccines • • • • Gender Age Concomitant illness Genetic factor - MHC Influence of H-2 genotype on the humoral immune response to HBsAg particles of different compositions Immunogen Strain H-2 Specific antibody titer (1/dilution) S PreS2 PreS1 HBsAg (S) B10.D2 B10.S B10.M d s f 81,920 0 0 0 0 0 0 0 0 PreS2 + S B10.D2 B10.S B10.M d s f 40,960 1,280 0 10,240 10,240 0 0 0 0 PreS1 +PreS2 +S B10.D2 B10.S B10.M d s f 81,920 5,120 10,240 5,120 10,240 1,280 640 1,280 10,240 Milich et al. J. Immunol. 1986;137:315 Response to HB vaccine: multiple HLA genes are involved GOOD RESPONSE is associated with DRB1*010DR5 DPB1*040DQB1*0301 DQB1*0501 NON/POOR RESPONSE is associated with DRB1*07 DPB1*1101 DQB1*020- Desombere et al. Tissue Antigens 1998;51:593-604 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 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 Influence of H-2 genotype on the humoral immune response to HBsAg particles of different compositions Immunogen Strain H-2 Specific antibody titer (1/dilution) S PreS2 PreS1 HBsAg (S) B10.D2 B10.S B10.M d s f 81,920 0 0 0 0 0 0 0 0 PreS2 + S B10.D2 B10.S B10.M d s f 40,960 1,280 0 10,240 10,240 0 0 0 0 PreS1 +PreS2 +S B10.D2 B10.S B10.M d s f 81,920 5,120 10,240 5,120 10,240 1,280 640 1,280 10,240 Milich et al. J. Immunol. 1986;137:315 HBV envelope proteins and S-L* 1 126 preS1 175 preS2 12 52 400 HBsAg 175 S-L* 133-145 400 Antibody response to HBsAg following administration of three additional doses of Engerix-B or S-L* in poor responders Month Seroprotection rate (%) Engerix-B (n=18) S-L* (n=14) Geometric mean titer (mIU/ml) Engerix-B (n=18) S-L* (n=14) 0 1 2 3 0 0 83 57 89 71 89 93 3.4 3.7 241 26 385 65 540 198 Leroux-Roels et al. Vaccine 1997;15:1732-6 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 Persistence of anti-HBs Combined hepatitis A/B vaccine versus Engerix-B (schedule : 0-1-6 months) GMTs in mIU/ml (log scale) 10000 1000 100 Twinrix (B) Engerix-B 10 1 -6 0 6 12 18 24 30 36 TIMING (in months) 42 48 54 60 66 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 Demonstration of CMI towards HAV Methods - 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 Demonstration of CMI towards HAV Methods - Subjects (2) • Based on the anti-HAV titers measured on month 60, two groups were defined Group H Group L anti-HAV > 200 U/L anti-HAV < 200 U/L n=20 n=16 • At month 72 blood was drawn to measure antibodies and HAV-specific cell mediated immune responses RESULTS High Titered Group HAV CMI response Study # Subject # anti-HAV Proliferation (U/L) (SI) 10 300 3,1 58 1325 1,5 65 3316 3,1 101 1291 7,9 HAV-112 107 243 1,4 128 339 5,7 135 3731 24,2 149 2020 97,5 176 4738 9,2 184 290 2,2 8 804 15,6 16 287 10,2 18 407 29,5 19 666 8 HAV-123 21 2387 2,5 24 442 2,5 33 2541 47,2 50 377 5,7 55 1459 14,8 57 902 8,6 15/20 IFN-g (pg/ml) 63 10 1010 1050 10 1400 964 1400 94 70 534 197 492 1400 51 45 1400 65 1388 284 18/20 IL-5 (pg/ml) 5 5 5 20,5 5 214,8 5 49,8 5 5 17,2 5 5 55 5 5 5 5 15,8 5 TT Proliferation (SI) 14,6 27,4 13,2 20,9 1,9 8,6 120,3 117,1 60,8 81,4 22,5 119,8 112,3 61,1 12,2 26,1 29,7 28,9 22,6 12,2 RESULTS Low Titered Group HAV CMI response Study # Subject # anti-HAV Proliferation (U/L) (SI) 13 102 1,1 44 197 12 47 10 1,4 51 55 3,6 HAV-112 56 193 2,6 62 185 1,3 77 108 3 86 85 1,1 92 156 1,4 103 186 1,4 9 52 1,1 15 90 3,5 HAV-123 32 106 2 36 127 1,7 59 96 1,5 64 138 1,8 4/16 IFN-g (pg/ml) 10 349 10 377 399 10 606 10 10 10 10 62 10 10 109 10 6/16 IL-5 (pg/ml) 5 5 5 14,6 5 5 5 5 5 5 5 5 5 5 5 5 TT Proliferation (SI) 30,4 12,2 20,5 11,5 26,4 11,3 39,7 66,7 63,1 1,6 8,6 39,8 14,1 12,8 10,1 7,6 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 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 Results Binding Reactivity of Human anti-HBsAg mAb with Wild-type and Mutant HBsAg 1600 1400 A450 nm 1200 1000 800 600 Cut-off 400 320 200 0 Wild-type and mutant HBsAg 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 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 T and B cell responses during acute and chronic HBV infections HBV antigens Al/TH/CTL Acute infection Chronic infection HBsAg/pre-S Ab TH CTL + + +++ (PBL) +/+/+ (liver) HBc/HBeAg Ab TH CTL ++ +++ ++ (PBL) +++ + + (liver) Polymerase Ab CTL + +++ (PBL) ++ + (liver) 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 The principal actors B cell CD8+ CTL CD4+ Th cell Hepatocyte NK APC NKT cells 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 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 1 2 4 4 7 Engerix-B 2 S-L* Leroux-Roels et al. Vaccine 1997;15:1732-6 Severe combined immunodeficient mouse Prkdcscid/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 In vivo exposure to a recall antigen activates Ag-specificB cell clones Anti-HBs Titer in IU/L Donor HuPBLSCID HuPBLSCID + HBsAg Plasma 6981 180 2502 Culture supe 0 26 320 Depraetere et al. J Immunol 2001;166:2929