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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 non-response

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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
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
slide5

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

(

(

(

slide6

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

slide7

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

slide8

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

the hepatitis b vaccine choice of the immunogen
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
slide10

Envelope proteins

of HBV and

HBV vaccines

hbsag vaccine is effective in preventing hbv infection despite the fact that
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

preS1

preS2

Hepatocyte

Glyceraldehyde-3-P dehydrogenase

IgA receptor

Interleukin 6

Asialoglycoprotein receptor

Transferrin receptor

Polymerized-albumin-receptor

Fibronectin

HBV - Hepatocyte interactions(1)
hbv hepatocyte interactions 2
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

slide14

d/y

122

K

Molecular structure of the major

hydrophilic region of HBsAg

a

mechanisms of action of anti hbs

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

hbsag is a poor immunogen
HBsAg is a poor immunogen

VAX = 20 µg SL* in PBS

hbsag is special
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
slide18

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

hbsag binds to monocytes and suppresses their activation by lps
HBsAg binds to monocytes andsuppresses their activation by LPS

LBP

HBsAg

LPS

-

TNFa, IL1, ..

Monocyte/mF

host factors determining response to hb vaccines
Host factors determining response to HB vaccines
  • Gender
  • Age
  • Concomitant illness
  • Genetic factor - MHC
slide21

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
response to hb vaccine multiple hla genes are involved
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

slide23

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
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
slide25

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
hbv envelope proteins and s l
HBV envelope proteins and S-L*

1

126

175

400

preS1 preS2 HBsAg

12

52

175

400

S-L*

133-145

slide27
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

persistence of immunity
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
slide29

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)

persistence of immunity1
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
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
demonstration of cmi towards hav methods subjects 2
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
slide33

RESULTS

15/20

18/20

slide34

RESULTS

4/16

6/16

slide35

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
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
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

hbsag vaccine escape variants
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
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

vaccination induces memory
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

slide42

Y

Y

Y

Y

Y

CD8+

CTL

CD4+

Th cell

NK

APC

NKT

cells

The principal actors

B cell

Hepatocyte

strategies to overcome nonresponsiveness1
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
slide44

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

severe combined immunodeficient mouse prkdc scid prkdc scid scid
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
in vivo exposure to a recall antigen activates ag specificb cell clones
In vivo exposure to a recall antigen activates Ag-specificB cell clones

Depraetere et al. J Immunol 2001;166:2929