Development and utilization of the PreS/S hepatitis B vaccine in … · 2013-05-13 · preS1/preS2,...
Transcript of Development and utilization of the PreS/S hepatitis B vaccine in … · 2013-05-13 · preS1/preS2,...
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Development and utilization of the PreS/S hepatitis B vaccine in Israel
Daniel Shouval Liver Unit
Hadassah-Hebrew University Hospital Jerusalem, Israel
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The rational for development of a more immunogenic HBV vaccine
• Non–response to conventional HBV vaccines in special populations
• Fast induction of immunity to HBV in defined populations
• Low compliance with the 3 dose regimen of conventional HBV vaccines
• Emerging evidence on loss of post vaccination immune memory 20 years past primary immunization • Possible protection against HBV envelope mutant(s)
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HISTORY OF HEPATITIS B VACCINES
1st Generation: Plasma-derived (HBsAg, Pre-S1 / Pre-S2) 2nd Generation: DNA Recombinant, subunit vaccine (HBsAg, Pre-S2) -E. Coli-derived -Yeast-derived 3rd Generation: Mammalian cell derived (HBsAg, Pre-S) -HBsAg, Pre-S2 -HBsAg, Pre-S2, Pre-S1
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4 overlapping open reading frames
Reverse transcriptase/ DNA polymerase domain overlaps with surface gene
100 times more infective than HIV
Found in blood and body fluids
MMWR. 2003;52:1-33. Ott MJ and Aruda M. J Pediatr Health Care. 1999;13:211-216. Ribeiro RM, et al. Microbes and Infection. 2002;4:829-835.
1622
EcoRI 3221, 1
(+) (-)
polymerase
The Hepatitis B Virus
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Three Generations of Hepatitis B Vaccines
s
Vaccines
Vaccines*
rDNA
I
II
III
*Pre S/S HBV vaccine trade names: Bio Hep B, Hepimmune, Sci B Vac
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S
S (76.3%w)
Pre-S2
Pre-S1 (2%w) Pre-S2 (21.7%w)
L
S
M
P24 GP27
P24 GP27
P24 (46%w) GP27 (30.3%w)
GP36
GP33 (19.1%w)
GP36 P39
GP42
Peptide composition Recombinant HBV vaccines
(1.2%w)
(0.8%w) (2.6%w)
GP33
D. Diminsky and Y. Barenholz, 1990.
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BioHep B:Composition of HBsAg particles(%w)
protein
triglycerides
cholesterol ester
free cholesterol
phospholipids
59.7
34.0
3.0
2.1 1.2
D. Diminsky amd Y.Barenholz,1996.
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Bypass of Non-responsiveness to Immunization in Mice
0
400
800
1200
1600
2000
30 60
Bio-Hep-BH-B-VaxEngerix
1
10
100
1000
10000
100000
30 60
Days after vaccination
Anti-
HBs,
mIU
/ml
N=10
B-10s B-10m
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Development of an PreS/S HBV Vaccine
• Goals - Evaluation of Safety & Immunogenicity - Registration • Approach - GCP Standard Studies - Central Programs in Singapore & Israel
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Subject Adults Children Neonates No. of Studies 8 4 5 Age 10-60 y 2m-10yrs Newborn Regime (month) 0,1,6 0,1,6 0,1,6 Doses used (mcg) 5,10 or 20 2.5 or 5 2.5 or 5 Blood drawn at month 0,1,2,6,7,12 0,2,6,7,12 0,1,6,9,12 HBV Marker Test Abbott EIA Abbott EIA Abbott EIA
Clinical Evaluation and Protocols
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CLINICAL STUDIES – Bio Hep B
Study Group Dose (µg) No. of Subjects Enrolled 5.0 474 Adults 10 579 20 21*
Subtotal 1074 2.5 379 Children 5.0 213
Subtotal 592 2.5 883 Neonates 5.0 476 Subtotal 1359
Grand Total 3025
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Immunogenicity of Sci B Vac in Children
1
10
100
1000
10000
100000
1 2 6 7 12month
2.5µg, n=33 5µg, n=36
Age: 2m - 11y
anti-
HBs,
mIU
/ml
*Bi0Hep B
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EFFICACY OF SCI-B-VAC IN NEONATES* (COMPARATIVE STUDY)
0
20
40
60
80
100
1 7 12 Months
Sci-B-Vac (2.5ug) Engerix-B (10ug)
54
7
100 100
Sero
prot
ectio
n (%
)
*Three doses 0,1,6m
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Distribution of anti-HBs titers following three doses of PreS/S vaccine
Immunogenicity of the Pre S/S vaccine according to weight
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Comparative Immunogenicity of Hepatitis B Vaccines*
• Protocol • N - 36 (20M/16F) • Mean age - 23y (19-28)
• Protocol - 2 doses of Sci B Vac 10 µg/dose or - 2 doses of Engerix B 20 µg/dose • Time of i.m. injection: day 0; 6 months
*Shapira MY, Zeira E, Adler R, Shouval D. Rapid seroprotection against hepatitis B following the first dose of Pre-S1/Pre-S2/S vaccine. J. Hepatology 34(1):123-127, 2
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Comparative Immunogenicity of Two Hepatitis B Vaccines*
0 0
60%
12.5%
70%
25%
0
20
40
60
80
100
sero
prot
ectio
n
(%)
0 1 6 7
time after priming (months) Sci B Vac Engerix-B
V V
*Shapira M et al. J Hepatology 2000
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Area Under The Curve (AUC) of Anti-HBs during the First Month*
26.3
10.5
63.2
47.06
29.4123.53
0
10
20
30
40
50
60
70
<10 10-100 >100
Bio-Hep-B (365+16)
Engerix-B (85+48)
5 2 4 12 5 8
*Shapira MY et al. J. Hepatology 34(1):123-127, 2001.
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Immunogenicity of a Sci B Vac vaccine according to weight
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Immunogenicity of Sci B Vac in neonates born to HBsAg+ mothers (dose response)
0
10
20
30
40
50
60
70
80
90
100
1 6 9 12
Sci-B-Vac (2.5 ug Sci-B-Vac (5ug)
Sero
prot
ectio
n (%
)
Months
39
56
85
99 95 96 100 100
*Three doses 0,1,6m
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Immunogenicity of Sci B Vac in neonates born to HBsAg+ mothers (by HBeAg status)
Sci-B-Vac = 5 µg
20
50
Ser
opro
tect
ion
(%)
Months
85
94 94 98 98
94 Sci-B-Vac = 5 µg
Ser
opro
tect
ion
(%)
94 98
94
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SCI-B-VAC Neonate born to HBsAg+/HBeAg+ Mothers
Trial site Dosage No of subjects Seroprotection (%) Vietnam 2.5 mcg 17 83 Singapore + Vietnam 5.0 mcg 10 100 Singapore 5.0 mcg + HBIg 37 94 Total No 64
Data at month 12 (anti-HBs levels ≥10 mIU/ml)
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Serial changes in anti-HBs antibodies in patients with chronic hepatitis B after liver transplantation*
N=21
*All patients received lamivudine (no HBIG) Lo CM et al. HEPATOLOGY 2003;37:36-43
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Mathematical model of the antibody response to hepatitis B vaccines:
Implications for reduced schedules
• The model parameters are estimated from a data base of
10,815 post vaccination anti-HBs titer measurements obtained from 1923 adults participating in clinical vaccine trials
• Model simulation suggests that a single vaccine dose could prime immune memory as shown by one booster dose at 6m; thus a two dose schedule will be sufficient for long-term protection against HBV ( a concept not yet accepted by most immunologists)
Jamie N. Wilson , James Nokes, Graham F. Medley , Daniel Shouval. Vaccine 2007;25:3705
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Figure: Optimized 95% confidence intervals for each study.
• (a) The rate of antigen-dependent memory generation (γ).
• (b) The rate of antigen-independent memory generation (β).
• (c) The peak antibody/memory level (N). • (d) The predicted time taken for memory to reach 10
mIU/ml after a single vaccination.
Mathematical model of the antibody response to hepatitis B vaccines: Implications for reduced schedules
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Mathematical model of the antibody response to hepatitis B vaccines: Implications for reduced schedules
Jamie N. Wilson , James Nokes, Graham F. Medley , Daniel Shouval Vaccine 2007;25:3705
Vaccine Brandname
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Adoptive Transfer of Immunity in Mice: Comparison of Yeast and Mammalian cell Derived Vaccines
o Immunization of Balb/C mice with a rHBV vaccine
• Transplantation of bone marrow from immunized mice
to immune suppressed Balb/C mice
• Monitoring of cellular and humoral immune response
to HBV
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Adoptive transfer of immunity to HBV in mice: The humoral response
Comparison of yeast to CHO derived hepatitis B vaccines
21 37 47 76 88 106 10 1
10 2
10 3
10 4
10 5
S – yeast derived HBV vaccine
preS1/preS2, S – CHO derived HBV vaccin
day after BMT
booster
Ant
i-HB
s,m
IU/m
l
Day of BMT
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Clearance of Serum HBV Markers in an HBsAg Carrier Following BMT*
*Ilan Y. et al., Gastroenterology 1993; 104:1818
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Cellular and humoral immune response to a third generation hepatitis B vaccine (IFN Elispots)
Journal of Viral Hepatitis Volume 14, Issue 8, pages 592-598, 30 APR 2007 DOI: 10.1111/j.1365-2893.2007.00848.x http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2893.2007.00848.x/full#f2
L,M,S
L,M
S
Volunteers immunized with [•] Sci B Vac or [○] the control vaccine.
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Cellular and humoral immune response to a third generation hepatitis B vaccine Proliferation assay
Journal of Viral Hepatitis .x2893.2007.00848-1365/j.10.1111DOI: 2007 APR 30 , 598-592pages , 8, Issue 14Volume 3.x/full#f2893.2007.00848-1365/j.10.1111http://onlinelibrary.wiley.com/doi/
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Cellular and humoral immune response to a third generation hepatitis B vaccine
Journal of Viral Hepatitis Volume 14, Issue 8, pages 592-598, 30 APR 2007 DOI: 10.1111/j.1365-2893.2007.00848.x http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2893.2007.00848.x/full#f4
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© 2009 Lippincott Williams & Wilkins, Inc. Published by Lippincott Williams & Wilkins, Inc. 2
Adoptive Immune Transfer of Hepatitis B Virus Specific Immunity FromImmunized Living Liver Donors to Liver Recipients
.
Schumann, A. et al.Transplantation. 87(1):103-111,, 2009.
FIGURE 1. Humoral and cellular immune responses of 46 potential living liver donors (LLDs). The x-axis indicates the number of vaccinations or booster-vaccinations. Thirty-two donors (*) were excluded from transplantation because of medical or psychological reasons. Fourteen donors ([white up pointing small triangle] SYMBOL) donated a part of their liver to the corresponding recipients. Values in donors one to three who transferred their hepatitis B virus (HBV)-specific immunity are depicted as hollow triangles with numbers 1-3. (A) Antibodies to hepatitis B virus surface antigen (anti-HBs)-titers in the LLDs before transplantation or after the last immunization, (B) cellular immune response in the proliferation-assay, and (C) in the IFN-[gamma]-ELISpot. The horizontal lines indicate the cut-off (stimulation index of 2.5 or 10 spots, respectively).
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© 2009 Lippincott Williams & Wilkins, Inc. Published by Lippincott Williams & Wilkins, Inc. 2
Adoptive Immune Transfer of Hepatitis B Virus Specific Immunity From Immunized Living Liver Donors to Liver Recipients
FIGURE 2. Donor/recipient pair 1: Hepatitis B virus (HBV)-specific immunity of the donor pretransplantation and the recipient pre- and posttransplantation. The x-axis indicates time points of analysis. (A) The y-axis shows anti-HBs titers in IU/L of the donor (SYMBOL) and the HBV negative recipient (SYMBOL). The curve indicates the half-life value time of antibodies to hepatitis B virus surface antigen (anti-HBs) derived from blood products during the transplantation. Negative (-) values for hepatitis B virus surface antigen (HBsAg) and antibodies to hepatitis B virus core antigen (anti-HBc) detection are indicated at the top. (B) The y-axis shows the ratio between stimulated and unstimulated proliferations (stimulation index) of the donor and the HBV negative recipient using l-HBsAg as stimulus. The horizontal line indicates the cut-off (stimulation index of 2.5). n.t.: not tested.
Schumann, A. et al.Transplantation. 87(1):103-111,, 2009
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Summary In 17 Clinical trials : Sci-B-Vac was shown to be
safe & highly immunogenic :
Low dose/inj.
Rapid (early/higher) immune responses
High sero-protection Rates
Current data suggest that the regime of Sci-B-Vac
equally protects neonates from e-antigen +ve or
e-antigen –ve mothers.
Induces sero-conversion in non-responders
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Bypass of non-response to conventional immunization against HBV using a Pre-S/S
vaccine
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Comparative immunogenicity of a PreS/S hepatitis B vaccine in non- and low responders to conventional vaccine
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Study design
•Open
•Randomized
•Comparative
•Controlled
•Parallel-group
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Study aims
Primary objective To compare immunization with a PreS1/PreS2/S hepatitis B vaccine to conventional yeast derived HBV vaccine after one or two additional doses in healthy volunteers failing seroconversion after ≥4 prior vaccinations Secondary objective To evaluate immunogenicity of the two vaccines in low responders after ≥4 and non responders after 3 prior vaccinations
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Multy-center (8 centers)
• Switzerland: Lausanne (n=42) Lugano (n=8) Basel (n=8)
• Israel: Tel Aviv (n=60) Jerusalem (n=29)
• The Netherlands: Rotterdam (n=29) Utrecht (n=30)
• Austria: Vienna (n=505)
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Vaccines
• VACCINE I (group A- Sci B Vac): 0.5 ml Al(OH)3 HBV vaccine: 10µg HB S/preS1/preS2 antigen • VACCINE II (group B, Engerix B) 0.5 ml Al(OH)3 HBV vaccine:20 µg HBsAg small antigen
Ratio: 2:1
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Inclusion criteria
• Age: ≥18 years
• Non responders (HBs ≤ 9 IU/l) after ≥3 injections of conventional vaccine, or
• Low responders (HBs ≥ 10 to ≤99 IU/l) after ≥4 injections of conventional vaccine
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Exclusion criteria
• HBs antigenemia • Anti-HBc seropositivity • Severe atopy • Liver disease • Drug-induced immunosuppression • Investigational drug within 30 days • Immunoglobulins or blood transfusion in last 3 months • General contraindications against vaccination • Pregnancy or lactation
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Randomized
(n=719)
Pre-S/S vaccine
(n=479)
NR after≥4 vacc.
(n=226)
LR after ≥4 vacc. NR after 3 vacc.
(n=253)
Conventional
(n=237)
NR after ≥4 vacc.
(n=107)
LR after ≥4 vacc. NR after 3 vacc.
(n=130)
Study population
2:1
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Studypopulation II
3rd generation Conventional
Study population 474 (ITT) 235 (ITT)
Nonresponder after ≥4 vaccinations (1°)
Total 224 (m/f: 126/98) 107 (m/f: 62/42)
Age (a) 50,2 (20,2-76,3) 49,6 (19,7-78,5)
Lowresponder after≥4/Nonresponder after ≥3 vaccinations (2°)
Total 250 (m/f: 146/104) 129 (m/f: 76/53)
Age (a) 49,7 (18,3-80,1) 52,2 (21,4-78,6)
No. pre-vaccinations ≥5 (all vaccinees) 236 (49,2%) 118 (49,8%)
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day 1 day 36±7 day 85±7 day 120±7
Follow-up
*) if anti-HBs <100 IU/l
Time schedule
*)
(Subset: HLA)
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Blood draw Vaccination
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Immunogenicity
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1°study population: Seroprotection (after 1st or 2nd additional injection)
35.7
81.7
20.8
49.1
0
10
20
30
40
50
60
70
80
90
Response rate at 100 IU/l Response rate at 10 IU/l
% s
erop
rote
ctio
n
3rd generation vaccine Conventional vaccine
p=0.006
p<0.001
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2°study population: Seroprotection (after 1st or 2nd additional injection)
64,0
40,3
0
10
20
30
40
50
60
70
3rd generation vaccine Conventional vaccine
sero
prot
ectio
n %
at 1
00 IU
/l
p<0.001
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Geometric Mean Titres - GMT
61,4
153,7
39,9
80,5
0
20
40
60
80
100
120
140
160
180
200
Primary population Secondary population
GM
T3rd generation vaccine Conventional vaccine
p=0.054
p<0.001
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Safety
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MedDRA system organ class/preferred term Third-generation vaccine
Conventional vaccine
Any vaccine-related adverse event 284 (59.4%) 101 (42.6%)
General disorders & administrative site conditions 266 (55.6%) 93 (39.2%)
Fatigue 76 (15.9%) 28 (11.8%)
Injection site erythema 46 (9.6%) 14 (5.9%)
Injection site pain 215 (45.0%) 66 (27.8%)
Injection site pruritus 32 (6.7%) 12 (5.1%)
Injection site swelling 32 (6.7%) 8 (3.4%)
Malaise 32 (6.7%) 18 (7.6%)
Pyrexia 8 (1.7%) 2 (0.8%)
Musculoskeletal & connective tissue disorders 86 (18.0%) 29 (12.2%)
Arthralgia 27 (5.6%) 14 (5.9%)
Myalgia 75 (15.7%) 26 (11.0%)
Nervous system disorders 14 (2.9%) 2 (0.8%)
Headache 14 (2.9%) 1 (0.4%)
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Serious Adverse Events (SAEs)
• N=16
• 3% 3rd generation vaccine
• 0.8% conventional vaccine
• Only 1 SAE vaccine-related: One day after 3rd generation vaccine:
Severe pain, hives, facial oedema, hot feeling → resolved without sequelae (responder)
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Long-term follow-up
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Long-term follow-up Study population
ITT-FU population:
All subjects who succsessfully completed the core study (anti-HBs ≥100 IU/l)
3rd Generation ConventionalNo. FU 437 216ITT-FU analysis 209 63
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day 180 ± 7 Year 1 ± 56d Year 2 ± 56d
*) if anti-HBs <100 IU/l after 2nd vaccination
Follow-up Schedule of assessments
*)
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Blood draw 3rd Generation vaccination
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Long-term follow-up Seroprotection rate at 100 IU/l
p=0.302
p=0.016
p=0.533 59,5
29,123,4
50
13,617,9
0
10
20
30
40
50
60
70
80
90
100
month 6 year 1 year 2
Ser
opro
tect
ionr
ate
% a
t 100
IU/l
3rd generation conventional
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Pre S/S Vaccine in Non-responders Summary –
• Significantly higher immunogenicity after 2 additional injections of 3rdgeneration PreS/S vaccine compared to conventional S vaccine at anti-HBs 10 and 100 IU/l level
• Influence of age, BMI and gender less pronounced in 3rdgeneration PreS/S vaccinees
• Higher reactogenicity after 3rdgeneration compared to conventional vaccine
• Confirmes link between non response and DRB1*03 and *07, DQB1*02 HLA loci
Rendi-Wagner P & Shouval D Vaccine 2007
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Humoral immune response in 19 non responders immunized with Sci B Vac
Roggendorf M. et al
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Cellular immune response in 19 non-responders immunized with Sci B Vac
Roggendorf M. et al.
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Acknowledgements Ruth Adler Yaffa Ashur Chezi Barenholz Ron Dagan Devorah Diminsky Marian Gorecki Yaron Ilan Ronit Koren Judy Lau
George Lau Michael Roggendorf Arnon Nagler Amos Panet Michael Shapira Raul Raz Pamela Rendi-Wagner et al. Ivy Yap Shimon Slavin
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The Liver Unit at Hadassah 2011
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