Transcript DIPHTHERIA, TETANUS, PERTUSSIS, POLIOMYELITIS, HIB

HEXAVAC®
A new liquid DTacP-IPV-Hib-HB
hexavalent vaccine
Overview of its clinical profile
Benoît Soubeyrand M.D.
(Courtesy L. Hessel)
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HEXAVAC®: A NEW LIQUID DTaP-IPV-HIB-HB
HEXAVALENT COMBINATION VACCINE
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What is Hexavac® ?
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Clinical development plan
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Safety profile
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Immunogenicity
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Conclusions
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WHAT IS HEXAVAC® (1): Composition and Presentation
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A unique ready to use, preservative-free, liquid formulation,
combining all 6 antigens in 0.5 ml
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purified diphtheria toxoid,
purified tetanus toxoid,
adsorbed purified pertussis toxoid,
adsorbed purified FHA,
Polio type 1 (Mahoney strain),
Polio type 2 (MEF 1 strain),
Polio type 3 (Saukett strain),
PRP-T,
adsorbed, purified HBsAg,
20 IU (30 Lf)
40 IU (10 Lf)
25 g
25  g
40 D units
8 D units
32 D units
12 g (PRP)
5 g
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WHAT IS HEXAVAC® (2): Critical timelines
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Start of the project
1st clinical lot available
1st inclusion phase 1
1st inclusion phase 2
1st consistency batch (development scale)
1st inclusion phase 3
1st consistency batch (industrial scale)
1st industrial lot
EMEA submission
CPMP positive opinion
Market autorisation
Launch in Germany
Feb. 94
Jan. 95
Feb. 95
May 95
July 95
June 96
Dec. 98
April 99
July 99
June 00
Oct. 00
Oct. 00
i.e. - 5 years and 5 months: time to develop
- 6 years and 8 months: time to register / market
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WHAT IS HEXAVAC® (3): Formulation Process
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200 different experimental formulations prepared, varying :
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pH
ionic strength of different buffers (C032-, P043-)
batches of antigens
batches of adjuvant from different manufacturers
concentration of antigens
order of addition of antigens, adjuvant, buffer as well as conditions of
blending
 50 different hexavalent formulations physico-chemically and
immunologically tested
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7 optimized formulations extensively tested at 4°C, RT, 37°C
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2 semi-final formulations tested, over time, at + 4°C
1 final formulation for clinical development and industrial production
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HEXAVAC: Clinical development Plan (1)
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Goals of clinical development :
 To show that the hexavalent combination vaccine is safe and
induces protective immune responses equivalent (non-inferior) to
previously licensed combination vaccines PENTAVAC™
and RECOMBIVAX®
 To support clinically the consistency of manufacture by
comparing the immunogenicity of three consecutively batches
 To support the use of the vaccine with various vaccination
regimens : 2, 3, 4 / 12-18 months or 2, 4, 6 / 12-18 months ;
3, 5 / 12 months
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HEXAVAC: Clinical development Plan (2)
PHASE I Study
PHASE II Study
Safety in toddler : France
• HEXAVAC® : n=30
Versus
• DTaP-IPV-Hib/HB : n=28
• 14-18 months
Choice of formulation : France
• HEXAVAC® : n=157
Versus
• DTaP-IPV-Hib/HB : n=155
• 2, 3, 4/12-14 months
PHASE III Studies
Pivotal study – France (A)
Schedule study – France (D)
• HEXAVAC® : n=423
• PENTAVAC™ + RECOMBIVAX ®n=425
• 2, 4, 6/12-18 months
• HEXAVAC®
• 2, 3, 4/15-17 months : n=258
Versus
• 2, 4, 6/15-17 months : n=258
Consistency lot study – Chile (B)
• HEXAVAC®
• 3 lots
• 2, 4, 6 months : n=311 to 359 per group
Large scale safety – Germany (C)
• HEXAVAC®
• 2, 4, 6/12-14 months : n=1,783
Schedule study – Sweden (E)
• HEXAVAC® : n=180
• 3, 5, 12 months
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HEXAVAC: Clinical development Plan (3)
PHASE III studies : booster vaccination
Safety of HEXAVAC® in children primed with DTwP-IPV-Hib (PENTACOQ®),
France (F)
• n = 1,304
• 2, 3, 4/16-20 months
Safety & Immunogenicity of HEXAVAC® in children primed with DTwP-IPV-Hib
(PENTACOQ®) + RECOMBIVAX®, France (G)
• n = 313
• 2, 3, 4/14-20 months
Safety & Immunogenicity of HEXAVAC® in children primed with DTaP-IPV-Hib
(PENTAVACTM) + RECOMBIVAX®, Turkey (H)
• n = 129
• 2, 3, 4/14-18 months
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HEXAVAC: Clinical development Plan (4)
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Database submitted in the application file to CPMP
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11 507 doses of vaccines administered to 3 905 infants in primary
series.
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4 437 booster doses given to toddlers primed with either wholecell or acellular Pertussis combination vaccines :
- Pentacoq™ ( DTwP-IPV//PRP-T)
- Pentavac™ ( DTaP-IPV//PRP-T)
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European license received on October 24th 2000
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HEXAVAC® : Safety profile (1)
In all studies, evaluation of safety included:
1.
Immediate reactions within the first 30 minutes after each
dose
2.
Local reactions and systemic events from 30 minutes to 72
hours following each dose
3.
Any adverse event that resulted in a visit to a physician 4 and
30 days after each injection
4.
Any serious adverse event (SAE) occurring throughout the
trial.
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HEXAVAC® : Safety profile (2)
Local reactions (%) following primary series in infants receiving
HEXAVAC® (N = 423) or PENTAVACTM + RECOMBIVAX® (N = 425)
25
20.3
HEXAVAC®
20
PENTAVACTM
15.8
14.5
% of Infants
15
RECOMBIVAX®
13.8
12.1
10
5
6.8
3.3
3.8
1.5
0
Any reaction
Swelling  2 cm
Redness  2cm
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HEXAVAC® : Safety profile (2)
Local reactions (%) within 3 days of a booster dose (12-18 months)
of HEXAVAC® (n=400) or PENTAVACTM + RECOMBIVAX® (n=402)
35
30
26.9
HEXAVAC®
28.7
% of infants
PENTAVACTM
24.4
25
19.9
20
RECOMBIVAX®
20.9 20.7
15
10
10.2
8.0
8.0
5
0
Any
reaction
Swelling
 2cm
Redness
 2cm
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HEXAVAC® : Safety profile (3)
Systemic reactions (%) following primary series in infants receiving
HEXAVAC® (N = 402-423) or PENTAVACTM + RECOMBIVAX® (N = 425)
HEXAVAC®
PENTAVACTM +RECOMBIVAX®
60
% of infants
50
45.7
42.2
40
30
26.9
20
14.7
14.5
10
11.3
23.7
9.9
0
Any event
Fever
 38°C
drowsiness
Irritability
Mallet E. et al. Pediatr Infect Dis J, 2000; 19:1119-27
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HEXAVAC® : Safety profile (4)
Systemic reactions (%) within 3 days of a booster dose (12-18 months)
of HEXAVAC® (n=400) or PENTAVACTM + RECOMBIVAX® (n=402)
Systemic adverse events
50
% of infants
40
HEXAVAC®
PENTAVACTM +RECOMBIVAX®
47.6
40.5
29.4
30
32.4
20
18.2
10
20.0
7.0
3.7
0
Any event
Fever  38°C
Drowsiness
Irritability
Mallet E. et al.
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HEXAVAC® : Safety profile (5), summary
Local and systemic reactions (%) within 3 days following primary series in
infants and booster in children primed with Hexavac®
Number of infants
Local reactions
Any local reaction
Redness  2 cm
Induration and/or swelling  2 cm
Dose # 1
3897
Dose # 2
3826
Dose # 3
3784
All doses
11507
Booster
2688
14.1
17.9
19.6
17.2
21.3
6.8
10.0
12.2
9.4
17.4
10.2
12.6
13.4
12.0
15.6
25.7
15.2
25.3
8.8
22.0
6.3
24.4
10.1
15.6
5.7
9.06
0.44
0.03
18.0
1.6
0.13
18.0
2.7
0.16
15.0
1.6
0.10
24.9
3.6
0.74
Systemic adverse events
Irritability and/or unusual crying
Drowsiness
Fever  38°C
38-38.9°C
39-39.9°C
 40°C
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HEXAVAC®: Immunogenicity (1)
ANTIGEN
CRITERIA FOR SEROCONVERSION OR
SEROPROTECTION
PRP
antibody titre  0.15 µgml
HBs
antibody titre  10 mlU/ml
Diphtheria
Tetanus
antibody titre  0.01 lU/ml *
antibody titre  0.01 lU/ml
PT
four-fold rise of pre-immunisation titre*
FHA
four-fold rise of pre-immunisation titre*
Poliovirus type 1, 2, 3
antibody titre  5
(reciprocal dilution for each serotype)
* Response measured by EIA
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HEXAVAC®: Immunogenicity (2)
Comparison of Seroprotection / Seroconversion rates between Hexavac® and PentavacTM +
Recombivax® 1 month after the primary series (2, 4, 6 months)
96.6
100
100
99.7
93.7
100 100
91.8
93.7
100 99.7
100 100
90.5 88.6
Seroprotection rate (%)
80
HEXAVAC®
60
(n = 305-331)
PENTAVACTM+RECOMBIVAX®
40
(n = 301-332)
20
0
HBsAg
Seroprotective
titres
10
mIU/ml
PRP
PT
FHA
Tetanus
Diphtheria
Poliovirus
0.15
4- fold
4- fold
0.01
0.01
5
µg/ml
increase
increase
IU/ml
IU/ml
(1/dil)
Mallet E. et al. Pediatr Infect Dis J 2000; 19 : 1119-27
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HEXAVAC®: Immunogenicity (3)
Post-dose 3, pre- and post-booster antibody results (GMTs)
1000
10
1000
PT
FHA
10
D
1
100
T
1
100
10
10
Post 3
post-boos Post 3
pre-boos
10000
pre boos
postboos
0,1
0,01
0,01
Post 3
Polio 2
Polio 1
pre -boos
post-boos Post 3
pre boos
postboos
10000
10000
1000
0,1
Polio 3
1000
1000
PentavacTM + Recombivax®
100
100
100
10
10
10
Post 3
pre-boos
post-boos
Post 3
preboos
postboos
Post 3
Hexavac®
pre-boos
post-boos
Mallet E. et al. Pediatr Infect Dis J 2000; 19 : 1119-27
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HEXAVAC®: Immunogenicity (4)
Post- dose 3, pre-booster and post-booster anti-HBs antibody responses:
GMTs (% seroprotection rates)
HBs antibody (mIU/ml)
10000
3026 (100)
1000
HBs
983 (100)
932 (96.6)
434 (96.6)
332 (98.4)
100
PentavacTM + Recombivax®
Hexavac®
47.3 (81.7)
10
post dose 3
pre-booster
post-booster
Mallet E. et al. Pediatr Infect Dis J 2000; 19 : 1119-27
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HEXAVAC® : Protection against Hepatitis B
anti HBs (mIU / ml) after primo-immunisation with various vaccines
AGE (m)
N
GMT
%  10
HEXAVAC®
2, 4, 6
300
434
96.6
PENTAVAC® + RECOMBIVAX®
2, 4, 6
300
983
100
RECOMBIVAX®
0, 1, 6
100
931
100
PEDVAX® + RECOMBIVAX®
2, 4
180
256
98.4
PROCOMVAX®
2, 4
550
114
92.1
Vaccine
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HEXAVAC®: Immunogenicity (5)
Post dose 3, pre-booster and post-booster anti-PRP antibody responses:
GMTs (% seroprotection rates)
Anti-PRP antibody (µg/ml)
100
23.0 (100)
16.7 (100)
10
Hib
3.69 (99.7)
2.06 (93.7)
1
0.6 (91.4)
0.4 (77.5)
0,1
PentavacTM + Recombivax®
Hexavac®
0,01
post dose 3
pre-booster
post-booster
Mallet E. et al. Pediatr Infect Dis J 2000; 19 : 1119-27
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HEXAVAC®: Protection against Hib
GMC after primary immunisation in the first 6 months of life
Anti-PRP titres (µg/ml)
100
PentavacⓇ
HexavacⓇ
10
1
0.1
HbOC
PRP-D
PRPOMP
PRP-T
PRP-T
separate
PRP-T
mixed
Eskola J. Lancet 1999; 354 : 2063
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HEXAVAC®: Immunogenicity (6)
Seroprotection / seroconversion rates one month following the administration of
HEXAVAC® at 2, 4, 6, or 2, 3, 4, months of age
2, 3, 4 month (n = 480-192)
100
95,8 97,1
90
2, 4, 6,month (n=158-170)
100 100
100 100
100 99,4
Diphtheria
Poliovirus
92,7 93,5 92,9 89,5 90,6 91,8
80
70
60
50
40
30
20
10
0
Seroprotective titres
HBs Ag
PRP
PT
FHA
Tetanus
10 mIU/ml
 0.15
 4- fold
µg/ml
increase
4- fold
increase
 0.01
IU/ml
Camier P. et al. ESPID 2000
 0.01
IU/ml
5
(1/dil)
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HEXAVAC®: Immunogenicity (7)
Seroprotection / seroconversion rates one month following the booster dose of
HEXAVAC® given at 2, 3, 4 / 15-17, or 2, 4, 6 / 15-17 or 3, 5 / 12 months of age
2, 3, 4 / 15-17 (n= 305-331)
100
94.5
97.7 97.2
98.3 98.3
95.9
94.3
96
2, 4, 6 / 15-17 (n=301-332)
100 100 100
100
3, 5 / 12 (n=180)
99.4
99.4
97.8
100 100 100
90
80
75.4
72.3
67.8
70
60
50
40
30
20
10
0
HBs Ag
Seroprotective
titres
10
mIU/ml
PRP
1.0
µg/ml
PT
FHA
4- fold
increase
4- fold
increase
Tetanus
0.10
IU/ml
Diphtheria
Poliovirus
0.10
IU/ml
5
(1/dil)
Camier P. et al : ESPID 2000; Flodmark CE et al : PIDS 2001
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CONCLUSIONS
Hexavac®, the liquid combined hexavalent vaccine :
 is well tolerated
 provides protection and seroconversion in the range
of other licensed vaccines containing aP
 immune responses to PRP and HBs are in the range
of those reported with vaccines proven to be
efficacious
 confers excellent priming for all antigens as
evidenced by strong booster responses
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HEXAVAC®: Clinical development team
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Investigators :
E. Mallet, J. Lang, P. Camier, P. Reinert,
F. Undreiner, F. Roussel, R. Lagos, M. Levine
B. Belohradsky, J. Liese, S. Stojanov, G. Kanra,
P. Carriere, M. Girard, M. Muller
and all participating pediatricians
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Hexavac project team
Aventis Pasteur
Merck & Co.
Aventis Pasteur MSD
A. Hoffenbach
E. Pines
P. Fabre
E. Vidor
H. Salomon
M. Dupuy
C. Blondeau
P. Mendelman
J. Boslego
F. Schödel
H. Matthews
T. Staub
G. Chryssomalis
M. Garnier
L. Hessel
 And
all participating babies and parents
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