B. Soubeyrand - VHPB October 2001 Malte 1 HEXAVAC ® A new liquid DTacP-IPV-Hib-HB hexavalent vaccine Overview of its clinical profile Benoît Soubeyrand

B. Soubeyrand - VHPB October 2001 Malte 1

HEXAVAC®

A new liquid DTacP-IPV-Hib-HBhexavalent vaccine

Overview of its clinical profile

Benoît Soubeyrand M.D.

(Courtesy L. Hessel)


What is Hexavac® ?

Clinical development plan

Safety profile

Immunogenicity

Conclusions

HEXAVAC®: A NEW LIQUID DTaP-IPV-HIB-HB HEXAVALENT COMBINATION VACCINE

.


purified diphtheria toxoid, 20 IU (30 Lf) purified tetanus toxoid, 40 IU (10 Lf) adsorbed purified pertussis toxoid, 25 g adsorbed purified FHA, 25 g Polio type 1 (Mahoney strain), 40 D units Polio type 2 (MEF 1 strain), 8 D units Polio type 3 (Saukett strain), 32 D units PRP-T, 12 g (PRP) adsorbed, purified HBsAg, 5 g

WHAT IS HEXAVAC® (1): Composition and Presentation

A unique ready to use, preservative-free, liquid formulation, combining all 6 antigens in 0.5 ml


Start of the project Feb. 94 1st clinical lot available Jan. 95 1st inclusion phase 1 Feb. 95 1st inclusion phase 2 May 95 1st consistency batch (development scale) July 95 1st inclusion phase 3 June 96 1st consistency batch (industrial scale) Dec. 98 1st industrial lot April

99 EMEA submission July 99 CPMP positive opinion June 00 Market autorisation Oct. 00 Launch in Germany Oct. 00

WHAT IS HEXAVAC® (2): Critical timelines

i.e. - 5 years and 5 months: time to develop - 6 years and 8 months: time to register / market


200 different experimental formulations prepared, varying : pH ionic strength of different buffers (C03

2-, 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

7 optimized formulations extensively tested at 4°C, RT, 37°C

2 semi-final formulations tested, over time, at + 4°C

1 final formulation for clinical development and industrial production

WHAT IS HEXAVAC® (3): Formulation Process


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

HEXAVAC: Clinical development Plan (1)


Pivotal study – France (A)

• HEXAVAC® : n=423• PENTAVAC™ + RECOMBIVAX ®n=425 • 2, 4, 6/12-18 months

Schedule study – France (D)

• 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

Safety in toddler : France

• HEXAVAC® : n=30Versus

• DTaP-IPV-Hib/HB : n=28 • 14-18 months

Schedule study – Sweden (E)

• HEXAVAC® : n=180• 3, 5, 12 months

PHASE I Study PHASE II Study

PHASE III Studies

Choice of formulation : France

• HEXAVAC® : n=157Versus

• DTaP-IPV-Hib/HB : n=155• 2, 3, 4/12-14 months



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 DTaP-IPV-Hib (PENTAVACTM) + RECOMBIVAX®, Turkey (H)

• n = 129• 2, 3, 4/14-18 months

Safety & Immunogenicity of HEXAVAC® in children primed with DTwP-IPV-Hib (PENTACOQ®) + RECOMBIVAX®, France (G)

• n = 313• 2, 3, 4/14-20 months



Database submitted in the application file to CPMP

11 507 doses of vaccines administered to 3 905 infants in primary

series.

4 437 booster doses given to toddlers primed with either whole-

cell or acellular Pertussis combination vaccines :

- Pentacoq™ ( DTwP-IPV//PRP-T)

- Pentavac™ ( DTaP-IPV//PRP-T)

European license received on October 24th 2000



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.


Local reactions (%) following primary series in infants receiving HEXAVAC® (N = 423) or PENTAVACTM + RECOMBIVAX® (N = 425)

% o

f In

fant

s

0

5

10

15

20

25

Any reaction Swelling 2 cm Redness 2cm

20.3

15.8

3.3

14.513.8

3.8

12.1

6.8

1.5

HEXAVAC®

PENTAVACTM

RECOMBIVAX®



Local reactions (%) within 3 days of a booster dose (12-18 months) of HEXAVAC® (n=400) or PENTAVACTM + RECOMBIVAX® (n=402)

% o

f in

fan

ts

0

5

10

15

20

25

30

35

Anyreaction

Redness 2cm

Swelling 2cm

26.928.7

10.2

19.9

24.4

8.0

20.9 20.7

8.0

HEXAVAC®

PENTAVACTM

RECOMBIVAX®



0

10

20

30

40

50

60

Any event Fever 38°C

drowsiness Irritability

% o

f in

fan

ts

45.742.2

14.714.5

11.3

26.923.7

9.9

Mallet E. et al. Pediatr Infect Dis J, 2000; 19:1119-27


Systemic reactions (%) following primary series in infants receiving HEXAVAC® (N = 402-423) or PENTAVACTM + RECOMBIVAX® (N = 425)

HEXAVAC®

PENTAVACTM +RECOMBIVAX®


Systemic reactions (%) within 3 days of a booster dose (12-18 months) of HEXAVAC® (n=400) or PENTAVACTM + RECOMBIVAX® (n=402)

% o

f in

fan

ts

0

10

20

30

40

50

Systemic adverse events

40.5

47.6

29.432.4

3.77.0

18.2 20.0

HEXAVAC®

PENTAVACTM +RECOMBIVAX®


Any event Fever 38°C Drowsiness Irritability

Mallet E. et al.


Local and systemic reactions (%) within 3 days following primary series inprimary series in infants and booster in children primed with Hexavac®

HEXAVAC® : Safety profile (5), summary

Number of infantsDose # 1

3897Dose # 2

3826Dose # 3

3784All doses

11507Booster

2688

Local reactions

Any local reaction 14.1 17.9 19.6 17.2 21.3

Redness 2 cm 6.8 10.0 12.2 9.4 17.4

Induration and/or swelling 2 cm 10.2 12.6 13.4 12.0 15.6

Systemic adverse events

Irritability and/or unusual crying 25.7 25.3 22.0 24.4 15.6

Drowsiness 15.2 8.8 6.3 10.1 5.7

Fever 38°C

38-38.9°C 9.06 18.0 18.0 15.0 24.9

39-39.9°C 0.44 1.6 2.7 1.6 3.6

40°C 0.03 0.13 0.16 0.10 0.74


ANTIGENCRITERIA FOR SEROCONVERSION OR

SEROPROTECTION

PRP antibody titre 0.15 µgml

HBs antibody titre 10 mlU/ml

Diphtheria antibody titre 0.01 lU/ml *

Tetanus 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

HEXAVAC®: Immunogenicity (1)


Seroprotective titres

Ser

opro

tect

ion

rat

e (%

) HEXAVAC®

PENTAVACTM+RECOMBIVAX®

(n = 305-331)

(n = 301-332)

0

20

40

60

80

100

HBsAg PRP PT FHA Tetanus Diphtheria Poliovirus

0.15

µg/ml

10

mIU/ml

4- fold

increase

4- fold

increase

0.01

IU/ml

0.01

IU/ml

5

(1/dil)

96.6100

93.7

99.7

91.8 93.790.5 88.6

100 100 100 99.7 100 100

Comparison of Seroprotection / Seroconversion rates between Hexavac® and PentavacTM + Recombivax® 1 month after the primary series (2, 4, 6 months)

Mallet E. et al. Pediatr Infect Dis J 2000; 19 : 1119-27



10

100

1000

Post 3 pre-boos post-boos

10

100

1000

Post 3 pre -boos

post-boos

0,01

0,1

1

10

Post 3 pre -boos

post-boos

PT FHA

0,01

0,1

1

10

Post 3 pre -boos post-boos

D T

10

100

1000

10000


10

100

1000

10000

Post 3 pre-boos

post-boos

Polio 1

10

100

1000

10000


Polio 2 Polio 3

Post-dose 3, pre- and post-booster antibody results (GMTs)



PentavacTM + Recombivax®

Hexavac®


Post- dose 3, pre-booster and post-booster anti-HBs antibody responses: GMTs (% seroprotection rates)

434 (96.6)

10

100

1000

10000

HBs3026 (100)

932 (96.6)983 (100)

47.3 (81.7)

332 (98.4)



HB

s an

tib

ody

(mIU

/ml)


Hexavac®

post dose 3 pre-booster post-booster


anti HBs (mIU / ml) after primo-immunisation with various vaccines

HEXAVAC® : Protection against Hepatitis B

Vaccine 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


Post dose 3, pre-booster and post-booster anti-PRP antibody responses: GMTs (% seroprotection rates)

3.69 (99.7)2.06 (93.7)


Hexavac®

23.0 (100)

16.7 (100)

0,01

0,1

1

10

100

post dose 3 pre-booster post-booster

Hib0.6 (91.4)

0.4 (77.5)


An

ti-P

RP

an

tibo

dy (

µg/

ml)



GMC after primary immunisation in the first 6 months of life

HEXAVAC®: Protection against Hib

100

10

1

0.1

An

ti-P

RP

tit

res

(µg/

ml)

PentavacⓇ

HexavacⓇ

Eskola J. Lancet 1999; 354 : 2063

PRP-T separate

PRP-T mixed

PRP-D PRP-OMP

PRP-THbOC


Seroprotection / seroconversion rates one month following the administration of HEXAVAC® at 2, 4, 6, or 2, 3, 4, months of age

10010010095,8

90,692,7 92,9100 99,4100

91,889,597,1

93,5

0

10

20

30

40

50

60

70

80

90

100

HBs Ag PRP PT FHA Tetanus Diphtheria Poliovirus

2, 3, 4 month (n = 480-192) 2, 4, 6,month (n=158-170)

Seroprotective titres 10 mIU/ml 4- foldincrease

0.01 IU/ml

0.01 IU/mlµg/ml

0.15 5

(1/dil)

4- fold

increase


Camier P. et al. ESPID 2000


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

9698.3

75.4

94.5 100 99.4 10098.397.7 94.3

67.8

99.4100100 100

97.8100

72.3

10095.997.2

0

10

20

30

40

50

60

70

80

90

100

HBs Ag PRP PT FHA Tetanus Diphtheria Poliovirus

2, 3, 4 / 15-17 (n= 305-331) 2, 4, 6 / 15-17 (n=301-332) 3, 5 / 12 (n=180)

Camier P. et al : ESPID 2000; Flodmark CE et al : PIDS 2001


Seroprotective titres

10 mIU/ml

0.10IU/ml

0.10IU/ml

1.0µg/ml

5(1/dil)

4- foldincrease

4- foldincrease


CONCLUSIONSCONCLUSIONS

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


Aventis Pasteur Merck & Co. Aventis Pasteur MSDA. HoffenbachE. PinesP. FabreE. VidorH. SalomonM. DupuyC. Blondeau

P. MendelmanJ. BoslegoF. SchödelH. MatthewsT. Staub

G. ChryssomalisM. GarnierL. Hessel

Investigators : E. Mallet, J. Lang, P. Camier, P. Reinert, F. Undreiner, F. Roussel, R. Lagos, M. LevineB. Belohradsky, J. Liese, S. Stojanov, G. Kanra, P. Carriere, M. Girard, M. Muller

and all participating pediatricians

Hexavac project team

And all participating babies and parents

HEXAVAC®: Clinical development team

Documents

B. Soubeyrand - VHPB October 2001 Malte 1 HEXAVAC ® A new liquid DTacP-IPV-Hib-HB hexavalent vaccine Overview of its clinical profile Benoît Soubeyrand