B. Soubeyrand - VHPB October 2001 Malte 1 HEXAVAC ® A new liquid DTacP-IPV-Hib-HB hexavalent vaccine Overview of its clinical profile Benoît Soubeyrand M.D. (Courtesy L. Hessel)

B. Soubeyrand - VHPB October 2001 Malte 2 What is Hexavac ® ? Clinical development plan Safety profile Immunogenicity Conclusions HEXAVAC ® : A NEW LIQUID DTaP-IPV-HIB-HB HEXAVALENT COMBINATION VACCINE.

B. Soubeyrand - VHPB October 2001 Malte 3  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

B. Soubeyrand - VHPB October 2001 Malte 4 Start of the projectFeb. 94 1st clinical lot availableJan. 95 1st inclusion phase 1Feb. 95 1st inclusion phase 2May 95 1st consistency batch (development scale) July 95 1st inclusion phase 3June 96 1st consistency batch (industrial scale)Dec. 98 1st industrial lotApril 99 EMEA submissionJuly 99 CPMP positive opinionJune 00 Market autorisationOct. 00 Launch in GermanyOct. 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

B. Soubeyrand - VHPB October 2001 Malte different experimental formulations prepared, varying :  pH  ionic strength of different buffers (C0 3 2-, P )  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

B. Soubeyrand - VHPB October 2001 Malte 6 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 / months or 2, 4, 6 / months ; 3, 5 / 12 months HEXAVAC  : Clinical development Plan (1)

B. Soubeyrand - VHPB October 2001 Malte 7 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=30 Versus DTaP-IPV-Hib/HB : n= months Schedule study – Sweden (E) HEXAVAC ® : n=180 3, 5, 12 months PHASE I StudyPHASE II Study PHASE III Studies Choice of formulation : France HEXAVAC ® : n=157 Versus DTaP-IPV-Hib/HB : n=155 2, 3, 4/12-14 months HEXAVAC  : Clinical development Plan (2)

B. Soubeyrand - VHPB October 2001 Malte 8 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 (PENTAVAC TM ) + 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 HEXAVAC  : Clinical development Plan (3)

B. Soubeyrand - VHPB October 2001 Malte 9 Database submitted in the application file to CPMP  doses of vaccines administered to infants in primary series.  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) E uropean license received on October 24 th 2000 HEXAVAC  : Clinical development Plan (4)

B. Soubeyrand - VHPB October 2001 Malte 10 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.

B. Soubeyrand - VHPB October 2001 Malte 11 Local reactions (%) following primary series in infants receiving HEXAVAC ® (N = 423) or PENTAVAC TM + RECOMBIVAX ® (N = 425 ) % of Infants Any reaction Swelling  2 cmRedness  2cm HEXAVAC ® PENTAVAC TM RECOMBIVAX ® HEXAVAC ® : Safety profile (2)

B. Soubeyrand - VHPB October 2001 Malte 12 Local reactions (%) within 3 days of a booster dose (12-18 months) of HEXAVAC ® (n=400) or PENTAVAC TM + RECOMBIVAX ® (n=402) % of infants Any reaction Redness  2cm Swelling  2cm HEXAVAC ® PENTAVAC TM RECOMBIVAX ® HEXAVAC ® : Safety profile (2)

B. Soubeyrand - VHPB October 2001 Malte Any eventFever  38°C drowsiness Irritability % of infants Mallet E. et al. Pediatr Infect Dis J, 2000; 19: HEXAVAC ® : Safety profile (3) Systemic reactions (%) following primary series in infants receiving HEXAVAC ® (N = ) or PENTAVAC TM + RECOMBIVAX ® (N = 425) HEXAVAC ® PENTAVAC TM + RECOMBIVAX ®

B. Soubeyrand - VHPB October 2001 Malte 14 Systemic reactions (%) within 3 days of a booster dose (12-18 months) of HEXAVAC ® (n=400) or PENTAVAC TM + RECOMBIVAX ® (n=402) % of infants Systemic adverse events HEXAVAC ® PENTAVAC TM + RECOMBIVAX ® HEXAVAC ® : Safety profile (4) Any event Fever  38°C DrowsinessIrritability Mallet E. et al.

B. Soubeyrand - VHPB October 2001 Malte 15 primary series in Local and systemic reactions (%) within 3 days following primary series in infants and booster in children primed with Hexavac ® HEXAVAC ® : Safety profile (5), summary Number of infants Dose # Dose # Dose # All doses Booster 2688 Local reactions Any local reaction Redness  2 cm Induration and/or swelling  2 cm Systemic adverse events Irritability and/or unusual crying Drowsiness Fever  38°C °C °C  40°C

B. Soubeyrand - VHPB October 2001 Malte 16 ANTIGEN CRITERIA 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)

B. Soubeyrand - VHPB October 2001 Malte 17 Seroprotective titres Seroprotection rate (%) HEXAVAC ® PENTAVAC TM +RECOMBIVAX ® (n = ) (n = ) HBsAgPRPPTFHATetanusDiphtheriaPoliovirus  0.15 µg/ml  10 mIU/ml  4- fold increase  4- fold increase  0.01 IU/ml  0.01 IU/ml 55 (1/dil) Comparison of Seroprotection / Seroconversion rates between Hexavac ® and Pentavac TM + Recombivax ® 1 month after the primary series (2, 4, 6 months) Mallet E. et al. Pediatr Infect Dis J 2000; 19 : HEXAVAC ® : Immunogenicity (2)

B. Soubeyrand - VHPB October 2001 Malte 18 PT FHA D T Polio 1 Polio 2 Polio 3 Post-dose 3, pre- and post-booster antibody results (GMTs) Mallet E. et al. Pediatr Infect Dis J 2000; 19 : HEXAVAC ® : Immunogenicity (3) Pentavac TM + Recombivax ® Hexavac ®

B. Soubeyrand - VHPB October 2001 Malte 19 Post- dose 3, pre-booster and post-booster anti-HBs antibody responses: GMTs (% seroprotection rates) 434 (96.6) HBs 3026 (100) 932 (96.6) 983 (100) 47.3 (81.7) 332 (98.4) Mallet E. et al. Pediatr Infect Dis J 2000; 19 : HEXAVAC ® : Immunogenicity (4) HBs antibody (mIU/ml) Pentavac TM + Recombivax ® Hexavac ® post dose 3pre-boosterpost-booster

B. Soubeyrand - VHPB October 2001 Malte 20 anti HBs (mIU / ml) after primo-immunisation with various vaccines HEXAVAC ® : Protection against Hepatitis B VaccineAGE (m)NGMT %  10 HEXAVAC ® 2, 4, PENTAVAC ® + RECOMBIVAX ® 2, 4, RECOMBIVAX ® 0, 1, PEDVAX ® + RECOMBIVAX ® 2, PROCOMVAX ® 2,

B. Soubeyrand - VHPB October 2001 Malte 21 Post dose 3, pre-booster and post-booster anti-PRP antibody responses: GMTs (% seroprotection rates) 3.69 (99.7) 2.06 (93.7) Pentavac TM + Recombivax ® Hexavac ® 23.0 (100) 16.7 (100) 0,01 0, post dose 3pre-boosterpost-booster Hib 0.6 (91.4) 0.4 (77.5) Mallet E. et al. Pediatr Infect Dis J 2000; 19 : Anti-PRP antibody (µg/ml) HEXAVAC ® : Immunogenicity (5)

B. Soubeyrand - VHPB October 2001 Malte 22 GMC after primary immunisation in the first 6 months of life HEXAVAC ® : Protection against Hib Anti-PRP titres (µg/ml) Pentavac Ⓡ Hexavac Ⓡ Eskola J. Lancet 1999; 354 : 2063 PRP-T separate PRP-T mixed PRP-DPRP- OMP PRP-THbOC

B. Soubeyrand - VHPB October 2001 Malte 23 Seroprotection / seroconversion rates one month following the administration of HEXAVAC® at 2, 4, 6, or 2, 3, 4, months of age Seroprotective titres  10 mIU/ml  4- fold increase  0.01 IU/ml  0.01 IU/ml µg/ml  0.15  5 (1/dil)  4- fold increase HEXAVAC ® : Immunogenicity (6) Camier P. et al. ESPID 2000

B. Soubeyrand - VHPB October 2001 Malte 24 Seroprotection / seroconversion rates one month following the booster dose of HEXAVAC® given at 2, 3, 4 / 15-17, or 2, 4, 6 / or 3, 5 / 12 months of age Camier P. et al : ESPID 2000; Flodmark CE et al : PIDS 2001 HEXAVAC ® : Immunogenicity (7) Seroprotective titres  10 mIU/ml  0.10 IU/ml  0.10 IU/ml  1.0 µg/ml  5 (1/dil)  4- fold increase  4- fold increase

B. Soubeyrand - VHPB October 2001 Malte 25 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

B. Soubeyrand - VHPB October 2001 Malte 26 Aventis PasteurMerck & 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 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 Hexavac project team And all participating babies and parents HEXAVAC ® : Clinical development team