C-1 PENTACEL ® Diphtheria and Tetanus Toxoids and Acellular Pertussis Adsorbed, Inactivated Poliovirus Vaccine and Haemophilus b Conjugate (Tetanus Toxoid.

C-1 PENTACEL ® Diphtheria and Tetanus Toxoids and Acellular Pertussis Adsorbed, Inactivated Poliovirus Vaccine and Haemophilus b Conjugate (Tetanus Toxoid Conjugate) Vaccine Combined (DTaP-IPV/Hib Combined) Vaccine and Related Biological Products Advisory Committee January 25, 2007 The vaccines business of sanofi-aventis Group

C-2 PENTACEL - Agenda Introduction Luc Kuykens, MD, MPH VP Regulatory Affairs Safety Immunogenicity Michael Decker, MD, MPH VP Scientific and Medical Affairs Canadian Post-Marketing Effectiveness Scott Halperin, MD Professor of Pediatrics Dalhousie University, Halifax, Canada US Perspective David Greenberg, MD Director Scientific and Medical Affairs Conclusion Luc Kuykens, MD, MPH VP Regulatory Affairs

C-3 PENTACEL: First Candidate DTaP-IPV-Hib Combination Vaccine in the US Unique Benefits for Entire Immunization Community  Patient Benefits – Maximum shot reduction – Well established safety profile; 9 years exclusive use in Canada  Health Care Provider Benefits – Optimizes implementation of immunization recommendations – Simplifies administration  Public Health Benefits – May improve vaccination coverage rates and timeliness – Improves combination vaccine supply

C-4 PENTACEL Formulation QuadracelPENTACEL Tetanus Toxoid 5 Lf Diphtheria Toxoid 15 Lf Pertussis Toxoid 20 µg Filamentous Hemagglutinin 20 µg Pertactin 3 µg Fimbriae Types 2 and 3 5 µg IPV Types 1, 2, 3 40, 8, 32 DAU PRP-T (ActHIB) - 10 µg Adjuvant: 0.33 mg aluminum; 0.6% v/v 2-phenoxyethanol

C-5 Vaccine Formulation PENTACELDaptacelAdacel Tetanus Toxoid 5 Lf Diphtheria Toxoid 15 Lf 2 Lf 5 Component Pertussis Antigens 5 Component Pertussis Antigens Pertussis Toxoid 20 µg 10 µg 2.5 µg Filamentous Hemagglutinin 20 µg 5 µg Pertactin 3 µg Fimbriae Types 2 and 3 5 µg IPV Types 1, 2, 3 40, 8, 32 DAU -- PRP-T 10 µg -- Adjuvant: 0.33 mg aluminum; 0.6% v/v 2-phenoxyethanol

C-8 Pertussis Antibody Levels vs Protection Pattern of Antibodies* Protective Efficacy † FIMPRNPT% LowLowHigh46 HighLow High or Low 72 LowHigh 75 HighHigh 85 *High (>5 units) or Low (0 to 5 units) or Low (0 to <5 units) levels of antibody before pertussis exposure. † Efficacy against WHO-defined pertussis. Storsaeter et al. Vaccine. 1998;16:1907-16.

C-9 PENTACEL Clinical Development Program  Demonstration of safety and immunogenicity – Comparison to the standard of care – Comparison of 3 consistency lots – Concomitant administration of other recommended vaccines – Comparison of a 4 th dose when administered at 15 to 16 vs 17 to 18 months of age  Immunogenicity of PENTACEL compared to Daptacel in the Sweden I Efficacy Study

C-10 PENTACEL Clinical Studies for US Licensure † Total number of PENTACEL recipients: 7146 StudyPurposeNPENTACEL P3T06 PENTACEL vs Standard of Care (SC) (Daptacel, IPOL, ActHIB) 1939485 494-01 Lot consistency, PENTACEL vs Formulation Equivalent (FE) (HCPDT, Poliovax, ActHIB) 35382506 M5A07 Interaction with Prevnar (Infant Series) 11661166 494-03 Interaction with Prevnar, MMR and Varivax vaccines (4 th Dose) 12071207 5A9908 Administration at 15-16 vs 17-18 months of age 17821782 † All subjects who received at least one dose

C-11 Composition of Studied Vaccines Standard of Care (SC) Formulation Equivalent (FE) AntigenPENTACELDaptacelIPOLActHIB HCPDT † PoliovaxActHIB Diphtheria Toxoid 15 Lf Tetanus Toxoid 5 Lf PT 20 µ g 10 µ g 20 µ g FHA 5 µ g 20 µ g PRN 3 µ g FIM 5 µ g Poliovirus Type 1 40 DAU Poliovirus Type 2 8 DAU Poliovirus Type 3 32 DAU PRP-T 10 µ g † PENTACEL formulation component

C-12 Safety Immunogenicity † StudyPENTACELControlPENTACELControl P3T0648514543741167 494-01250610321136403 494-031207NA274NA M5A07NANA886NA Total4198248626701570 Overall Summary (Infant Series): Safety and Immunogenicity Populations † Per-protocol population

C-13 Safety Immunogenicity † StudyPENTACELControlPENTACELControl P3T06431418371349 494-011862739883291 494-03958NA819NA 5A99081782NA735NA Total503311572808640 Overall Summary (4 th Dose): Safety and Immunogenicity Populations † Per-protocol population

C-14 PENTACEL Key Findings  Comparable immunogenicity to standard of care  Safety profile similar to separate vaccines  Can be given concomitantly with other recommended vaccines  In Canada, where PENTACEL was introduced in 1997 and is used universally – Invasive Hib disease remains rare – Rates of pertussis have decreased among children aged 1-9 years

C-16 Safety Objectives  Compare safety of PENTACEL against safety of control vaccines  Assess safety of PENTACEL with or without other recommended vaccines Safety Population: defined as those who had at least 1 scheduled dose of study vaccines

C-17 Infant Series and 4 th Dose: Safety Profile  Immediate Reactions – 30 minutes post-vaccination  Solicited Local and Systemic Reactions  Non-Serious Unsolicited Adverse Events  Events of Special Interest  Serious Adverse Events

C-18 Infant Series: Immediate Reactions Controlled Studies Non-controlled Studies PENTACEL 494-01, P3T06 N=2293 SC N=418 FE N=739 PENTACEL 494-03, 5A9908 N=2740 n%n%n%n% Total participants with at least one reaction 1<0.130.210.100.0 Urticaria1<0.100.000.000.0 Allergic reaction 00.010.100.000.0 Crying00.010.100.000.0 Erythema00.010.100.000.0 Diarrhea00.000.010.100.0 Irritability00.010.100.000.0

C-19 4 th Dose: Immediate Reactions Controlled Studies Non-controlled Studies PENTACEL 494-01, P3T06 N=2293 SC N=418 FE N=739 PENTACEL 494-03, 5A9908 N=2740 n%n%n%n% Total participants with at least one reaction20.110.200.0311.1 Injection site erythema 20.100.000.0240.9 Injection site bruising 00.000.000.020.1 Injection site burning 00.000.000.01<0.1 Injection site induration 00.010.200.01<0.1 Injection site irritation 00.000.000.01<0.1 Local edema upper limb 00.000.000.01<0.1 Dermatitis00.000.000.01<0.1 Mottled skin 00.000.000.01<0.1 Urticaria00.000.000.01<0.1 Nasopharyngitis00.000.000.01<0.1 Tremor00.000.000.01<0.1

C-20 Infant Series and 4 th Dose: Safety Profile  Immediate Reactions  Solicited Local and Systemic Reactions – Redness, swelling, tenderness, and change in limb circumference (4 th dose, only) collected on diary cards, days 0-7, severity documented  Non-Serious Unsolicited Adverse Events  Events of Special Interest  Serious Adverse Events

C-21 Infant Series: Solicited Local Reactions After PENTACEL, Days 0-7, Any Dose 0 20 40 60 80 100 01234567 Days PercentRednessSwellingTenderness

C-22 4 th Dose: Solicited Local Reactions After PENTACEL, Days 0-7 0 20 40 60 80 100 Percent 01234567 DaysRednessSwellingTenderness

C-23 Infant Series: Solicited Local Reactions After PENTACEL, Days 0-3, by Dose TendernessSwellingRedness Any5.74.84.85.63.82.844.236.437.4 Mild3.94.03.93.22.82.125.626.227.3 Moderate1.40.60.91.80.80.714.07.98.3 Severe0.40.10.10.50.20.04.62.21.9 5.7 4.8 5.6 3.8 2.8 44.2 36.4 37.4 0 20 40 60 80 100 Dose 1 Percent Dose 2Dose 3Dose 1Dose 2Dose 3Dose 1Dose 2Dose 3 MildModerateSevere

C-24 Infant Series: Solicited Local Swelling, Days 0-3, Comparison to Controls † by Dose † Percentages are based on the most severe reaction at any of the vaccination sites for the individual control vaccines 10 20 30 40 50 Percent Dose 1Dose 2Dose 3Dose 1Dose 2Dose 3Dose 1Dose 2Dose 3Dose 1Dose 2Dose 3 PENTACEL 494-01, P3T06 SC Controlled Studies 0 Any5.33.92.76.05.27.87.14.03.36.53.3 3.1 Mild3.23.12.03.64.36.55.83.43.03.32.12.3 Moderate1.60.80.72.00.91.21.20.50.32.40.60.7 Severe0.40.00.00.40.10.10.10.10.00.80.50.1 3.1 3.3 6.5 3.3 4.0 7.1 7.8 5.2 6.0 2.7 3.9 5.3 PENTACEL 494-03 FE MildModerateSevere

C-25 4 th Dose: Solicited Local Swelling, Days 0-3, Comparison to Controls † PENTACEL 494-01, P3T06 SCFEPENTACEL 494-03, 5A9908 0 10 20 30 40 50 Percent MildModerateSevere † Percentages are based on the most severe reaction at any of the vaccination sites for the individual control vaccines Any11.311.613.916.0 Mild6.97.79.26.6 Moderate3.22.63.57.9 Severe1.21.31.31.6 16.0 13.9 11.6 11.3 Controlled Studies

C-26 4 th Dose: Change in Limb Circumference, Days 0-3, Comparison to Control † PENTACEL 494-01, P3T06 SCHCPDTPENTACEL 494-03, 5A9908 0 10 20 30 40 50 Percent MildModerateSevere † Percentages are based on the most severe reaction at any of the vaccination sites for the individual control vaccines Any27.037.521.734.4 Mild22.328.218.526.6 Moderate4.58.23.17.0 Severe0.31.10.00.8 34.4 21.7 37.5 27.0 Controlled Studies

C-27 Infant Series and 4 th Dose: Safety Profile  Immediate Reactions  Solicited Local and Systemic Reactions – Fever, less active, crying, fussiness, vomiting, diarrhea, anorexia and rash (presence or absence) collected on diary cards, days 0-7, severity documented  Non-Serious Unsolicited Adverse Events  Events of Special Interest  Serious Adverse Events

C-28 Infant Series: Solicited Fever After PENTACEL, Day 0-7, Any Dose

C-29 Infant Series: Solicited Fever, Days 0-3, Comparison to Controls by Dose 10 20 30 40 50 Percent 0 MildModerateSevere PENTACEL 494-01, P3T06 SCFE PENTACEL 494-03 Controlled Studies Any7.713.718.79.316.115.813.815.720.611.516.5 18.4 Mild6.210.412.97.711.810.711.510.816.010.012.713.9 Moderate1.13.15.11.53.94.82.24.33.91.53.44.0 Severe0.40.20.70.10.40.30.10.60.70.00.40.5 Dose 1Dose 2Dose 3Dose 1Dose 2Dose 3Dose 1Dose 2Dose 3Dose 1Dose 2Dose 3 18.4 16.5 11.5 20.6 15.7 13.8 15.816.1 9.3 18.7 13.7 7.7 PENTACEL 494-03

C-30 Infant Series: Non-Inferiority of Fever Rates, Days 0-3, 90% CI of Difference (PENTACEL minus Control) by Dose Within Limit Outside Limit -10-80101214 -224-4-6 68 P3T06 1st Dose -3.49 3rd Dose 0.56 2nd Dose -5.26 494-01-1.40 -1.33 3rd Dose 1st Dose -5.70

C-31 4 th Dose: Solicited Fever After PENTACEL, Days 0-7

C-32 4 th Dose: Solicited Fever, Days 0-3, Comparison to Controls PENTACEL 494-01, P3T06 SCFEPENTACEL 494-03, 5A9908 0 10 20 30 40 50 Percent MildModerateSevere Any11.28.713.114.5 Mild8.15.59.19.3 Moderate2.52.43.54.3 Severe0.60.80.50.8 14.5 13.1 8.7 11.2 Controlled Studies

C-33 4 th Dose: Non-Inferiority of Fever Rates, Days 0-3, 90% CI of Difference (PENTACEL minus Control) Within Limit Outside Limit -10-80101214 -224-4-6 68 494-01-2.42 P3T064.66

C-34 Infant Series and 4 th Dose: Safety Profile  Immediate Reactions  Solicited Local and Systemic Reactions  Non-Serious Unsolicited Adverse Events – Any non-serious unsolicited event, days 0-7, severity documented – Any non-serious event requiring healthcare provider contact, days 8-60, severity documented  Events of Special Interest  Serious Adverse Events

C-35 Infant Series and 4 th Dose: Non-serious Unsolicited Adverse Events  No difference in rates between PENTACEL and control groups for frequently reported and rare events  Most events were common childhood conditions such as URI, otitis media, teething and nasal congestion  Majority assessed as non-related by the investigators

C-36 Infant Series and 4 th Dose: Safety Profile  Immediate Reactions  Solicited Local and Systemic Reactions  Non-Serious Unsolicited Adverse Events  Events of Special Interest – Hypotonic-hyporesponsive episode (HHE), hypotonia, non-febrile seizure, febrile seizure, and possible seizure collected days 0-60, severity documented  Serious Adverse Events

C-37 Infant Series: Events of Special Interest, Days 0-7, Comparison to Controls After Any Dose P3T06 P3T06 494-01 494-01494-03 PENTACEL N=485 Standard of Care N=1454 PENTACEL N=2506 Formulation Equivalent N=1032 PENTACEL N=1207 n%n%n%n%n% HHE00.000.000.000.000.0 Hypotonia00.010.130.100.010.1 Non-Febrile Seizure 00.010.11<0.110.100.0 Febrile Seizure 00.000.000.000.000.0 Possible Seizure 00.000.01<0.100.000.0

C-38 4 th Dose: Events of Special Interest, Days 0-7, Comparison to Control P3T06494-01494-035A9908 PENTACEL N=431 Standard of Care N=418 PENTACEL N=1862 Formulation Equivalent N=739 PENTACEL N=958 PENTACEL N=1782 n%n%n%n%n%n% HHE00.000.000.000.000.000.0 Hypotonia00.000.000.000.000.000.0 Non-Febrile Seizure 00.000.000.000.000.000.0 Febrile Seizure 00.000.000.020.300.020.1 Possible Seizure 00.000.000.000.000.000.0

C-39 Infant Series and 4 th Dose: Safety Profile  Immediate Reactions  Solicited Local and Systemic Reactions  Non-Serious Unsolicited Adverse Events  Events of Special Interest  Serious Adverse Events – Any serious adverse event during the study through Day 60 post-dose 3 or post-dose 4 (Day 180 for P3T06), severity documented

C-40 Infant Series: Serious Adverse Events, Days 0-60, Comparison to Control After Any Dose P3T06494-01 494-03 PENTACEL N=485 Standard of Care N=1454 PENTACEL N=2506 Formulation Equivalent N=1032 PENTACEL N=1207 n%n%n%n%n% Total participants with at least one SAE255.2755.2381.5171.6494.1 elated SAE Total participants with at least one related SAE00.010.100.000.000.0

C-41 Infant Series: Related Serious Adverse Events After Any Dose  No SAEs were reported as related to PENTACEL  A 7-week-old female (Study P3T06) experienced non- febrile seizure with apnea 12 hours post-Dose 1 of Daptacel, ActHIB, IPOL. Recombivax and Prevnar were co-administered. The event was considered probably related to vaccination

C-42 Infant Series: Deaths  A total of 3 deaths occurred during the Infant Series: – A 2-month-old female (Study 494-03, PENTACEL) died following an automobile accident, 22 days post-Dose 1 – A 4-month-old male (Study 494-03, PENTACEL) died 52 days post-Dose 1. Cause of death reported as Sudden Infant Death Syndrome – An 8-month-old female (Study P3T06, SC) developed symptoms 54 days post-Dose 3 and was diagnosed with ependymoma. Death occurred 222 days post-Dose 3; primary cause of death reported as aspiration  All deaths were considered unrelated to vaccination

C-43 4 th Dose: Serious Adverse Events P3T06494-01494-035A9908 PENTACEL N=431 Standard of Care N=418 PENTACEL N=1862 Formulation Equivalent N=739 PENTACEL N=958 PENTACEL N=1782 n%n%n%n%n%n% 0-60 days 92.171.770.440.5111.1291.6 61-180 days 9†9†9†9†2.120.5NANANANA  No SAEs were reported as related to PENTACEL or Control vaccines † Upper respiratory infections (3), congenital malformations (2), reaction to antibiotic, reaction to insect bite, post-infection cerebellar ataxia, seizure

C-44 4 th Dose: Deaths  One death occurred after Day 60 of the Infant Series and before the administration of the 4 th dose – A 9-month-old male (Study 494-01, PENTACEL) developed symptoms 95 days post-Dose 3. Subject was later diagnosed with neuroblastoma, which eventually led to death 256 days post-Dose 3  One death occurred after administration of the 4th dose – A 15-month-old male (Study P3T06, PENTACEL) died 9 days post-Dose 4. Cause of death reported as suffocation  Both deaths were considered unrelated to vaccination

C-45 Canadian Post-Marketing Safety Experience with PENTACEL

C-46 Canadian Post-Marketing Safety Experience  Introduced in May 1997, exclusively used since 1998  More than 12 million doses distributed  Similar dosing schedule as proposed for US  Passive surveillance data from spontaneous reports to sanofi pasteur

C-47 Canadian Post-Marketing Safety Experience: Reported Events  288 reports received from May 1997 through April 2006 – 221 were non-serious  Most commonly reported adverse events were injection site reactions

C-48 Post-marketing Experience: Most Frequently Reported Adverse Events Following PENTACEL Vaccination MedDRA AE Preferred Term 1 Number of AEs 2 Injection site reaction 65 Pyrexia64 Crying51 Injection site inflammation 35 Irritability31 Urticaria25 Vomiting24 Rash20 Convulsion 3 19 Injection site mass 16 1 MedDRA coding dictionary version 9.0 2 AE: adverse event. Includes both medically-confirmed and consumer cases 3 Includes MedDRA PT terms of Convulsion, Febrile convulsion, Status epilepticus and Convulsion local

C-49 Distribution of Spontaneously Reported Events of Special Interest* Total reports received N=288** Post- Dose 1 Post- Dose 2 Post- Dose 3 Post- Dose 4 Post- Any Dose nnnnn HHEs 1,4 840012 All Seizures 2,4 362819 Febrile Seizures 4 00022 Encephalopathy 4 11013 Fatal Reports 3,4 1010314 * For the period 1 May 1997 and 30 April 2006. **Medically-confirmed and consumer reports 1 Reported as HHE, or where the symptoms reported corresponded to the definition used for an HHE 2 MedDRA PT terms of Convulsion, Febrile convulsion, Status epilepticus and Convulsion local 3 Includes SIDS, Death Due to Unknown cause, and Death Due to Known Cause 4 For instances where dose information was not provided, the dose number was assumed based on the patient’s age and the latency to the event.

C-50 Safety Conclusions  Safety profile of PENTACEL is similar to that of the separate administration of standard of care vaccines (Daptacel, IPOL, and ActHIB) or formulation-equivalent component vaccines (HCPDT, Poliovax, and ActHIB)  PENTACEL is safe when administered alone or concomitantly with other age-recommended vaccines  No unexpected safety signals were identified in the Canadian post-marketing safety experience, which confirms conclusions from clinical trials

C-52 Immunological Endpoints and Analyses  Geometric Mean Titers (GMT) – A primary endpoint for all antigens  4-Fold Rise (from pre-Dose 1) – A primary endpoint for pertussis antigens  Seroprotection (  post-Dose threshold) – A primary endpoint for Diphtheria, Tetanus, Hib, Polio  Vaccine Response (  cutoff point and  baseline) – All pertussis antigens  Reverse Cumulative Distribution Curves (RCDC) – All antigens  Serological bridge to efficacy – All pertussis antigens

C-53 Immunogenicity Presentation Sequence  Pertussis Immunogenicity  Hib (PRP) Immunogenicity  Diphtheria and Tetanus Immunogenicity  Polio Immunogenicity  Co-Administration with Other Licensed Vaccines

C-54 P3T06: PENTACEL vs US Standard of Care Vaccines Study Characteristics  Multi-center, randomized, controlled, open-label study – 1939 infants – Vaccinated at 2, 4, 6, and 15-16 months of age  PENTACEL vaccine (n=484) vs Daptacel (3 lots), IPOL, ActHIB (n=1455) – All subjects received concomitant Recombivax HB and Prevnar  Objective – Demonstrate non-inferiority of PENTACEL vs US standard of care vaccines Daptacel, IPOL, ActHIB

C-55 P3T06: PENTACEL vs US Standard of Care Vaccines Post-Dose 3: Pertussis GMTsPENTACEL Daptacel, IPOL, ActHIB 0 20 40 60 80100 GMT (EU/mL) 0 50 100 150 200 250300 PTFHAPRNFIM PENTACEL90.073.736.1268.2 Control63.829.243.3267.2

C-56 P3T06: PENTACEL vs US Standard of Care Vaccines Post-Dose 3: Pertussis 4-Fold Rise Rates PENTACEL93.681.974.291.7 Control86.160.975.486.3 PENTACEL Daptacel, IPOL, ActHIB 0 20 40 60 80 100 PTFHAPRNFIM Percent

C-57 Non-Inferiority Comparisons P3T06: PENTACEL vs US Standard of Care Vaccines Post-Dose 3: Pertussis Non-Inferiority Comparisons Non-inferiority is based on 90% confidence intervals.

C-58 P3T06: PENTACEL vs US Standard of Care Vaccines Post-Dose 4: Pertussis GMTs PENTACEL174.0107.993.6553.4 Control168.564.0186.1513.5 PENTACEL Daptacel and ActHIB 0 40 80 120 160 200 PTFHAPRN 0 100 200 300 400 500 600 FIM GMT (EU/mL)

C-59 P3T06: PENTACEL vs US Standard of Care Vaccines Post-Dose 4: Pertussis 4-Fold Rise Rates PENTACEL97.488.492.793.5 Control97.179.398.391.6 PENTACEL Daptacel and ActHIB 0 20 40 60 80 100 Percent PTFHAPRNFIM

C-60 Non-Inferiority Comparisons P3T06: PENTACEL vs US Standard of Care Vaccines Post-Dose 4: Pertussis Non-Inferiority Comparisons Non-inferiority is based on 90% confidence intervals.

C-61 P3T06: PENTACEL vs US Standard of Care Vaccines Post-Dose 4: 4-Fold Rise Responses to Multiple Pertussis Antigens PENTACEL0.999.198.294.379.8 Control0.499.698.794.873.3 PENTACEL Daptacel and ActHIB None Any 1 of 4 Any 2 of 4 Any 3 of 4 All 4 0 20 40 60 80 100 Percent

C-62 PENTACEL Bridge to Efficacy P3T06 vs Sweden I Efficacy Trial  NIH-sponsored efficacy trial in Sweden 1992-1995 – Infants received Daptacel at 2, 4, 6 months of age – 85% efficacy vs WHO-defined classic pertussis – 78% efficacy vs any pertussis (lab-confirmed,  1 day of cough)  Pertussis antibody levels in Sweden I Efficacy Trial were compared to those following 4 doses of PENTACEL in US pivotal trials P3T06 and 494-01  Sera from P3T06, 494-01 and the Sweden I Efficacy Trial were tested contemporaneously in same laboratory, under same conditions, using the same validated assay

C-63 P3T06: PENTACEL vs Sweden I (Bridge to Efficacy) GMTs PENTACEL174.0107.993.6553.4 Sweden I 87.540.7111.3339.3 PENTACEL 0 40 80 120 160 200 PTFHAPRN 0 100 200 300 400 500 600 FIM GMT (EU/mL)

C-64 P3T06: PENTACEL vs Sweden I (Bridge to Efficacy) Non-Inferiority Analyses Non-inferiority is based on 90% confidence intervals for GMTs and VR; 95% for 4-fold rise.

C-65 494-01: Lot Consistency PENTACEL vs Control  Multi-center, randomized, controlled, open-label lot-consistency study – 3538 infants – Vaccinated at 2, 4, 6, and 15 months of age  PENTACEL (3 lots, n=2506) vs HCPDT, Poliovax, ActHIB given separately (n=1032) – All subjects received concomitant Recombivax HB – Most subjects received concomitant Prevnar  Objectives – Lot consistency – Non-inferiority

C-66 494-01: Lot Consistency, Post-Dose 3, Pertussis Lot consistency is based on 90% confidence intervals.

C-67 494-01: PENTACEL vs HCPDT, Poliovax, ActHIB Post-Dose 3: Pertussis GMTs PENTACEL99.776.239.6270.3 Control84.569.238.6246.0 0 20 40 60 80 100 PTFHAPRNFIM 0 50 100 150 200 250 300 GMT (EU/mL) PENTACEL HCPDT, Poliovax, ActHIB GMT (EU/mL)

C-68 494-01: PENTACEL vs HCPDT, Poliovax, ActHIB Post-Dose 3: Pertussis 4-Fold Rise Rates PENTACEL90.380.373.286.2 Control89.778.078.687.0 PENTACEL HCPDT, Poliovax, ActHIB 0 20 40 60 80 100 Percent PTFHAPRNFIM

C-69 494-01: PENTACEL vs HCPDT, Poliovax, ActHIB Post-Dose 3: Pertussis Non-Inferiority Analyses Non-inferiority is based on 90% confidence intervals.

C-70 494-01: PENTACEL vs HCPDT, Poliovax, ActHIB Post-Dose 4: Pertussis GMTs PENTACEL202.2134.694.9514.2 Control188.6128.3129.9350.3 PENTACEL HCPDT, Poliovax, ActHIB 0 25 50 75 100 125 150 175 200 225 0 50 100 150 200 250 300 350 400 450 500 550 GMT (EU/mL) PTFHAPRNFIM

C-71 494-01: PENTACEL vs HCPDT, Poliovax, ActHIB Post-Dose 4: Pertussis 4-Fold Rise Rates PENTACEL95.490.289.391.3 Control94.486.392.887.9 PENTACEL HCPDT, Poliovax, ActHIB 0 20 40 60 80 100 Percent PTFHAPRNFIM

C-72 494-01: PENTACEL vs HCPDT, Poliovax, ActHIB Post-Dose 4: Pertussis Non-Inferiority Analyses Non-inferiority is based on 90% confidence intervals.

C-73 494-01: PENTACEL vs Sweden I (Bridge to Efficacy) GMTs PENTACEL Sweden I 0 40 80 120 160 200 0 100 200 300 400 500 600 GMT (EU/mL) PTFHAPRNFIM PENTACEL195.1129.990.8506.6 Sweden I 87.540.7111.3339.3

C-74 494-01: PENTACEL vs Sweden I (Bridge to Efficacy) 4-Fold Rise Rates PENTACEL94.991.789.291.5 Sweden I 86.368.898.886.3 PENTACEL 0 20 40 60 80 100 Percent PTFHAPRNFIM

C-75 494-01: PENTACEL vs Sweden I (Bridge to Efficacy) Non-Inferiority Analyses Non-inferiority is based on 90% confidence intervals for GMTs and VR; 95% for 4-fold rise.

C-76 Box Plot of 2-Month Baseline PRN Antibody Levels 494-01: PENTACEL vs Sweden I (Bridge to Efficacy) Box Plot of 2-Month Baseline PRN Antibody Levels Pertactin (EU/mL) 494-01 Stage I (n=507)Sweden I (n=80) 0 20 40 80 60 100 120 140 160 180 200  12: 11% (65/507)  12: 1% (1/80)

C-77 PENTACEL Post-Dose 4 vs Sweden I RCDCs: PT PENTACEL, P3T06 PENTACEL, M5A07 PENTACEL, 494-01 PENTACEL, 494-03 PENTACEL, 5A9908 Daptacel, SWEDEN I

C-78 PENTACEL Post-Dose 4 vs Sweden I RCDCs: FHA PENTACEL, P3T06 PENTACEL, M5A07 PENTACEL, 494-01 PENTACEL, 494-03 PENTACEL, 5A9908 Daptacel, SWEDEN I

C-79 PENTACEL Post-Dose 4 vs Sweden I RCDCs: PRN PENTACEL, P3T06 PENTACEL, M5A07 PENTACEL, 494-01 PENTACEL, 494-03 PENTACEL, 5A9908 Daptacel, SWEDEN I

C-80 PENTACEL Post-Dose 4 vs Sweden I RCDCs: FIM FIM Antibody (EU/mL) PENTACEL, P3T06 PENTACEL, M5A07 PENTACEL, 494-01 PENTACEL, 494-03 PENTACEL, 5A9908 Daptacel, SWEDEN I

C-81 5 th Dose Follow-up Studies to 494-01, P3T06: P3T10 and P3T11 (Studies Currently Underway)  Both studies were multi-center, randomized, open-label  Solicited all PENTACEL or Daptacel recipients in P3T06 and 494-01 to participate  Sample size for pertussis immunogenicity – 259 in P3T10 – 363 in P3T11 (89 primed with PENTACEL, 274 primed with Daptacel)  Blood obtained for serology immediately prior to 5 th dose

C-82 Percent Seropositive* at Pre-Dose 5, By Study and Pertussis Antigen *  LOQ: PT, 5; FHA, 3; PRN, 3; FIM, 17 75.3 89.6 89.6 77.6 74.2 74.2 87.6 68.5 58.8 59.3 95.3 54.7 Percent  LOQ PENTACEL (P3T10) PENTACEL (P3T11) Daptacel (P3T11) 0 20 40 60 80 100 PTFHAPRNFIM

C-84 P3T06: PENTACEL vs US Standard of Care Vaccines Post-Doses 3 and 4: Hib Seroprotection RatesPENTACEL Daptacel, IPOL, ActHIB PENTACEL92.372.197.8 Control93.370.895.9 Percent Post-Dose 4 Post-Dose 3 0 20 40 60 80 100  0.15 µg/mL  1.0 µg/mL

C-85 P3T06: PENTACEL vs US Standard of Care Vaccines Post-Doses 3 and 4: Hib GMTsPENTACEL Daptacel, IPOL, ActHIB PENTACEL2.3117.71 Control2.2920.49 GMT (µg/mL) Post-Dose 3 Post-Dose 4 0 1 2 3 0 5 10 15 20 25 GMT (µg/mL)

C-86 P3T06: Non-inferiority Testing of Hib Seroprotection Rates (Control-PENTACEL) and GMT Ratios (Control/PENTACEL) %  0.15 µg/mL %  1.0 µg/mL

C-87 %  1.0 µg/mL %  0.15 µg/mL 494-01: Lot Consistency, Post-Dose 3: Hib Lot consistency is based on 90% confidence intervals.

C-88 494-01: GMTs and Seroprotection Rates, PENTACEL Lots at Post-Dose 3: Hib Lot 1 Lot 2 Lot 3 0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 GMT (µg/mL) 0 20 40 60 80 100 Percent 94.5 78.5 95.0 77.2 96.7 81.7  0.15 µg/mL  1.0 µg/mL 3.1 2.9 3.6

C-89 494-01: PENTACEL vs HCPDT, Poliovax, ActHIB Post-Doses 3 and 4: Hib Seroprotection Rates PENTACEL95.479.198.2 Control98.388.899.0 PENTACEL HCPDT, Poliovax, ActHIB 0 20 40 60 80 100 Percent  0.15 µg/mL  1.0 µg/mL Post-Dose 3 Post-Dose 4  1.0 µg/mL

C-90 P3T06 and 494-01: Comparison of Hib GMTs Post-Doses 3 and 4 PENTACEL3.19 Control6.23 PENTACEL Control 0 1 2 3 4 5 6 7 494-01 Post-Dose 3 0 5 10 15 20 25 30 35 40 494-01 Post-Dose 424.1235.90 GMT (µg/mL)

C-91 P3T06 and 494-01: Comparison of Hib GMTs Post-Doses 3 and 4 PENTACEL2.313.19 Control2.296.23 PENTACELControl 0 1 2 3 4 5 6 7 P3T06494-01 GMT (µg/mL) P3T06494-0117.7124.1220.4935.90 Post-Dose 3 Post-Dose 4 0 5 10 15 20 25 30 35 40

C-92 494-01: Non-inferiority Testing of Hib Seroprotection Rates (Control-PENTACEL) and GMT Ratios (Control/PENTACEL) Non-inferiority is based on 90% confidence intervals. %  0.15 µg/mL %  1.0 µg/mL

C-93 P3T06 and 494-01: Comparison of Hib GMTs Post-Doses 3 and 4 PENTACEL2.313.19 Control2.296.23 PENTACELControl 0 1 2 3 4 5 6 7 P3T06494-01 GMT (µg/mL) P3T06494-0117.7124.1220.4935.90 Post-Dose 3 Post-Dose 4 0 5 10 15 20 25 30 35 40

C-94 US and Canadian PENTACEL Licensure Trials: Post-Dose 3: Hib GMTs by Trial PENTACEL Studies: 494-01, P3T06, M5A07, 494-03, M5A03, PB9502, PB9601 ActHIB Studies: P3T07, 494-01, P3T06, PB9502 0 1 2 3 4 5 6 7 8 PENTACELActHIB GMT (µg/mL) 494-01

C-95 PENTACEL Studies: 494-01, P3T06, 5A9908, 494-03, M5A03, PB9502, PB9601 ActHIB Studies: 494-01, P3T06, PB9502 US and Canadian PENTACEL Licensure Trials: Post-Dose 4: Hib GMTs by Trial 494-01 0 5 10 15 20 25 30 35 40 45 GMT (µg/mL) PENTACELActHIB

C-96 P3T06: Hib GMTs by Study Site (  10 Subjects), Post-Dose 3 0 1 2 3 4 5 67PENTACELActHIB GMT (µg/mL)

C-97 P3T06: Hib GMTs by Study Site Post-Dose 3: PENTACEL vs Control by Site Shows only sites with  10 PENTACEL subjects per group 0 1 2 3 4 5 6 7 PENTACELActHIB GMT (µg/mL)

C-98 Hib GMTs at Post-Dose 3, By Study PENTACEL ActHIB Given Separately 4.4 7.1 3.2 2.8 2.3 3.0 3.5 3.8 6.2 2.3 3.0 0 1 2 3 4 5 6 7 8 PENTACELControl GMT (µg/mL) PB9502PB9601494-01494-03P3T06M5A03M5A07494-01P3T06P3T07PB9502

C-99 Hib GMTs at Pre-Dose 4, By Study 0.42 0.60 0.38 0.31 0.56 0.29 0.30 0.37 0.56 0.25 0.25 0.50 0.75 1.00 GMT (µg/mL) ControlPENTACEL ActHIB Given Separately 0.32 PB9502PB96015A9908494-01494-03P3T06M5A03PB9502494-01P3T06M5A07 PENTACEL 0

C-100 Hib GMTs at Post-Dose 4, By Study PENTACEL ActHIB Given Separately 10 20 30 40 30.1 PB9502 39.8 PB9601 32.5 5A9908 24.1 494-01 36.7 494-03 17.7 P3T06 25.6 M5A03 27.1 PB9502 35.9 494-01 20.5 P3T06 GMT (µg/mL) 24.1 M5A07 ControlPENTACEL 0

C-101 Hib GMTs at Pre-Dose 5, By Study 2.06 1.48 1.39 GMT (μg/mL) 0 0.5 1.0 1.5 2.0 2.5 2.52PENTACEL Separate Vaccines ActHIB TD508 P3T10 P3T11 PENTACELControl

C-102 Hib Seroprotection (  1.0 µg/mL) at Post-Dose 3, By Study PENTACEL ActHIB Given Separately 84.7 95.5 79.1 75.6 72.1 78.578.4 88.988.8 70.8 75.7 Percent 0 20 40 60 80 100 PB9502PB9601494-01494-03P3T06M5A03M5A07494-01P3T06P3T07PB9502 PENTACELControl

C-103 Hib Seroprotection (  0.15 µg/mL) at Pre-Dose 4, By Study PENTACEL ActHIB Given Separately 75.4 84.8 73.0 68.6 83.8 65.4 67.7 73.1 80.8 60.7 69.1 PB9502PB96015A9908494-01494-03P3T06M5A03PB9502494-01P3T06M5A07 Percent 0 20 40 60 80 100 ControlPENTACEL

C-104 Hib Seroprotection (  1.0 µg/mL) at Post-Dose 4, By Study PENTACEL ActHIB Given Separately 99.0 100.0 98.8 98.2 99.1 97.8 97.3 100.0 99.0 95.9 97.9 Percent 0 20 40 60 80 100 PB9502PB96015A9908494-01494-03P3T06M5A03PB9502494-01P3T06M5A07 ControlPENTACEL

C-105 Hib Seroprotection (≥0.15 µg/mL) at Pre-Dose 5, By Study PENTACEL ActHIB Given Separately 96.5 91.7 94.3 P3T11 0 20 40 60 80 100 98.4 TD508 P3T10 P3T11 PENTACELControl Percent

C-106 P3T07: Daptacel+IPOL+ActHIB - No Concomitant Prevnar M5A07: PENTACEL - No Concomitant Prevnar Post-Dose 3: Hib Seroprotection Rates and GMTs ≥0.15 μg/mL ≥1.0 μg/mL PENTACEL95.379.63.6 Daptacel, IPOL, ActHIB 93.573.22.7 PENTACEL 0 1 2 3 4 5 0 20 60 80 100 40 Percent GMT (μg/mL)

C-107 P3T07: Daptacel+IPOL+ActHIB - with Concomitant Prevnar M5A07: PENTACEL - with Concomitant Prevnar Post-Dose 3: Hib Seroprotection Rates and GMTs PENTACEL, Prevnar 95.877.13.3 Daptacel, IPOL, ActHIB, Prevnar 94.480.33.8 PENTACEL, Prevnar Daptacel, IPOL, ActHIB, Prevnar 0 1 2 3 4 5 0 20 60 80 100 40 Percent ≥0.15 μg/mL ≥1.0 μg/mL GMT (μg/mL)

C-108 PENTACEL vs Standard of Care Post-Dose 3: Hib RCDCs Hib Antibody (µg/mL)

C-110 P3T06: PENTACEL vs US Standard of Care Vaccines Post-Dose 3: Diphtheria, Tetanus Seroprotection Rates PENTACEL100.098.8100.099.7 Control100.098.5100.0100.0 PENTACEL Daptacel, IPOL, ActHIB  0.01 IU/mL  0.1 IU/mL DiphtheriaTetanus  0.01 IU/mL  0.1 IU/mL 0 20 40 60 80 100 Percent

C-111 P3T06: PENTACEL vs US Standard of Care Vaccines Post-Dose 4: Diphtheria, Tetanus Seroprotection Rates PENTACEL100.096.5100.092.9 Control100.095.7100.099.4 PENTACEL Daptacel and ActHIB  0.1 IU/mL  1.0 IU/mL DiphtheriaTetanus  0.1 IU/mL  1.0 IU/mL 0 20 40 60 80 100 Percent

C-112 494-01: PENTACEL vs HCPDT, Poliovax, ActHIB Post-Dose 3: Diphtheria, Tetanus Seroprotection Rates PENTACEL99.892.1100.099.9 Control99.792.2100.0100.0 PENTACEL HCPDT, Poliovax, ActHIB  0.01 IU/mL  0.1 IU/mL DiphtheriaTetanus  0.01 IU/mL  0.1 IU/mL 0 20 40 60 80 100 Percent

C-113 494-01: PENTACEL vs HCPDT, Poliovax, ActHIB Post-Dose 4: Diphtheria, Tetanus Seroprotection Rates PENTACEL100.095.5100.093.4 Control99.795.1100.098.6 PENTACEL HCPDT, Poliovax, ActHIB 0 20 40 60 80 100 Percent  0.1 IU/mL  1.0 IU/mL DiphtheriaTetanus  0.1 IU/mL  1.0 IU/mL

C-114 PENTACEL Non-inferiority, P3T06 and 494-01: Diphtheria and Tetanus Seroprotection Rates Non-inferiority is based on 90% confidence intervals. %  0.1 IU/mL %  0.01 IU/mL %  0.1 IU/mL %  0.01 IU/mL %  0.1 IU/mL %  0.01 IU/mL %  0.1 IU/mL %  0.01 IU/mL %  0.1 IU/mL %  0.01 IU/mL %  0.1 IU/mL %  0.01 IU/mL %  0.1 IU/mL %  0.01 IU/mL %  0.1 IU/mL %  0.01 IU/mL

C-116 P3T06 and 494-01: PENTACEL vs Control Polio Seroprotection Rates (  1:8) PENTACEL99.4100.0100.099.7100.0100.0100.0100.0100.0 Control100.0100.0100.0100.0100.0100.0100.0100.0100.0 Polio 1 Polio 2 Polio 3 0 20 40 60 80 100 PercentPENTACEL Daptacel, IPOL and ActHIB HCPDT, Poliovax, ActHIB Polio 1 Polio 2 Polio 3 Polio 1 Polio 2 Polio 3 494-01 Post-Dose 3 494-01 Post-Dose 4 P3T06 Post-Dose 3

C-117 Polio 1 %  1:8 Polio 2 %  1:8 Polio 3 %  1:8 Polio 1 %  1:8 Polio 2 %  1:8 Polio 3 %  1:8 Polio 1 %  1:8 Polio 2 %  1:8 Polio 3 %  1:8 PENTACEL Non-inferiority, P3T06 and 494-01: Polio Seroprotection Rates Non-inferiority is based on 90% confidence intervals.

C-119 P3T06: PENTACEL vs US Standard of Care Vaccines Post-Dose 3: Pneumococcal Seroprotection Rates PENTACEL100.098.192.581.099.794.4100.096.3100.098.197.594.798.192.8 Control100.098.991.480.799.396.799.397.499.597.897.995.696.991.3 PENTACEL Daptacel, IPOL and ActHIB 0 20 40 60 80 100  0.15  0.50 46B9V1418C19F23F Percent  0.15  0.50  0.15  0.50  0.15  0.50  0.15  0.50  0.15  0.50  0.15  0.50

C-120 494-03: Co-Administration With Other Recommended Vaccines  Multi-center, randomized, open-label study – PENTACEL 4 th dose † given at 15 to 16 months of age concomitantly with, or separately from, MMR, Varivax, and Prevnar – Only 4 th dose data are presented (n=958)  Objective: – Determine the effect of PENTACEL on co-administered vaccines † PENTACEL was previously administered at 2, 4, and 6 months of age

C-121 494-03: Effect of PENTACEL on Concomitant Vaccines Prevnar 4 th Dose PENTACEL+Prevnar100.098.797.495.5100.098.7100.099.4100.098.7100.097.498.795.5 MMR+Varivax+Prevnar100.099.499.497.5100.099.4100.0100.099.498.799.496.298.795.6 PENTACEL+PrevnarMMR+Varivax+Prevnar 0 20 40 60 80 100  0.15  0.50 46B9V1418C19F23F Percent  0.15  0.50  0.15  0.50  0.15  0.50  0.15  0.50  0.15  0.50  0.15  0.50

C-122 0 25 50 75 100 125 150 0 50 100 150 200 250 300 PTFHAPRNFIM GMT (EU/mL) M5A07: PENTACEL+Prevnar vs PENTACEL Post-Dose 3: Pertussis GMTs PENTACEL+Prevnar103.682.445.7272.5 PENTACEL102.877.844.3281.0 PENTACELPENTACEL+Prevnar

C-123 M5A07: PENTACEL+Prevnar vs PENTACEL Post-Dose 4 Pertussis GMTs 0 40 80 120 160 200 0 100 200 300 400 500 GMT (EU/mL) PTFHAPRNFIM PENTACEL+Prevnar189.7116.298.2456.3 PENTACEL189.3107.693.3486.9 PENTACELPENTACEL+Prevnar

C-124 M5A07: PENTACEL+Prevnar vs PENTACEL Post-Dose 3: Hib Seroprotection Rates and GMTs PENTACEL+Prevnar95.877.1 PENTACEL95.379.6 3.323.60 0 20 40 60 80 100  0.15 µg/mL  1.0 µg/mL Percent GMT (µg/mL) 0 1 2 3 4 5 6 PENTACELPENTACEL+Prevnar

C-125 M5A07: PENTACEL+Prevnar vs PENTACEL Post-Dose 4: Hib Seroprotection Rates and GMTs  1.0 µg/mL PENTACELPENTACEL+Prevnar PENTACEL+Prevnar 97.7 PENTACEL 98.2 0 20 40 60 80 100 Percent 0 5 10 15 20 25 3021.726.7 GMT (µg/mL)

C-126 Overall Immunogenicity Conclusions  PENTACEL efficacy against Pertussis can be concluded based on favorable serological comparison to the Sweden I Efficacy Trial  PENTACEL produced Pertussis GMTs and seroresponse rates comparable to those seen with separately administered vaccines  Good similarity of responses demonstrated across all the US licensure trials (RCDCs)  Good antibody persistence up to 4-6 years of age  PENTACEL produced Diphtheria, Tetanus, and Poliovirus seroprotection rates comparable to those seen with separately administered vaccines

C-127 Overall Immunogenicity Conclusions  PENTACEL produced Hib GMTs and seroprotection rates that were: – Comparable to separately administered US standard of care vaccines – Similar across the full range of PENTACEL studies – Very high following the 4 th dose – Persisted into the pre-school booster age  PENTACEL can be co-administered with other routinely recommended infant and toddler vaccines  With respect to immune responses, PENTACEL is a suitable replacement for separately administered Daptacel, IPOL, and ActHIB

C-129 Canadian Post-Marketing Experience  Licensed May 1997  Introduced nationally 1997-1998  Universal and exclusive use  As of April 2006, more than 12 million doses  Canadian schedule: 2, 4, 6, and 18 months  Quadracel (DTaP-IPV; PENTACEL without Hib) at 4-6 years

C-130 Pertussis Incidence Rates, Canada, 1924 – 2000 Source: Canadian Immunization Guide, 6 th ed., 2005:169.

C-131 Age-specific Rates of Pertussis, Canada, 1988 – 2005 † † Provisional data for 2003-2005. Source: http://dsol-smed.hc-sc.gc.ca/dsol-smed/ndis/c_time_e.html and Notifiable Diseases Reporting System, Public Health Agency of Canada Year 0 50 100 150 200 250 300 Rate per 100,000 889092949698000204 † PENTACEL Introduced <1 yr1-4 yr5-9 yr

C-132 Canadian IMPACT Surveillance Network  12 pediatric hospitals throughout Canada  90% of tertiary care pediatric beds  Referrals from all provinces and territories  Children from birth through 16 years of age  Surveillance conducted by nurse monitor at each site

C-133 Annual Number of Hospitalized Cases of Pertussis, IMPACT Centers, 1993 – 2005 Source: Bettinger et al., 6th Canadian Immunization Conference, Montreal, Quebec, Dec 5-8, 2004. Bettinger et al., Pediatr Infect Dis J. 2007;26:31-5. PENTACEL Era PENTACEL Introduction Whole Cell Era PENTACEL Used Nationally 0 50 100 150 200 250 300 350 93949596979899000102030405 Year Number of Cases

C-134 Number of Pertussis Cases by Age Group, Northwest Territories Age (years) Number of Cases 10 20 30 40 50 < 11-45-9 1993-1996 Whole Cell 1997-2000 PENTACEL 2001-2004 PENTACEL 0 Source: Kandola K, et al. Can J Infect Dis Med Microbiol. 2005;16:271-4.

C-135 Incidence of Invasive Hi* Disease in Children Aged <5 Years, Canada, 1989 – 2005 Data for 2003-2005 are provisional. Source: Public Health Agency of Canada, 2006. *Not all Haemophilus influenzae were confirmed as type b. Year PENTACEL Introduced

C-136 Invasive Hib Disease Among Children Admitted to Hospitals in the IMPACT † Surveillance Network, 1985 – 2005 † Immunization Monitoring Program, Active Source: Can Med Assoc J. 1996;154:1041-1047 and 2005;172:53-6; Can Commun Dis Rep. 1998;24:105-108; 2000;26:93-96; 2001;27:149-150; Paediatr Child Health. 2005;10:314; and David Scheifele, IMPACT. PENTACEL Introduced

C-137 Invasive Hib Disease, Children Aged <5 Years IMPACT Surveillance Network, 2001 – 2005  Only 34 cases during 2001 – 2005  Of these, 11 occurred among native children (Aboriginal – First Nation and Inuit) – 2 unvaccinated – 7 partially vaccinated (1 or 2 doses) – 2 received 3 doses (1 with recurrent pneumonia history)  Only 2 breakthrough cases during 5-year period

C-138 International Circumpolar Surveillance PHAC, Canada and CDC, US CanadaUS Regions Yukon, Northwest Territories, Nunavut, northern Labrador and Quebec Alaska Total population 137,000664,000 Native population 75,000 (55%) 120,000 (18%) Surveillance 5 years (2000-2004) 5 years (2002-2006) VaccinePENTACELPRP-OMP Hib cases <5 y/o 4 (3 Native) 7 (6 Native) Ages (Doses) 1.6 mo (0) 3.7 mo (unknown) 3.9 mo (partial) 1.4 yr (partial) 0.4 mo (2) 0.5 mo (0) 0.8 mo (2) 1.1 yr (2) 2.4 yr (3) 2.6 yr (3) 3.6 yr (3)

C-139 2007 NACI Recommendations for Use of Combination Vaccines in Canada  “Combination vaccines against diphtheria, pertussis, polio, tetanus and…Hib infections have become the standard for routine primary immunization of infants in Canada.”  “Like its monovalent constituent vaccines, PENTACEL has been highly successful in controlling these infectious diseases in Canada but has the additional benefit of fewer injections.” NACI = Canadian National Advisory Committee on Immunization CCDR 2007;33(ASC-1):1-14

C-140 Conclusions: Effectiveness of PENTACEL Against Pertussis and Invasive Hib Disease  9 years of clinical experience with more than 12 million doses of PENTACEL in Canada  Multiple surveillance systems confirm very low rates of pertussis and Hib disease  PENTACEL provides sustained protection against pertussis through 9 years of age  PENTACEL provides excellent protection against invasive Hib disease – Hib cases are rare among vaccinated children, including high risk populations

C-142 US Perspective  US Experience – Pertussis and Hib epidemiology – Comparison to Canadian experience  Benefits of PENTACEL Vaccine – Patient, healthcare provider, public health – Immunization schedule – Coverage rates and timeliness

C-143 Epidemiology of Pertussis: United States, 1922 – 2005 CDC. MMWR. 2002;51:73-76; CDC. Summary of notifiable diseases, US, 2003. Published Apr 22, 2005, MMWR 2003:52(54):72-76; CDC. Summary of notifiable diseases, US, 2004. Published June 16, 2006, MMWR 2004:53(53):19; CDC. MMWR. 2005;55:890. Epidemiology of Pertussis; Canada, 1924-2000

C-144 Pertussis Incidence, US, 2005 Rates per 100,000 persons; National Center for Immunization and Respiratory Diseases, CDC. Pertussis Surveillance Reports for 2005. 0 10 20 30 40 50 160 <6 mos6-11 mos1-4 yrs5-9 yrs10-19 yrs20+ yrs Incidence per 100,000 140

C-145 0 0.1 0.2 0.3 0.4 0.5 949596979899000102030405 Year Hib: Invasive Disease in US Children <5 Years National Data, 1994 – 2005 Note: Rates per 100,000 persons; Only cases confirmed as type b are shown. Source: MMWR 1995;44:545-50; 1996;45:901-6; 1998;47:993-8; 2001;50:48; 2002:51:16; 2002;51:234-7; 2004;53:691; 2005;54:775; and 2006;55:887. Rate per 100,000

C-146 Hib: Invasive Disease in US Children <5 Years ABCs Data, 1994 – 2005 Note: Rates per 100,000 persons; 2005 data are provisional Source: http://www.cdc.gov/ncidod/dbmd/abcs/reports.htm IMPACT Surveillance Network

C-147 ActHIB Vaccine Market Share in the US, 1996 – 2005 Note: Assumed market of 15.2 million Hib conjugate vaccine doses per year; includes TriHIBit ®. Source: Data on file, sanofi pasteur.

C-148 Summary of US and Canadian Experiences  Pertussis epidemiology is similar in US and Canada – In Canada, PENTACEL has led to sustained protection against pertussis through 9 years of age  The epidemiology of invasive Hib disease is similar in US and Canada – ActHIB is the dominant Hib vaccine used in the US – ActHIB, in PENTACEL, is the exclusive Hib vaccine used in Canada  In light of these data, PENTACEL is expected to perform as well in US as it has in Canada

C-149 2007 Recommended Childhood Immunization Schedule: Birth – 18 Months

C-150 ACIP, AAP, AAFP Recommendations: Combination Vaccines  “To minimize the number of injections children receive, parenteral combination vaccines should be used, if licensed and indicated for the patient’s age, instead of their equivalent component vaccines.”  “The use of licensed combination vaccines is preferred over separate injection of their equivalent component vaccines.” Centers for Disease Control and Prevention (CDC). MMWR. 1999;48(No. RR-5):1-2.

C-151 CDC: Timeliness of Childhood Immunizations, United States  2003 National Immunization Survey (n=14,810)  Only 17% of 24-35 month old children were immunized on time for 6 vaccines  Undervaccinated by mean of 172 days  37% undervaccinated >6 months for  1 vaccine – IPV 9% – DTaP 16% – Hib21% Luman et al. JAMA. 2006;293:1204-11.

C-152 Improved Coverage Rates, 2 Years of Age Georgia Medicaid 2003 Marshall et al. 40th National Immunization Conference, Atlanta, GA, March 2006. All comparisons, P<0.001

C-153 Improved Coverage Rates, 15 Months of Age Germany, 1996 – 2003 0 10 20 30 40 50 Percent Fully Immunized by 15 Months of Age HibIPV Hepatitis B Monovalent 1996 DTaP-Hib 1997-1998 DTaP-IPV-Hib 1998-2000 DTaP-IPV-Hib-HepB 2001-2003 Kailies et al. Pediatr Infect Dis J. 2006;25:507-12. N=2701 children with immunization booklets available

C-154 2007 Recommended Childhood Immunization Schedule: Birth – 18 Months

C-155 Reduction of the Number of Injections Through 18 Months of Age with Combination Vaccines 23 -10 -5 0 5 10 15 20 25 Total # of Shots Single Entity 20 -3 Comvax 18 -5 Pediarix 16 -7 PENTACEL 22 TriHIBit Shot Reduction vs Single Entity

C-156 PENTACEL: First Candidate DTaP-IPV-Hib Combination Vaccine in the US  Patient Benefits – Maximum shot reduction – Safety profile encourages compliance  Healthcare Provider Benefits – Optimizes implementation of immunization recommendations – Simplifies administration  Public Health Benefits – Expected to improve vaccination coverage rates and timeliness – Facilitates optimal HepB schedule – Improves combination vaccine supply for infant series

C-157 PENTACEL - Agenda Introduction Luc Kuykens, MD, MPH VP Regulatory Affairs Safety Immunogenicity Michael Decker, MD, MPH VP Scientific and Medical Affairs Canadian Post-Marketing Experience Scott Halperin, MD Professor of Pediatrics Dalhousie University, Halifax, Canada US Experience David Greenberg, MD Director Scientific and Medical Affairs Conclusion Luc Kuykens, MD, MPH VP Regulatory Affairs

C-158 PENTACEL Clinical Safety Conclusions  Safety profile of PENTACEL similar to that of separate administration of US standard of care vaccines (Daptacel, IPOL, and ActHIB)  PENTACEL is safe when administered alone or concomitantly with other age-recommended vaccines

C-159 PENTACEL Immunogenicity Conclusions  PENTACEL efficacy against Pertussis can be concluded based on favorable serological comparison to the Sweden I Efficacy Trial  PENTACEL produced Hib GMTs and seroprotection rates that were comparable to separately administered US standard of care vaccines  Immune responses were similar when PENTACEL was administered alone or concomitantly with other vaccines

C-160 PENTACEL Benefits  Proven safety record after 9 years of exclusive use in Canada  Proven effective in controlling pertussis and Hib disease in Canada – Similar epidemiology of pertussis and Hib in Canada and US predicts similar success with PENTACEL  Patient benefits with maximum shot reduction  Provider benefits with simplified administration  Public health benefits through potential improvement of vaccination timeliness and coverage

C-161 PENTACEL ® Diphtheria and Tetanus Toxoids and Acellular Pertussis Adsorbed, Inactivated Poliovirus Vaccine and Haemophilus b Conjugate (Tetanus Toxoid Conjugate) Vaccine Combined (DTaP-IPV/Hib Combined) Vaccine and Related Biological Products Advisory Committee January 25, 2007 The vaccines business of sanofi-aventis Group

C-1 PENTACEL ® Diphtheria and Tetanus Toxoids and Acellular Pertussis Adsorbed, Inactivated Poliovirus Vaccine and Haemophilus b Conjugate (Tetanus Toxoid.

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C-1 PENTACEL ® Diphtheria and Tetanus Toxoids and Acellular Pertussis Adsorbed, Inactivated Poliovirus Vaccine and Haemophilus b Conjugate (Tetanus Toxoid.

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Presentation on theme: "C-1 PENTACEL ® Diphtheria and Tetanus Toxoids and Acellular Pertussis Adsorbed, Inactivated Poliovirus Vaccine and Haemophilus b Conjugate (Tetanus Toxoid."— Presentation transcript:

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About project

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