1. 1 Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine, Adsorbed (Tdap, ADACEL™) Aventis Pasteur, Ltd. VRBPAC – March 15, 2005 ChrisAnna M. Mink, M.D. FDA/OVRR/DVRPACBER

2. 2 Composition of Study Vaccines Component ADACEL  (Tdap) DAPTACEL  1 (DTaP) Td 2 Tetanus toxoid5Lf Diphtheria toxoid2 Lf15 Lf2 Lf PT2.5 ug10 ug- FHA5 ug - PRN3 ug - FIM 2/35 ug - Aluminum 3 0.33 mg Thimerosal--0.01% 1 DTaP – licensed in U.S. for first 4 doses of primary series; evaluated in Sweden I 2 Td – manufactured by Aventis Pasteur Inc, U.S. (API) 3 Aluminum as AlPO 4

3. 3 Indication Sought ADACEL™ is indicated for the active immunization for the prevention of diphtheria, tetanus and pertussis in adolescents and adults aged 11 through 64 years as a booster. ADACEL™ is indicated for the active immunization for the prevention of diphtheria, tetanus and pertussis in adolescents and adults aged 11 through 64 years as a booster. The dosing schedule is one dose administered intramuscularly (IM). The dosing schedule is one dose administered intramuscularly (IM).

4. 4 Tdap Trials Submitted to the BLA Pivotal Pivotal Td506 – Comparative study Td506 – Comparative study Serology Bridge for Efficacy (lab study) Serology Bridge for Efficacy (lab study) Td505 – Lot consistency Td505 – Lot consistency Non-Pivotal (Concomitant immunizations) Non-Pivotal (Concomitant immunizations) Td502 – Tdap with influenza vaccine Td502 – Tdap with influenza vaccine Td501 – Tdap with hepatitis B vaccine Td501 – Tdap with hepatitis B vaccine Historical Trials – 3 abbreviated reports Historical Trials – 3 abbreviated reports Safety Database = 6803 Tdap recipients Safety Database = 6803 Tdap recipients

5. 5 Pivotal Trial – Td506 Phase 3, randomized, observer-blinded, controlled trial comparing Tdap (ADACEL™) with Td in adolescents and adults 11-64 years of age Phase 3, randomized, observer-blinded, controlled trial comparing Tdap (ADACEL™) with Td in adolescents and adults 11-64 years of age No diphtheria-tetanus-pertussis containing vaccines in previous 5 years No diphtheria-tetanus-pertussis containing vaccines in previous 5 years Stratified within age groups Stratified within age groups Tdap : Td 3:2 for 11-17yr Tdap : Td 3:2 for 11-17yr 3:1 for 18-64yr One 0.5 mL IM dose of Tdap or Td One 0.5 mL IM dose of Tdap or Td

6. 6 Pivotal Trial – Td506 Monitoring Monitoring Immunogenicity Immunogenicity Randomly selected subset in each age strata Randomly selected subset in each age strata Serum - pre-vac and post-vac (35 + 7 days) Serum - pre-vac and post-vac (35 + 7 days) Safety Safety Immediate adverse events (AEs) – 30 min Immediate adverse events (AEs) – 30 min Solicited AEs – diary card x 14 days Solicited AEs – diary card x 14 days SAEs, new onset medical conditions – 6 mo SAEs, new onset medical conditions – 6 mo

7. 7 Td506 - Objectives Tdap vs. Td Tdap vs. Td To compare safety To compare safety To assess the immune responses to diphtheria (dip) and tetanus (tet) To assess the immune responses to diphtheria (dip) and tetanus (tet) Tdap vs. DTaP (DAPTACEL®) Tdap vs. DTaP (DAPTACEL®) To compare the immune response to pertussis antigens To compare the immune response to pertussis antigens Separate assessments for adolescents (11-17 yrs) and adults (18-64 yrs)

8. 8 Td506 Results: Enrollment Vaccine Group Population Tdap N Td N Total N Adolescents (11-17 years) 12258182053 Adults (18-64 years) 18076002427 Total (11-64 years) 303214184480* * 19 were not vaccinated

9. 9 Td506 Results: Populations Demographic characteristics Demographic characteristics Similar for Tdap and Td groups Similar for Tdap and Td groups Populations for analysis Populations for analysis Intent-to-treat, safety (ITTS) – all randomized and received study vaccine (Tdap or Td) Intent-to-treat, safety (ITTS) – all randomized and received study vaccine (Tdap or Td) ITT, Immunogenicity (ITTI) – randomized, vaccinated and bled ITT, Immunogenicity (ITTI) – randomized, vaccinated and bled Per-Protocol Immunogenicity (PPI) – ITTI subset with no major protocol violations Per-Protocol Immunogenicity (PPI) – ITTI subset with no major protocol violations

10. 10 Td506: Endpoints - Dip and Tet Immune Responses Tdap vs. Td, % of subjects achieving response non-inferior if lower limit (LL) of 2-sided 95% CI of the difference (  ) in rates is > -10% Tdap vs. Td, % of subjects achieving response non-inferior if lower limit (LL) of 2-sided 95% CI of the difference (  ) in rates is > -10% Seroprotective levels Seroprotective levels Defined > 0.1 IU/mL Defined > 0.1 IU/mL Booster responses Booster responses Defined as 4-fold rise if pre-vac level below cut-off and 2-fold rise if above the cut-off level (2.56 IU/mL for dip and 2.7 IU/mL for tet) Defined as 4-fold rise if pre-vac level below cut-off and 2-fold rise if above the cut-off level (2.56 IU/mL for dip and 2.7 IU/mL for tet)

11. 11 Td506 Results: Dip and Tet Seroprotective Levels in Adolescents Tdap N=527 % Td N=516 %Diff % (95% CI) Diphtheria > 0.1 IU/mL (pre)72.570.71.8 (-3.7, 7.3) > 0.1 IU/mL (post)99.8 0.0 (-0.5, 0.5) > 1.0 IU/mL (pre)15.717.3-1.5 (-6.0, 3.0) > 1.0 IU/mL (post)98.798.40.3 (-1.2, 1.7) Tetanus > 0.1 IU/mL (pre)99.699.20.4 (-0.5, 1.3) > 0.1 IU/mL (post)100 0.0 (0.0, 0.0) > 1.0 IU/mL (pre)44.643.80.8 (-5.2, 6.8) > 1.0 IU/mL (post)99.699.40.2 (-0.6, 1.0)

12. 12 Td506 Results: Dip and Tet Seroprotective Levels in Adults Tdap N=741 % Td N=506 %Diff % (95% CI) Diphtheria > 0.1 IU/mL (pre)62.663.3-0.70 (-6.2, 4.8) > 0.1 IU/mL (post)94.195.1-1.0 (-3.6, 1.5) > 1.0 IU/mL (pre)14.316.0-1.7 (-5.7, 2.4) > 1.0 IU/mL (post)78.079.9-0.9 (-3.5, 1.7) Tetanus > 0.1 IU/mL (pre)97.395.91.4 (-0.7, 3.5) > 0.1 IU/mL (post)10099.80.2 (-0.2, 0.6) > 1.0 IU/mL (pre)73.070.32.7 (-2.5, 7.7) > 1.0 IU/mL (post)97.898.2-0.1 (-1.0, 0.8)

13. 13 Td506 Results: Dip and Tet Booster Response Rates AdolescentsAdults Booster Response* Tdap N=527 % Td N=516 % Diff % (95% CI) Tdap N=741 % Td N=506 % Diff % (95% CI) Diphtheria95.195.00.1 (-2.5, 2.8) 87.483.44.0 (0.0, 8.0) Tetanus91.791.30.4 (-3.0, 3.8) 63.166.8-3.7 (-9.0, 1.6) *Defined as 4-fold rise if pre-vac level below cut-off and 2-fold rise if above the cut-off level (2.56 IU/mL for dip and 2.7 IU/mL for tet)

14. 14 Td506: Endpoints - Pertussis Immune Responses for Efficacy Bridge Tdap vs. DTaP (DAPTACEL®) Tdap vs. DTaP (DAPTACEL®) DTaP ~85% efficacy against B. pertussis infection with 21 days of paroxysmal cough in Sweden I Efficacy Trial DTaP ~85% efficacy against B. pertussis infection with 21 days of paroxysmal cough in Sweden I Efficacy Trial Geometric mean concentrations (GMCs) for each antigen (PT, FHA, PRN and FIM), non-inferior if: Geometric mean concentrations (GMCs) for each antigen (PT, FHA, PRN and FIM), non-inferior if: LL of 2-sided 95% CI ratio of GMC (Tdap/DTaP) > 0.67 LL of 2-sided 95% CI ratio of GMC (Tdap/DTaP) > 0.67

15. 15 Serologic Bridge to Efficacy DTaP (DAPTACEL®) Samples from Sweden I DTaP (DAPTACEL®) Samples from Sweden I 80 of original 181 paired samples available (not randomized) 80 of original 181 paired samples available (not randomized) Samples obtained pre- and 1 mo post-3 rd dose from infants immunized at 2, 4 and 6 mo of age Samples obtained pre- and 1 mo post-3 rd dose from infants immunized at 2, 4 and 6 mo of age Laboratory Laboratory Assayed concurrently with Tdap samples from adolescents in Td505 using ELISA in 2002 at APL Assayed concurrently with Tdap samples from adolescents in Td505 using ELISA in 2002 at APL Antibody values for comparisons with adolescents and adults in Td506 (primary comparisons for efficacy bridge) Antibody values for comparisons with adolescents and adults in Td506 (primary comparisons for efficacy bridge)

16. 16 Tdap and DTaP Pertussis Post-Vaccination GMC* *GMC = geometric mean concentration (ELISA Units/mL) ‡ 1 month after 3 doses (2, 4 and 6 mo) in Sweden I Efficacy Trial InfantsAdolescentsAdults Post GMC DTaP‡ N=80 Tdap – 505 N=1053 Tdap - 506 N=526 Tdap N=741 PT86.6338.1309.3178.8 FHA39.9265.5214.8192.9 FIM341.11804.81792.4852.7 PRN108.1367.3344.5341.9

17. 17 Efficacy Bridge: Tdap vs. DTaP Post-Vaccination GMC Ratios Antigen Adolescents Tdap/DTaP GMC Ratio (95% CIs) Adults Tdap/DTaP GMC Ratio (95% CIs) PT3.6 (2.8, 4.5)2.1 (1.6, 2.7) FHA5.4 (4.5, 6.5)4.8 (3.9, 5.9) FIM5.3 (3.9, 7.1)2.5 (1.8, 3.5) PRN3.2 (2.5, 4.1)3.2 (2.6, 4.4) All lower limits of 95% CI for GMC ratios for Tdap/DTaP for adolescents and adults exceeded 0.67 criterion

18. 18 Td506: Endpoints – Pertussis Booster Responses Tdap vs. Historical limits for Tdap Tdap vs. Historical limits for Tdap Booster Responses - % of subjects achieving booster response compared to acceptable rate for each antigen determined in historical studies, non-inferior if the LL 95% CI > acceptable rate (~80%) Booster Responses - % of subjects achieving booster response compared to acceptable rate for each antigen determined in historical studies, non-inferior if the LL 95% CI > acceptable rate (~80%)

19. 19 Td506 Results: Pertussis Booster Responses *Rates in historical trials used to define rate for each antigen Non-inferiority demonstrated, LL of 95% CIs > acceptable rate for each antigen AdolescentsAdults Antigen N=524 % (95% CI) N=739 % (95% CI) Pre-defined Acceptable Rate* PT92.0 (89.3, 94.2)84.4 (81.6, 87.0)81.2 FHA85.6 (82.3, 88.4)82.7 (79.8, 85.3)77.6 FIM94.9 (92.6, 96.6)95.9 (83.2, 88.4)82.4 PRN94.5 (92.2, 96.3)93.8 (91.8, 95.4)86.4

20. 20 Td506: Endpoints - Safety Tdap vs. Td – Safety Tdap vs. Td – Safety Safety comparisons for erythema, swelling, pain and fever from Days 0-14 Safety comparisons for erythema, swelling, pain and fever from Days 0-14 Rates of events, non-inferior if upper limit (UL) of 2-sided 95% CI  < 10% Rates of events, non-inferior if upper limit (UL) of 2-sided 95% CI  < 10%

21. 21 Td506: Safety Endpoint Comparisons in Adolescents Adolescents “Any” Intensity Solicited AEs (Days 0-14) Tdap N=1175 % Td N=787 %Diff % (95% CI) Erythema20.819.71.1 (-2.6, 4.7) Swelling20.718.32.6 (-0.9, 6.2) Pain77.871.06.8 (2.8, 10.7) Fever (> 38 o C/100.4 o F)4.92.72.2 (0.6, 3.9) Non-inferiority was demonstrated for all comparisons, except pain

22. 22 Td506: Safety Endpoint Comparisons in Adults Adults “Any” Intensity Solicited AEs (Days 0-14) Tdap N=1698 % Td N=561 %Diff % (95% CI) Erythema24.721.63.2 (-0.8, 7.1) Swelling21.017.33.7 (0.0, 7.4) Pain65.762.92.7 (-1.9, 7.3) Fever (> 38 o C/100.4 o F)1.41.10.3 (-0.7, 1.4) Non-inferiority was demonstrated for all comparisons

23. 23 Td506 Results: Safety Overview AdolescentsAdults Safety Event Tdap N=1175 % Td N=792 % Tdap N=1752 % Td N=573 % Immediate AEs0.50.60.2 Any Local AEs 1 Day 0-14 80.474.068.467.0 Any Systemic AEs 2 Day 0-14 65.561.050.347.6 SAEs0.91.01.9 1 Local AE – pain, swelling, erythema; axillary node swelling 2 Systemic – fever, chills, headache, nausea, vomiting, bodyache, lethargy, rash, sore/swollen joints

24. 24 Td506 Results: Safety Immediate AEs – no anaphylaxis events Immediate AEs – no anaphylaxis events Solicited systemic AE rates similar in Tdap and Td groups Solicited systemic AE rates similar in Tdap and Td groups Sore/swollen joints reported by ~11.5% Tdap and Td adolescent groups; 9.1% in Tdap and 7% in Td adult groups Sore/swollen joints reported by ~11.5% Tdap and Td adolescent groups; 9.1% in Tdap and 7% in Td adult groups Unsolicited AEs (Days 0-28) – no pattern Unsolicited AEs (Days 0-28) – no pattern Trend for higher rate of local AEs in Tdap and Td vaccinees in young adolescents (11-14 yrs) Trend for higher rate of local AEs in Tdap and Td vaccinees in young adolescents (11-14 yrs)

25. 25 Td506 Results: Safety SAEs SAEs 83 events in 63 participants 83 events in 63 participants Rate of 1.5% in both Tdap and Td groups Rate of 1.5% in both Tdap and Td groups No deaths reported No deaths reported 2 neuropathic events in adults 2 neuropathic events in adults 1 day post-Tdap, 26yo female hospitalized for migraine and unilateral facial paralysis; ↑BP (160/100) at time of vaccination 1 day post-Tdap, 26yo female hospitalized for migraine and unilateral facial paralysis; ↑BP (160/100) at time of vaccination 12 days post-Tdap, 49yo female hospitalized for dysasthesia in neck and left arm; evaluated for myocardial infarction and diagnosed as “nerve compression” 12 days post-Tdap, 49yo female hospitalized for dysasthesia in neck and left arm; evaluated for myocardial infarction and diagnosed as “nerve compression”

26. 26 Td506 – Trial Summary Safety and immunogenicity endpoints were met for both adolescents and adults: Safety and immunogenicity endpoints were met for both adolescents and adults: Safety Safety Non-inferiority was demonstrated for AE rates after ADACEL™ as compared to AE rates after Td (except “any” pain in adolescents) Non-inferiority was demonstrated for AE rates after ADACEL™ as compared to AE rates after Td (except “any” pain in adolescents)

27. 27 Td506 – Trial Summary, cont. Immunogenicity for dip and tet Immunogenicity for dip and tet Non-inferiority was demonstrated for dip and tet following ADACEL™ as compared to Td for: Non-inferiority was demonstrated for dip and tet following ADACEL™ as compared to Td for: Seroprotective rates Seroprotective rates Booster responses Booster responses

28. 28 Td506 – Trial Summary, cont. Immunogenicity for pertussis antigens Immunogenicity for pertussis antigens Non-inferiority was demonstrated for the immune responses to the pertussis antigens following ADACEL™ as compared to the immune responses following 3 doses of DAPTACEL® in infants in the Sweden I Efficacy Trial Non-inferiority was demonstrated for the immune responses to the pertussis antigens following ADACEL™ as compared to the immune responses following 3 doses of DAPTACEL® in infants in the Sweden I Efficacy Trial Booster responses demonstrated Booster responses demonstrated

29. 29 Pivotal Trial – Td505 Lot Consistency Study Phase 3, randomized, double-blind trial to assess the lot consistency of 3 consecutively produced lots of Tdap, as measured by safety and immunogenicity, when given as a booster to 11-17 year olds Phase 3, randomized, double-blind trial to assess the lot consistency of 3 consecutively produced lots of Tdap, as measured by safety and immunogenicity, when given as a booster to 11-17 year olds 99.9% had documented 5 previous doses of dip, tet and pertussis-containing vaccine 99.9% had documented 5 previous doses of dip, tet and pertussis-containing vaccine Received 0.5mL IM dose of one of 3 lots of Tdap Received 0.5mL IM dose of one of 3 lots of Tdap Assessments for safety and immunogenicity were performed similar to Td506 (except no 6 mo check) Assessments for safety and immunogenicity were performed similar to Td506 (except no 6 mo check)

30. 30 Td505: Endpoints – Immunogenicity Immunogenicity - Consistency demonstrated (equivalence testing) if: Immunogenicity - Consistency demonstrated (equivalence testing) if: Dip and tet – 2-sided 95% CI of difference in seroprotection rates and booster rates between any 2 lots were within interval (-10%, 10%) Dip and tet – 2-sided 95% CI of difference in seroprotection rates and booster rates between any 2 lots were within interval (-10%, 10%) Pertussis antigens – 2-sided 90% CI for the ratio of GMCs for any 2 lots within interval (0.67, 1.5) Pertussis antigens – 2-sided 90% CI for the ratio of GMCs for any 2 lots within interval (0.67, 1.5)

31. 31 Td505: Results Enrolled N=1811 (~equal in each lot) Enrolled N=1811 (~equal in each lot) Demographic characteristics similar for each lot Demographic characteristics similar for each lot Lot consistency demonstrated Lot consistency demonstrated Immunogenicity - similar results for each of the 3 lots for dip, tet and pertussis responses; similar to Td506 adolescents Immunogenicity - similar results for each of the 3 lots for dip, tet and pertussis responses; similar to Td506 adolescents

32. 32 Td505: Safety Endpoints and Results Safety Safety Erythema, swelling, pain and fever from Days 0-14 for “any” or “moderate & severe”, equivalence testing Erythema, swelling, pain and fever from Days 0-14 for “any” or “moderate & severe”, equivalence testing Safety evaluations  contributed to safety database Safety evaluations  contributed to safety database Results similar between lots and similar to adolescents in Td506 Results similar between lots and similar to adolescents in Td506 No anaphylaxis events No anaphylaxis events 4 SAEs, not vaccine related 4 SAEs, not vaccine related

33. 33 Td505 Summary Consistency of manufacturing of 3 production lots was demonstrated Consistency of manufacturing of 3 production lots was demonstrated Contributed ~1800 adolescents to the safety database of the BLA Contributed ~1800 adolescents to the safety database of the BLA Serum samples were assayed at the same time as Sweden I trial samples (Serology Bridging Study) Serum samples were assayed at the same time as Sweden I trial samples (Serology Bridging Study)

34. 34 Td502 – Concomitant Study of ADACEL™ and Influenza Vaccine Open-labeled, randomized, controlled trial of the safety and immunogenicity of Tdap and influenza vaccines when given concurrently or separately in adults, 19-64 years of age Open-labeled, randomized, controlled trial of the safety and immunogenicity of Tdap and influenza vaccines when given concurrently or separately in adults, 19-64 years of age Group A – Tdap and Flu concurrently (Tdap+flu) Group A – Tdap and Flu concurrently (Tdap+flu) Group B – Flu then Tdap 4-6 weeks later (flu, Tdap) Group B – Flu then Tdap 4-6 weeks later (flu, Tdap) Assessments were performed similar to Td506 Assessments were performed similar to Td506 No active safety monitoring after flu vaccine alone No active safety monitoring after flu vaccine alone

35. 35 Td502: Comparisons for Group A (Tdap + flu) vs. Group B (flu, Tdap) Dip and Tet Dip and Tet Endpoints similar to Td506 Endpoints similar to Td506 Pertussis Antigens Pertussis Antigens GMC ratio A/B, if LL of 2-sided 90% CI > 0.67 GMC ratio A/B, if LL of 2-sided 90% CI > 0.67 Influenza Strains (A/H3N2, A/H1N1, B) Influenza Strains (A/H3N2, A/H1N1, B) Seroprotection rates (defined as HAI* > 1:40) Seroprotection rates (defined as HAI* > 1:40) Seroconverison (defined as > 4-fold rise) Seroconverison (defined as > 4-fold rise) Non-inferior if UL of 2-sided 95% CI  in Non-inferior if UL of 2-sided 95% CI  in rates (B-A) < 10% *HAI = hemagglutination inhibition

36. 36 Td502 Results: Enrollment Total =720 Total =720 Group A = 359 and Group B = 361 Group A = 359 and Group B = 361 Discontinued = 24 Discontinued = 24 21 in Group B after flu but prior to Tdap 21 in Group B after flu but prior to Tdap Demographics were similar for both groups Demographics were similar for both groups 69% reported history of 5 previous dip-tet- pertussis containing vaccines 69% reported history of 5 previous dip-tet- pertussis containing vaccines

37. 37 Td502 Results: Immune Responses Dip, Tet and Pertussis Immune Response Group A Tdap + Flu N=354 Group B Flu, Tdap N=324 Seroprotection > 0.1 IU/mL%Diff % Diphtheria86.2870.9 (-4.3, 6.0) Tetanus99.798.1-1.6 (-3.1, 0.0) Post-GMCGMC Ratio A/B (90% CI) PT186.4234.50.79 (0.70, 0.90) FHA200.6242.20.83 (0.75, 0.91) FIM925.81136.30.81 (0.68, 0.98) PRN191.7260.30.74 (0.61, 0.88)

38. 38 Td502: Influenza Immune Responses Group A Tdap+flu N=354 Group B Flu, Tdap N=324B-A Immune Response%Diff % 95% CI Seroprotection (HAI > 1:40) A/Panama/2007/99 (H3N2)86.588.82.3-2.9, 7.4 A/New Caledonia/20/99 ( H1N1 )54.046.9-7.0-14.8, 0.8 B/Yamanashi/166/9880.680.3-0.3-6.5, 5.9 Seroconversion Rate (4-fold rise) A/Panama/2007/99 (H3N2)69.569.4-0.1-7.3, 7.1 A/New Caledonia/20/99 (H1N1) 68.367.7-0.6-7.9, 6.6 B/Yamanashi/166/9862.865.12.3-5.1, 9.8

39. 39 Td502 Results: Safety Non-inferiority of AE rates for concomitant vs. separate was demonstrated for erythema, swelling, and fever but not for pain (‘any” and “moderate & severe” intensity) Non-inferiority of AE rates for concomitant vs. separate was demonstrated for erythema, swelling, and fever but not for pain (‘any” and “moderate & severe” intensity) > 1 local AEs were frequent (A=69% and B=64%) > 1 local AEs were frequent (A=69% and B=64%) Solicited systemic AE rates higher for concomitant Solicited systemic AE rates higher for concomitant No anaphylaxis events No anaphylaxis events Two SAEs (one in each group) reported, not vaccine related; no deaths reported Two SAEs (one in each group) reported, not vaccine related; no deaths reported

40. 40 Td502: Trial Summary Not all endpoints were met: Not all endpoints were met: Safety Safety Pain – more frequent with concomitant Pain – more frequent with concomitant Immunogenicity – for pertussis Immunogenicity – for pertussis Non-inferiority of responses (GMCs) for concomitant vs. separate was demonstrated for PT, FHA and FIM, but not PRN Non-inferiority of responses (GMCs) for concomitant vs. separate was demonstrated for PT, FHA and FIM, but not PRN Robust rises in antibodies for both groups, though responses lower for concomitant administration Robust rises in antibodies for both groups, though responses lower for concomitant administration Clinical significance of failed endpoints not clear; should be considered in the context of risks and benefits of concomitant immunization Clinical significance of failed endpoints not clear; should be considered in the context of risks and benefits of concomitant immunization

41. 41 Trial Td501 – Concomitant Study of ADACEL™ and Hepatitis B Vaccine Open-labeled, randomized, controlled trial of safety and immune responses of Tdap and hepatitis B vaccines in adolescents 11-14 years of age Open-labeled, randomized, controlled trial of safety and immune responses of Tdap and hepatitis B vaccines in adolescents 11-14 years of age Study Groups: Study Groups: 1 dose of Tdap and 2 dose regimen (1.0 mL per dose) of Hep B vaccine given ~ 4 months apart: 1 dose of Tdap and 2 dose regimen (1.0 mL per dose) of Hep B vaccine given ~ 4 months apart: Group A – Tdap and Hep B #1 concurrently Group A – Tdap and Hep B #1 concurrently (Tdap + Hep B) Group B – Tdap then Hep B dose #1, 4-6 weeks later (Tdap, Hep B) Group B – Tdap then Hep B dose #1, 4-6 weeks later (Tdap, Hep B)

42. 42 Td501: Comparisons for Group A (Tdap + Hep B) vs. Group B (Tdap, Hep B) Dip, Tet and Pertussis Comparisons Dip, Tet and Pertussis Comparisons Similar to Td502 Similar to Td502 Hepatitis B Hepatitis B Seroprotection rates (> 10 mIU/mL, Abbott RIA Kit), non-inferior if UL of 2-sided 95% CI  in rates (B-A) 10 mIU/mL, Abbott RIA Kit), non-inferior if UL of 2-sided 95% CI  in rates (B-A) < 10% Safety (monitoring after Tdap similar to other trials) Safety (monitoring after Tdap similar to other trials) Erythema, swelling, pain and fever, non-inferior if rates of events A vs. B, if UL of 95% CI  (A-B) < 10% Erythema, swelling, pain and fever, non-inferior if rates of events A vs. B, if UL of 95% CI  (A-B) < 10%

43. 43 Td501 Results: Enrollment Total = 410 Total = 410 Group A (Tdap + Hep B) = 206 Group A (Tdap + Hep B) = 206 Group B (Tdap, Hep B) = 204 Group B (Tdap, Hep B) = 204 Demographics comparable for 2 groups Demographics comparable for 2 groups 89% with 5 previous dip-tet-pertussis vaccines 89% with 5 previous dip-tet-pertussis vaccines

44. 44 Td501 Results: Immune Responses to Diphtheria, Tetanus and Pertussis Immune Responses Group A Tdap + Hep B N=161 Group B Tdap, Hep B N=151 Seroprotectio n > 0.1 IU/mL %Diff % Diphtheria10099.3-0.7 (-1.9, 0.6) Tetanus100 0.0 (0.0, 0.0) Post-GMCGMC Ratio A/B (90% CI) PT 303.5321.60.94 (0.8, 1.1) FHA 301.5305.40.99 (0.8, 1.2) FIM 1906.41926.70.99 (0.8, 1.2) PRN 292.9284.61.03 (0.8, 1.3)

45. 45 Td501 Results: Hepatitis B Post-Vaccination Seroprotection Levels Seroprotection > 10 mIU/mL Group A Tdap + Hep B N=161 % Group B Tdap, Hep B N=151 % Diff % (95% CI) Hepatitis B96.397.31.0 (-2.8, 4.9)

46. 46 Td501 Results: Safety Safety endpoints were met for fever and “any” pain but not for “any” erythema, and “any” and “moderate & severe” swelling Safety endpoints were met for fever and “any” pain but not for “any” erythema, and “any” and “moderate & severe” swelling Local AEs were common in both groups (concomitant = 88% and separate = 86.6%) Local AEs were common in both groups (concomitant = 88% and separate = 86.6%)

47. 47 Td501 Results: Safety Solicited systemic AEs after Tdap generally higher for concomitant group Solicited systemic AEs after Tdap generally higher for concomitant group Sore and/or swollen joints - frequent in both concomitant (22.5%) and separate (18%); higher rates than other trials Sore and/or swollen joints - frequent in both concomitant (22.5%) and separate (18%); higher rates than other trials No anaphylaxis events No anaphylaxis events Two SAEs, one in each group, reported - not vaccine related; no deaths reported Two SAEs, one in each group, reported - not vaccine related; no deaths reported

48. 48 Td501: Trial Summary All of the immunogenicity, but not all of the safety endpoints (local AEs) were met All of the immunogenicity, but not all of the safety endpoints (local AEs) were met The clinical significance of the failed safety endpoints not clear; should be considered in the context of risks and benefits of concomitant immunization The clinical significance of the failed safety endpoints not clear; should be considered in the context of risks and benefits of concomitant immunization

49. 49 Safety Events of Interest Across Trials Whole limb swelling Whole limb swelling No occurrences reported in 4 main trials No occurrences reported in 4 main trials Seizures Seizures 3 seizure events 3 seizure events 15 yo male 135 days post-Tdap (known Sz) 15 yo male 135 days post-Tdap (known Sz) 17 yo male 133 days post-Td (known Sz) 17 yo male 133 days post-Td (known Sz) 51 yo female 22 days post-Tdap (substance abuse) 51 yo female 22 days post-Tdap (substance abuse)

50. 50 Safety Events of Interest Across Trials Diabetes and Autoimmune Disorders Diabetes and Autoimmune Disorders 1 new-onset insulin-dependent diabetes mellitus (IDDM) in 11yo 23 days post-Tdap (sibling with IDDM) 1 new-onset insulin-dependent diabetes mellitus (IDDM) in 11yo 23 days post-Tdap (sibling with IDDM) 1 non-IDDM in 56yo 13 days post-Tdap with suprasellar mass and trauma 1 non-IDDM in 56yo 13 days post-Tdap with suprasellar mass and trauma 1 IDDM in 11yo 105 days post-Td 1 IDDM in 11yo 105 days post-Td No other autoimmune disorders identified No other autoimmune disorders identified

51. 51 Safety Events of Interest Pregnancy (Td506, 6 month follow-up) Pregnancy (Td506, 6 month follow-up) 30 women with 31 pregnancies, data for 29: 30 women with 31 pregnancies, data for 29: 19 of 29 healthy full-term infants 19 of 29 healthy full-term infants 5 spontaneous abortions (Tdap=4, Td=1) 5 spontaneous abortions (Tdap=4, Td=1) 1 therapeutic abortion 1 therapeutic abortion 4 premature infants, otherwise healthy 4 premature infants, otherwise healthy No congenital abnormalities No congenital abnormalities

52. 52 Safety Events Exploratory Analyses of Local AEs Age at Immunization Age at Immunization Trend for higher rates of local AEs for younger adolescents (11 - 13 yrs) compared to older adolescents (14 - 17 yrs) Trend for higher rates of local AEs for younger adolescents (11 - 13 yrs) compared to older adolescents (14 - 17 yrs) Gender Gender Trend for higher rates of local AEs in females than in males (in adolescents and adults) Trend for higher rates of local AEs in females than in males (in adolescents and adults)

53. 53 ADACEL™ BLA Summary Data submitted support: Data submitted support: Similar safety profile of ADACEL™ as compared to a U.S. licensed Td Similar safety profile of ADACEL™ as compared to a U.S. licensed Td Non-inferiority of the immune responses to dip and tet as compared to a U.S. licensed Td Non-inferiority of the immune responses to dip and tet as compared to a U.S. licensed Td

54. 54 ADACEL™ BLA Summary Data submitted support: Data submitted support: Non-inferiority of the immune responses to the pertussis antigens following ADACEL™ as compared to those observed after three doses of DAPTACEL ® in infants in Sweden I Efficacy Trial Non-inferiority of the immune responses to the pertussis antigens following ADACEL™ as compared to those observed after three doses of DAPTACEL ® in infants in Sweden I Efficacy Trial A booster response to all of the vaccine antigens A booster response to all of the vaccine antigens Consistency of manufacture of ADACEL™ Consistency of manufacture of ADACEL™ Additionally, data to assess concomitant use of Tdap with influenza and hepatitis B vaccines were provided Additionally, data to assess concomitant use of Tdap with influenza and hepatitis B vaccines were provided

55. 55 Douglas Pratt, M.D. Ms. Martha Monser Bruce Meade, Ph.D. Henry Hsu, Ph.D. DVRPA