1. 1 Vaccines and Related Biological Products Advisory Committee Meeting Prevnar 13: Pneumococcal 13-valent Conjugate Vaccine [Diphtheria CRM 197 Protein] Applicant: Wyeth Pharmaceuticals Inc. Tina Khoie, M.D., M.P.H FDA/CBER/OVRR/DVRPA November 18, 2009

2. 2 Presentation Outline  Product Composition Comparison with Prevnar ®  Proposed Indications and Usage  Prevnar Efficacy and Safety Background  Prevnar 13 Pediatric Clinical Development  Immunogenicity  Safety  Otitis Media Considerations

3. 3 Product Composition - Comparison with Prevnar Each 0.5 mL dose of Prevnar 13 and Prevnar contains: ComponentPrevnar 13Prevnar Capsular polysaccharides from pneumococcal serotypes individually conjugated to CRM 197 2.2 µg from serotypes 1, 3, 4, 5, 6A, 7F, 9V, 14, 18C, 19A, 19F, and 23F and 4.4 µg from serotype 6B 2.2 µg from serotypes 4, 9V, 14, 18C, 19F, and 23F and 4.4 µg from serotype 6B CRM 197 carrier protein~32 µg~20 µg Aluminum as AlPO 4 adjuvant0.125 mg Polysorbate 80 (P80)*0.02%None 5mM succinate buffer5mMNone * P80 added to the final Prevnar 13 formulation late in clinical development

4. 4 Prevnar 13: Applicant’s Proposed Indications and Usage  Active immunization of infants and toddlers for the prevention of invasive disease caused by Streptococcus pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F  Active immunization of infants and toddlers for the prevention of otitis media caused by serotypes included in the vaccine  Prevnar 13 is to be administered to infants as a 4 dose series at 2, 4, 6, and 12-15 months of age

5. 5 Prevnar Efficacy Background  Approved by FDA in Feb 2000 to prevent vaccine serotype invasive pneumococcal disease (IPD) in young children.  Efficacy against vaccine serotype IPD was 97.4% (95% CI 82.7, 99.9)  Approved by FDA in Oct 2002 for prevention of vaccine serotype otitis media (OM) based on data from:  an acute otitis media (AOM) efficacy trial in Finland, involving tympanocentesis, evaluating serotype-specific efficacy  a U.S. health-care utilization study on impact on all-cause OM  Efficacy against vaccine serotype AOM was 57% (95% CI 44, 67) and 7% (95% CI 4.1, 9.7) against all OM regardless of etiology  Prevnar efficacy data are referenced in the Prevnar 13 BLA

6. 6 Prevnar Prelicensure Safety Background  Safety evaluated in 5 U.S. clinical studies  18,168 subjects received 58,699 doses of Prevnar  Subjects received Prevnar at 2, 4, 6, and 12-15 months of age along with other routine childhood vaccines  Overall, Prevnar safety profile characterized by:  Increased rates of local reactions compared to Hib and DTaP  Increased rates of low grade fever and irritability compared to an unapproved meningococcal serogroup C conjugate vaccine  Increased rates of low grade fever compared to a control group that received no investigational products  Severe local reactions occurring more often in children 3-9 years of age (in ancillary studies) compared to infants

7. 7 Prevnar Postlicensure Safety  Postmarketing observational safety surveillance study  65,927 infants evaluated across doses, health-care settings and multiple post-vaccination time windows  Evaluated events of interest identified in prelicensure studies, including croup, gastroenteritis, allergic reactions, seizures, wheezing diagnoses and breath holding  Primary safety outcomes analyses did not demonstrate a consistently elevated risk of healthcare utilization for any of the evaluated events of interest.

8. 8 Prevnar 13 Pediatric Clinical Development  Placebo-controlled clinical efficacy study not feasible  Approach for inferring efficacy against IPD:  Evaluate non-inferiority of Prevnar 13 to Prevnar based on IgG ELISA antibody responses  Serologic criteria were based in part on WHO recommendations  Approach for inferring efficacy against otitis media  No consensus regarding serologic criteria for assessing efficacy against otitis media  Relevance of circulating IgG in preventing otitis media is unclear

9. 9 Main Prevnar 13 Pediatric Studies  004: Phase 3 immunogenicity and safety (N=663)  Randomized (1:1), double-blind, active-controlled trial in U.S. infants and toddlers  Primary objectives: demonstrate non-inferiority of PCV13 (without P80) compared with PCV7 one month after 3 and 4 doses  3005: Phase 3 safety and lot consistency (N=1699)  Randomized (2:2:2:1), double-blind trial in U.S. infants and toddlers; PCV7 active control included for safety  Primary objective: demonstrate equivalency of 3 independently produced lots of Prevnar 13

10. 10 Other Supportive Studies  003: Phase 1/2 safety and immunogenicity in U.S. infants and toddlers (N=247)  009: Phase 3, non-IND non-inferiority study comparing Prevnar 13 with P80 to Prevnar 13 without P80 in Poland (N=500)  3002: Open label, descriptive non-IND study evaluating Prevnar 13 catch-up in pneumococcal vaccine naïve children 7 months to < 72 months of age in Poland (N=354)

11. 11 Other Supportive Studies  Nine non-IND studies (N=4381) conducted in Europe, Canada, and India provide data on serious adverse events.  2322 and 2059 subjects randomized and vaccinated with at least one dose of Prevnar 13 or Prevnar, respectively.  Primary objective(s): evaluate country specific immunization schedules and/or country specific concomitant vaccinations.  Data supporting U.S. licensure of PCV13 were limited to serious adverse events, because studies included non-U.S. schedules, non- U.S. concomitant vaccinations, and less extensive safety monitoring than typically requested by CBER.

12. 12 Immunogenicity from Main Infant Study 004

13. 13 Main Immunogenicity Study 004 Design  666 healthy, 2 month old infants randomized 1:1 to receive:  Prevnar 13: 0.5 mL IM at 2, 4, 6, and 12-15 months  Prevnar (active control): 0.5 mL IM at 2, 4, 6, and 12-15 months  HBV (birth dose), rotavirus, and influenza vaccines permitted during study period Age (months) 246712-1513-16 PCV13 or PCV7++++ DTaP-HBV-IPV+++ PRP-T+++ PRP-OMP+ MMRV+ Blood draw+++

14. 14 Study 004 Immunogenicity Objectives & Endpoints  Primary Objectives: Demonstrate non-inferiority of Prevnar 13 to Prevnar for each of the vaccine serotypes and each primary endpoint.  Primary Endpoints:  IgG seroresponse rate ≥ 0.35 µg/mL 1 month after the 3 rd dose  Geometric mean IgG antibody concentration (GMC) 1 month after the 4 th dose  Secondary Endpoints:  IgG seroresponse rate ≥ 0.35 µg/mL 1 month after the 4 th dose  IgG GMC before the 4 th dose and 1 month after the 3 rd dose  IgG seroresponse rate ≥ 1.0 µg/mL 1 month after the 3 rd and 1 month after the 4 th dose

15. 15 Study 004 Non-inferiority Comparisons  For the 7 common serotypes, serotype-specific immune responses were compared between the two study groups  For the 6 additional serotypes not included in Prevnar, immune responses in Prevnar 13 recipients were compared to the lowest immune response among the 7 common serotypes in Prevnar recipients  Non-inferiority criteria:  IgG seroresponse rate: lower limit of 2-sided, 95% CI for the difference in proportions (PCV13 – PCV7) > - 10%  IgG GMC: lower limit of 2-sided, 95% CI for the GMC ratio (PCV13 / PCV7) > 0.5 (2-fold criterion)

16. 16 Study 004 Exploratory Objective and Endpoints  Exploratory objective: To assess opsonophagocytic activity (OPA) following Prevnar 13 relative to Prevnar in a subset (N=100 per study group), when measured 1 month after the 3 rd and 4 th doses.  Exploratory endpoints:  Proportion of subjects achieving an OPA titer ≥ 1:8 titer one month after the 3 rd and 4 th doses.  OPA geometric mean titer (GMT) one month after the 3 rd and 4 th doses.

17. 17 Study 004 Concomitant Vaccination Objectives*  To demonstrate that the immune response induced by concomitant antigens when administered with Prevnar 13 are noninferior to the corresponding immune response when administered with Prevnar  Antigens assessed 1 month after the 3 rd dose: diphtheria, pertussis (PT, FHA, PRN), and H. influenzae (PRP)  Antigens assessed 1 month after the 12 month dose: measles, mumps, rubella, varicella, and H. influenzae (PRP) *Tetanus, HBV and IPV types 1-3 assessed in study 3005

18. 18 Study 004 Demographics Prevnar 13 N=334 Prevnar N=332 Gender Male50.6%58.1% Race White68.3%70.8% Black or African American21.3%18.1% Other 7.5% 8.4% Asian 2.4% Native Hawaiian or other Pacific Islander 0.6% 0.3% Ethnicity Non-Hispanic and Non-Latino83.5%81.6% Hispanic or Latino16.5%18.4%

19. 19 Study 004 Primary Endpoint Immunogenicity Results

20. 20 Study 004: IgG Seroresponse Rates ≥ 0.35 µg/mL for the 7 Common Serotypes, 1 Month Post-dose 3 Prevnar 13 (N=251-252) Prevnar (N=250-252) Difference (95% CI) [PCV13 – PCV7] Serotype% 494.498.0-3.6 (-7.3, -0.1) 6B87.392.8-5.5 (-10.9, -0.1) 9V90.598.4-7.9 (-12.4, -4.0) 1497.697.20.4 (-2.7, 3.5) 18C96.898.4-1.6 (-4.7, 1.2) 19F98.097.60.4 (-2.4, 3.4) 23F90.594.0-3.6 (-8.5, 1.2) N = range in the number of subjects with a determinate IgG antibody concentration to the given serotype. Difference in proportions (PCV13 – PCV7 reference value) expressed as percentage. Non-inferiority criterion: lower limit of the 2-sided, 95% CI for the difference in two proportions > -0.1.

21. 21 Study 004: IgG Seroresponse Rates ≥ 0.35 µg/mL for the 6 Additional Serotypes, 1 month Post-dose 3 Prevnar 13 (N=249-252) Prevnar Reference (Serotype 6B) (N=250) Difference (95% CI) [PCV13 – PCV7] Serotype% 195.692.82.8 (-1.3, 7.2) 363.592.8-29.3 (-36.2, 22.4) 589.792.8-3.1 (-8.3, 1.9) 6A96.092.83.2 (-0.8, 7.6) 7F98.492.85.6 (1.9, 9.7) 19A98.492.85.6 (1.9, 9.7) N = range in the number of subjects with a determinate IgG antibody concentration to the given serotype. Difference in proportions (PCV13 – PCV7 reference value) expressed as percentage. For additional serotypes, the reference value is serotype 6B from the PCV7 group. Non-inferiority criterion: lower limit of the 2-sided, 95% CI for the difference in two proportions > -0.1.

22. 22 Study 004: IgG GMC (µg/mL) for the 7 Common Serotypes, 1 month Post-dose 4 Prevnar 13 (N=234-236) Prevnar (N=222-223) GMC Ratio (95% CI) [PCV13 / PCV7] SerotypeGMC (µg/mL) 43.75.50.68 (0.57, 0.80) 6B11.515.60.74 (0.61, 0.89) 9V2.63.60.72 (0.62, 0.85) 149.112.70.72 (0.60, 0.86) 18C3.24.70.68 (0.57, 0.81) 19F6.65.61.18 (0.98, 1.41) 23F5.17.80.65 (0.54, 0.78) N = range in the number of subjects with a determinate IgG antibody concentration to the given serotype. GMC ratio: PCV13 to PCV7 reference. For the additional serotypes, the reference value is serotype 9V from the PCV7 group. Non-inferiority criterion: lower limit of the 2-sided, 95% CI for the GMC ratio > 0.5 (2-fold criterion).

23. 23 Study 004: IgG GMC (µg/mL) for the 6 Additional Serotypes, 1 month Post-dose 4 Prevnar 13 (N=232-236) Prevnar Reference (Serotype 9V) (N=223) GMC Ratio (95% CI) [PCV13 / PCV7] SerotypeGMC (µg/mL) 15.13.61.40 (1.17, 1.66) 30.93.60.26 (0.22, 0.30) 53.73.61.03 (0.87, 1.20) 6A8.23.62.26 (1.93, 2.65) 7F5.73.61.56 (1.32, 1.85) 19A8.63.62.36 (2.01, 2.76) N = range in the number of subjects with a determinate IgG antibody concentration to the given serotype. GMC ratio: PCV13 to PCV7 reference. For the additional serotypes, the reference value is serotype 9V from the PCV7 group. Non-inferiority criterion: lower limit of the 2-sided, 95% CI for the GMC ratio > 0.5 (2-fold criterion).

24. 24 Study 004 Secondary Endpoints

25. 25 Study 004: IgG GMC (µg/mL) for the 7 Common Serotypes, Pre-dose 4 Prevnar 13 (N= 227-229) Prevnar (N= 205-208) GMC Ratio (95% CI) [PCV13 / PCV7] Calculated by CBER SerotypeGMC (µg/mL) 40.350.510.69 (0.59, 0.81) 6B0.781.010.78 (0.65, 0.94) 9V0.390.530.73 (0.63, 0.84) 141.892.490.76 (0.62, 0.92) 18C0.340.450.75 (0.65, 0.86) 19F0.730.651.12 (0.94, 1.33) 23F0.380.480.79 (0.65, 0.96) N = range in the number of subjects with a determinate IgG antibody concentration to the given serotype. GMC ratio calculated by CBER. The study was not powered to demonstrate non-inferiority for secondary endpoints.

26. 26 Study 004: IgG GMC (µg/mL) for the 6 Additional Serotypes, Pre-dose 4 Prevnar 13 (N=224-229) Prevnar Reference (Serotype 18C) (N=207) GMC Ratio (95% CI) [PCV13 / PCV7] Calculated by CBER SerotypeGMC (µg/mL) 10.640.451.42 (1.21, 1.65) 30.150.450.33 (0.28, 0.40) 50.770.451.71 (1.47, 1.99) 6A0.830.451.84 (1.60, 2.11) 7F0.830.451.85 (1.60, 2.15) 19A0.920.452.05 (1.74, 2.41) N = range in the number of subjects with a determinate IgG antibody concentration to the given serotype. GMC ratio calculated by CBER. For the additional serotypes, the reference value is serotype 18C from the PCV7 group. The study was not powered to demonstrate non-inferiority for secondary endpoints.

27. 27 Study 004: Serotype 6B IgG Secondary Endpoints N = number of subjects with a determinate IgG antibody concentration to the given serotype. Ratio of GMCs: PCV13 to PCV7 reference. Difference in proportions (PCV13 – PCV7) expressed as percentage. The study was not powered to demonstrate non-inferiority for secondary endpoints. Prevnar 13Prevnar Ratio or Difference (95% CI) Post-dose 3N=252N=250 IgG GMC (µg/mL)2.13.10.67 (0.52, 0.85) % with ≥ 1.0 µg/mL76.280.0-3.8 (-11.1, 3.5) Post-dose 4N=234N=233 % with ≥ 0.35 µg/mL99.6100.0-0.4 (-2.4, 1.3) % with ≥ 1.0 µg/mL97.499.6-2.1 (-5.1, 0.2)

28. 28 Study 004: Serotype 9V IgG Secondary Endpoints N = number of subjects with a determinate IgG antibody concentration to the given serotype. Ratio of GMCs; PCV13 to PCV7 reference. Difference in proportions (PCV13 – PCV7) expressed as percentage. Prevnar 13Prevnar Ratio or Difference (95% CI) Post-dose 3N=252 IgG GMC (µg/mL)0.981.400.70 (0.61, 0.80) % with ≥ 1.0 µg/mL48.066.3-18.3 (-26.7, -9.6) Post-dose 4N=234N=223 % with ≥ 0.35 µg/mL99.199.6-0.4 (-2.6, 1.7) % with ≥ 1.0 µg/mL89.795.1-5.3 (-10.4, -0.3)

29. 29 Study 004: Serotype 3 IgG Secondary Endpoints N = number of subjects with a determinate IgG antibody concentration to the given serotype. GMC ratio: PCV13 to PCV7 reference. For additional serotypes, reference value is serotype 9V from PCV7 group. Difference in proportions: PCV13 – PCV7 reference, expressed as percentage. PCV7 reference value is serotype 19F for evaluations at ≥ 0.35 µg/mL post-dose 4 and for evaluations at ≥ 1.0 µg/mL post-dose 4. PCV7 reference value is serotype 9V for evaluations at ≥ 1.0 µg/mL post-dose 3 and for GMC evaluations post-dose 3. Prevnar 13 Prevnar Reference Value Ratio or Difference (95% CI) Post-dose 3 N=249N=241-252 IgG GMC (µg/mL)0.491.400.35 (0.30, 0.41) % with ≥ 1.0 µg/mL21.766.3-44.6 (-52.2, -36.5) Post-dose 4N=232N=223 % with ≥ 0.35 µg/mL90.598.7-8.1 (-12.8, -4.0) % with ≥ 1.0 µg/mL44.894.6-49.8 (-56.8, -42.5)

30. 30 Study 004 Exploratory Endpoints

31. 31 Study 004: Serotype 6B OPA Exploratory Endpoints N = Number of subjects with a determinate antibody titer for the specified serotype. Prevnar 13Prevnar Post-dose 3N=94 OPA GMT1054 (817, 1361)1514 (1207, 1899) % with ≥ 1:8 OPA titer98.9 (94.2, 100.0)100.0 (96.2, 100.0) Post-dose 4N=92N=95 OPA GMT3100 (2337, 4111)4066 (3243, 5098) % with ≥ 1:8 OPA titer98.9 (94.1, 100.0)100.0 (96.2, 100.0)

32. 32 Serotype 9V OPA Exploratory Endpoints N = Number of subjects with a determinate antibody titer for the specified serotype. Prevnar 13Prevnar Post-dose 3N=93N=94 OPA GMT4035 (2933, 5553)3259 (2288, 4641) % with ≥ 1:8 OPA titer100.0 (96.1, 100.0)98.9 (94.2, 100.0) Post-dose 4N=90N=94 OPA GMT11856 (8810, 15955)18032 (14125, 23021) % with ≥ 1:8 OPA titer98.9 (94.0, 100.0)100.0 (96.2, 100.0)

33. 33 Serotype 3 OPA Exploratory Endpoints N = Number of subjects with a determinate antibody titer for the specified serotype. Prevnar 13Prevnar Post-dose 3N=94 OPA GMT120.7 (92.4, 157.6)6.7 (5.3, 8.5) % with ≥ 1:8 OPA titer96.8 (91.0, 99.3)21.3 (13.5, 30.9) Post-dose 4N=91N=96 OPA GMT380.41 (300.2, 482.1)11.81 (8.7, 16.1) % with ≥ 1:8 OPA titer97.8 (92.3, 99.7)43.8 (33.6, 54.3)

34. 34 Immune Responses to Concomitant Routine U.S. Licensed Childhood Vaccines  Noninterference of Prevnar 13 with routine childhood vaccines was demonstrated for:  H. influenzae (PRP)  Diphtheria toxoid  Pertussis  Measles  Tetanus toxoid  Polio types 1-3  Hepatitis B  Mumps, Rubella, and Varicella, assessments of immune interference are indeterminate at this time.

35. 35 Immunogenicity Summary: 7 Common Serotypes Primary endpoint Non-inferiority Comparisons Secondary endpoint Non-inferiority Comparisons (Study not powered for these evaluations) Common Serotypes % ≥ 0.35 Post-dose 3 GMC Post-dose 4 % ≥ 0.35 Post-dose 4 GMC Post-dose 3 % ≥ 1.0 Post-dose 3 % ≥ 1.0 Post-dose 4 GMC Pre-dose 4* 4 Failed 6BFailed Failed 9VFailed Failed 14 18C Failed 19F Failed 23F Failed Non-inferiority criteria: lower limit of the 2-sided, 95% CI for the difference in two proportions > -0.1 and lower limit of the 2-sided, 95% CI for the GMC ratio > 0.5 (2-fold criterion). * Calculated by CBER

36. 36 Immunogenicity Summary: 6 Additional Serotypes Primary endpoint Non-inferiority Comparisons Secondary endpoint Non-inferiority Comparisons (Study not powered for these evaluations) Additional Serotypes % ≥ 0.35 Post-dose 3 GMC Post-dose 4 % ≥ 0.35 Post-dose 4 GMC Post-dose 3 % ≥ 1.0 Post-dose 3 % ≥ 1.0 Post-dose 4 GMC Pre-dose 4* 1 3Failed 5 Failed 6A 7F 19A Non-inferiority criteria: lower limit of the 2-sided, 95% CI for the difference in two proportions > -0.1 and lower limit of the 2-sided, 95% CI for the GMC ratio > 0.5 (2-fold criterion). * Calculated by CBER

37. 37 Safety From Infant Studies

38. 38 Safety  Three U.S. studies (003, 004, and 3005) included:  Prevnar 13 or Prevnar control at 2, 4, 6, and 12-15 months of age  Concomitant routine U.S. licensed pediatric vaccines.  Remaining infant studies included:  Different vaccine schedules and concomitant vaccinations for consistency with country-specific recommendations and local clinical practice. Schedules included:  2, 3, 4, 11-12 months  3, 5, 11 months  2, 4, 12 months  6, 10, 14 weeks, 12 months  Safety monitoring less extensive compared to U.S. studies  Safety population included all subjects who received at least 1 dose of study vaccine and for whom safety information was available.  Safety analyses were based on the actual vaccine received.

39. 39 Prevnar 13Prevnar All 13 infant studies*47302760 Number of randomized subjects with ≥ 1 dose *Includes infant series data from 13 studies, toddler dose data from 9 studies (7 studies with 4-dose schedules), and 6-month follow-up data from 5 studies. Overall Infant Safety Database Prevnar 13Prevnar All 7 studies with 4 dose schedules and with dose 4 data 15701458 Number of randomized subjects with 4 doses

40. 40 U.S. Safety Database Vaccine Exposure and Study Completion Prevnar 13Prevnar Subjects RandomizedN=1922N=705 Dose 11908701 Doses 1, 2, and 31694626 Doses 1, 2, 3, and 4 350*361* * Post-dose 4 safety data from study 3005 were not available at the time the BLA was submitted to FDA. Applicant will submit these data when available.

41. 41 Safety Monitoring in Phase 3 U.S. Studies (Studies 004 and 3005)  30 minute observation period after each vaccination  Solicited local reactions and systemic adverse events recorded in e-diary on days 1-7 following each vaccination  Unsolicited adverse events occurring within 30 days after each vaccination collected at subsequent visit.  Newly diagnosed chronic medical conditions, hospitalizations, unsolicited, and serious adverse events (SAEs) occurring after the 3 rd study dose were collected at 4 th study dose clinic visit and by scripted telephone interview 6 months after 4 th study dose.  Serious adverse events collected throughout study period.

42. 42 13 Infant Studies Serious Adverse Events

43. 43 All Infant Studies: Percent of Randomized Subjects with a Serious Adverse Event PCV13 % (n/N) PCV7 % (n/N) From Dose 1 Thru Post-infant Series Blood Draw 3.7 (173/4723)3.5 (97/2754) Within 30 Days After Toddler Dose1.0 (24/2499)0.8 (12/1482) From Post-Toddler Dose Blood Draw to 6-month Follow-up Telephone Contact 3.3 (61/1860)2.7 (37/1356)

44. 44 Deaths: All studies Vaccine Received Age (months) at death Last doseDays since last dose Suspected cause of death Prevnar 13*2114SIDS Prevnar 13*423SIDS Prevnar 139376SIDS Prevnar2113SIDS * Possible contributing factors found on history.

45. 45 Studies 004 and 3005 Solicited Safety Data

46. 46 Study 004: Rates (%) of Solicited Local Reactions on Days 1-7 After Each Vaccination Dose 1Dose 2Dose 3Dose 4 PCV13 N=173- 264 PCV7 N=186- 270 PCV13 N=116- 200 PCV7 N=120- 216 PCV13 N=87- 178 PCV7 N=79- 176 PCV13 N=59- 149 PCV7 N=44- 147 Erythema Any 0.5 to 2.0 cm > 2.0 to 7.0 cm > 7.0 cm 35.6 34.5 4.5 0.0 32.3 31.4 2.6 0.0 45.2 44.5 1.7 0.0 37.8 37.0 3.2 0.0 48.9 47.7 5.5 0.0 50.0 48.7 5.0 0.0 54.4 53.9 8.1 0.0 65.5 63.5 14.0 0.0 Induration Any 0.5 to 2.0 cm > 2.0 to 7.0 cm > 7.0 cm 27.4 23.1 6.8 0.0 23.6 21.2 5.2 0.0 31.2 29.8 5.1 0.0 29.5 26.1 7.1 0.0 37.9 35.4 6.6 0.0 36.9 6.1 0.0 44.0 43.3 14.7 0.0 50.7 46.5 14.3 0.0 Tenderness Any Severe* 72.7 13.7 72.2 9.2 77.0 10.6 75.9 11.5 78.7 8.8 80.9 9.3 81.2 15.4 84.4 12.2 *Interferes with limb movement

47. 47 Study 3005: Rates (%) of Solicited Local Reactions on Days 1-7 After Each Vaccination Dose 1Dose 2Dose 3 PCV13 N=993-1229 PCV7 N=164-212 PCV13 N=733-1021 PCV7 N=127-176 PCV13 N=681-921 PCV7 N=111-156 Erythema Any 0.5 to 2.0 cm > 2.0 to 7.0 cm > 7.0 cm 22.5 21.3 1.7 0.0 22.8 21.7 1.2 0.0 33.4 32.0 2.8 0.0 30.1 28.8 3.1 0.0 37.7 35.8 5.1 0.0 39.4 38.5 7.8 0.0 Induration Any 0.5 to 2.0 cm > 2.0 to 7.0 cm > 7.0 cm 18.5 15.7 4.8 0.0 18.2 16.2 3.6 0.0 25.3 23.8 3.5 0.1 17.7 3.9 0.0 26.5 24.8 4.0 0.0 30.5 29.1 7.0 0.0 Tenderness Any Severe* 63.0 10.0 67.0 12.9 66.2 9.8 64.8 11.4 59.5 8.9 64.7 11.9 *Interferes with limb movement Dose 4 safety data from study 3005 were not submitted to the BLA.

48. 48 Antipyretics Within 7 Days of Vaccination  Use of antipyretics to treat or prevent symptoms related to vaccination were similar between the two vaccine groups in in studies 004 and 3005.  Study 004:  Approximately 72-87% of subjects after doses 1, 2, or 3.  Approximately 84-90% of subjects after dose 4.  Study 3005:  Approximately 63-75% of subjects after doses 1, 2, or 3.

49. 49 Study 004: Rates (%) of Fever on Days 1-7 After Each Vaccination Dose 1Dose 2Dose 3Dose 4 Fever PCV13 N=174- 196 PCV7 N=187- 203 PCV13 N=116- 146 PCV7 N=121- 151 PCV13 N=87-123 PCV7 N=80- 106 PCV13 N=60-99 PCV7 N=45-76 ≥ 38.0 o C and ≤ 39.0 o C 24.021.243.240.439.837.753.551.3 > 39.0 o C and ≤ 40.0 o C 2.8*0.0*2.54.98.52.56.612.5 > 40.0 o C 0.0 0.80.01.31.70.0 * Statistically significant difference between the two study groups (Fisher exact test, 2-sided).

50. 50 Study 3005: Rates (%) of Fever on Days 1-7 After Each Vaccination Dose 1Dose 2Dose 3 Fever PCV13 N=978-1043 PCV7 N=160-173 PCV13 N=718-830 PCV7 N=124-143 PCV13 N=674-764 PCV7 N=111-132 ≥ 38.0 o C and ≤ 39.0 o C 24.326.035.128.028.532.6 > 39.0 o C and ≤ 40.0 o C 0.61.23.4*0.0*3.96.2 > 40.0 o C 0.10.60.10.00.10.9 * Statistically significant difference between the two study groups (Fisher exact test, 2-sided). Dose 4 safety data from study 3005 were not submitted to BLA.

51. 51 Study 004: Rates (%) of Solicited Systemic AEs, Days 1-7 After Each Vaccination Dose 1Dose 2Dose 3Dose 4 PCV13 N=178- 289 PCV7 N=188- 290 PCV13 N=118- 236 PCV7 N=120- 236 PCV13 N=89-216 PCV7 N=79-218 PCV13 N=62-199 PCV7 N=47-175 Decreased appetite 54.845.459.952.359.259.665.573.6 Irritability 89.685.989.891.588.492.292.093.1 Decreased sleep 45.747.949.155.860.463.458.464.2 Increased sleep 79.578.579.373.571.369.870.474.3 Hives 1.71.12.50.04.50.04.86.4

52. 52 Study 3005: Rates (%) of Solicited Systemic AEs, Days 1-7 After Each Vaccination Dose 1Dose 2Dose 3 PCV13 N=996-1300 PCV7 N=164-226 PCV13 N=741-1123 PCV7 N=127-201 PCV13 N=686-1038 PCV7 N=112-186 Decreased appetite 48.949.048.549.448.250.0 Irritability 86.487.685.881.180.984.4 Decreased sleep 44.446.447.548.447.1*56.5* Increased sleep 71.272.666.863.358.051.4 Hives 0.70.01.30.81.51.8 * Statistically significant difference between the two study groups (Fisher exact test, 2-sided). Dose 4 safety data from study 3005 were not submitted to BLA.

53. 53 Safety Summary  Overall Prevnar 13 safety database included ~4700 infants and toddlers  No imbalance of SAE’s compared to PCV 7  4 deaths due to SIDS across all studies (3 PCV 13)  Overall, rates of solicited local and systemic adverse events (other than fever) were similar to PCV7. There were no consistent trends identified.  Tenderness was the most frequently reported local reaction  Irritability was the most frequently reported systemic adverse event  In the largest U.S. safety study (study 3005), moderate fever occurred at a statistically significantly higher rate in Prevnar 13 recipients compared to Prevnar recipients after the 2 nd dose. This finding was not observed in study 004 (a smaller study).

54. 54 Otitis Media Indication

55. 55 Otitis Media Indication Considerations  The 0.35 µg/mL anti-pneumococcal antibody reference value applies only to IPD and not to otitis media or other non-invasive disease endpoints  Clinical relevance of circulating IgG in preventing otitis media is unclear  Currently, there is no consensus regarding serologic criteria for inferring efficacy of new pneumococcal conjugate vaccines in preventing otitis media  Prevnar otitis media indication was based on serotype-specific efficacy data from a Finnish clinical endpoint study and U.S. health-care utilization data on the impact on all-cause OM from the NCKP Prevnar trial

56. 56 CBER Summary and Conclusions  Data submitted to the BLA in support of the IPD indication demonstrate that 10 of 13 serotypes contained in Prevnar 13 met non-inferiority criteria for both primary endpoints when compared to Prevnar. All serotypes demonstrated some functional antibody response. Postmarketing studies are currently planned to evaluate IPD effectiveness.  In the largest U.S. safety study (study 3005), moderate fever occurred at a statistically significantly higher rate in Prevnar 13 recipients compared to Prevnar recipients after the 2 nd dose. Postmarketing plans include a phase 4 observational safety study.  No data in BLA directly supporting an otitis media indication for Prevnar 13. The details regarding postmarketing studies evaluating effectiveness against otitis media are the subject of ongoing discussion with the Applicant.

57. 57 EXTRA SLIDES

58. 58 Prevnar 13 Pediatric Development Program: Supportive Studies  6096A1-002: Phase 1 adult safety (U.S.)  6096A1-003: Phase 2 safety and immunogenicity in infants and toddlers (U.S.)  6096A1-006: Main phase 3 safety and immunogenicity (Germany) 1,2  6096A1-009: Phase 3 final formulation in infants and toddlers (Poland) 1,2  6096A1-008: Phase 3 catch-up for 6 additional serotypes following one PCV13 dose in toddlers with 3 prior PCV7 doses (France) 1,2  6096A1-500: Safety and immunogenicity in infants and toddlers (Italy) 1,2  6096A1-3000: Lot consistency (Poland) 1,2  6096A1-3002: Catch-up in pneumococcal vaccine naïve  6096A1-3008: Safety and immunogenicity (Canada) 2,3  6096A1-501: Safety and immunogenicity (Spain) 1,2,3  6096A1-3007: Safety and immunogenicity (Spain) 1,2,3  6096A1-007: Safety and immunogenicity (UK) 1,2,3  6096A1-011: Safety and immunogenicity (India) 1,2 1 Study design includes non-U.S. vaccination schedule 2 Study design includes non-U.S. licensed vaccines 3 Study includes active control (PCV7) group only for concomitant antigen and safety assessments

59. 59 Main Immunogenicity Study 004  Key exclusion criteria:  Known or suspected immune deficiency or suppression  Known major congenital malformation or serious chronic disorder  Significant neurological disorder or history of seizure, including febrile seizure, or significant stable or evolving disorders  Receipt of blood or gamma-globulin products  Previous vaccination with any study vaccine  History of culture-proven invasive disease caused by S. pneumoniae or H. influenzae type b or confirmed measles, mumps, rubella, or varicella infection

60. 60 Immunogenicity Analysis Populations  Evaluable infant and evaluable toddler immunogenicity population (per- protocol):  Received dose 1 at ≥ 41 and ≤ 99 days of age (infant)  Received dose 4 at ≥ 364 and ≤ 456 days of age (toddler)  Received 3 (infant) or 4 (toddler) study vaccinations according to randomized treatment  Received all expected study concomitant assignment vaccinations at all 3 (infant) or 4 (toddler) doses  At least 1 valid and determinate assay result  Blood draws within 27 to 56 days after 3 rd (infant) or 4 th (toddler) vaccination  Received no prohibited vaccines  No other protocol violations  All-available infant and toddler immunogenicity population  All subjects who had at least 1 valid and determinate post-dose 3 (infant) or pre- or post-dose 4 (toddler) assay result

61. 61 Study 004: IgG Seroresponse Rates ≥ 0.35 µg/mL for the 7 Common Serotypes, Pre-dose 4 Prevnar 13 (N=227-229) Prevnar (N=205-208) Difference [PCV13 – PCV7] (95% CI) Serotype% (95% CI) 446.7 ( 40.1, 53.4 )66.8 (60.0, 73.2)-20.1 (-29.1, -10.9) 6B80.8 ( 75.1, 85.7 )86.8 (81.4, 91.1)-6.0 (-13.0, 1.0) 9V56.8 ( 50.1, 63.4 )71.4 (64.7, 77.4)-14.5 (-23.4, -5.5) 1493.0 ( 88.9, 95.9 )96.1 (92.5, 98.3)-3.1 ( -7.7, 1.2) 18C45.9 ( 39.3, 52.5 )62.8 (55.8, 69.4)-17.0 (-26.1, -7.6) 19F79.0( 73.2, 84.1 )73.7 (67.1, 79.5)5.4 ( -2.8, 13.5) 23F 54.1 ( 47.5, 60.7 ) 61.4 (54.4, 68.0)-7.2 (-16.5, 2.1) N = number of subjects with a determinate IgG antibody concentration to the given serotype. n = Number of subjects with an antibody concentration ≥ 0.35 μg/mL for the given serotype. Difference in proportions (13vPnC – PCV7 reference value) expressed as percentage.

62. 62 Study 004: IgG Seroresponse Rates ≥ 0.35 µg/mL for the 6 Additional Serotypes, Pre-dose 4 Prevnar 13 (N=) Prevnar Reference (Serotype 23F) (N=250) Difference [PCV13 – PCV7] (95% CI) Serotype% (95% CI) 179.5 (73.7, 84.5)61.4 (54.4, 68.0)18.1 (9.5, 26.6) 316.1 (11.5, 21.5)61.4 (54.4, 68.0)-45.3 (-53.3, -36.7) 583.8 (78.3, 88.3)61.4 (54.4, 68.0)22.4 (14.0, 30.6) 6A90.4 (85.8, 93.9)61.4 (54.4, 68.0)29.0 (21.2, 36.7) 7F89.9 (85.2, 93.5)61.4 (54.4, 68.0)28.6 (20.7, 36.3) 19A85.6 (80.4, 89.9)61.4 (54.4, 68.0)24.2 (16.0, 32.3) N = number of subjects with a determinate IgG antibody concentration to the given serotype. n = Number of subjects with an antibody concentration ≥ 0.35 μg/mL for the given serotype. Difference in proportions (13vPnC – PCV7 reference value) expressed as percentage. For additional serotypes, the reference value is serotype 23F from the PCV7 group.

63. 63 Study 004: OPA GMTs for the 7 Common Serotypes, 1 Month Post-dose 3 Prevnar 13 (N=92-94) Prevnar (N=92-94) SerotypeGMT 4359 (276, 468)536 (421, 681) 6B1055 (817, 1361)1514 (1207, 1899) 9V4035 (2933, 5553)3259 (2288, 4641) 141240 (935, 1646)1481 (1133, 1934) 18C276 (210, 361)376 (292, 484) 19F54 (40, 74)45 (34, 60) 23F791 (605, 1034)924 (709, 1204) N = range in the number of subjects with a determinate antibody titer to the given serotype. GMT ratio: PCV13 to PCV7 reference.

64. 64 Study 004: OPA GMTs for the 6 Additional Serotypes, 1 Month Post-dose 3 Prevnar 13 (N=91-94) Prevnar (N=89-94) SerotypeGMT 152 (39, 69)4 (4, 4) 3121 (92, 158)7 (5, 9) 591 (67, 123)4 (4, 4) 6A980 (783, 1226)100 (66, 152) 7F9494 (7339, 12281)128 (80, 206) 19A152 (105, 220)7 (5, 9) N = range in the number of subjects with a determinate antibody titer to the given serotype. GMT ratio: PCV13 to PCV7 reference.

65. 65 Study 004: OPA GMTs for the 7 Common Serotypes, 1 Month Post-dose 4 Prevnar 13 (N=88-92) Prevnar (N=92-96) SerotypeGMT 41180 (847, 1643)1492 (1114, 1999) 6B3100 (2337, 4111)4066 (3243, 5098) 9V11856 (8810, 15955)18032 (14125, 23021) 142002 (1453, 2760)2366 (1871, 2992) 18C993 (754, 1308)1722 (1327, 2236) 19F200 (144, 276)167 (121, 230) 23F2723 (1961, 3782)4981 (3886, 6387) N = range in the number of subjects with a determinate antibody titer to the given serotype. GMT ratio: PCV13 to PCV7 reference.

66. 66 Study 004: OPA GMTs for the 6 Additional Serotypes, 1 Month Post-dose 4 Prevnar 13 (N=89-92) Prevnar (N=92-96) SerotypeGMT 1164 (114, 237)5 (4, 6) 3380 (300, 482)12 (9, 16) 5300 (229, 393)5 (4, 6) 6A2242 (1707, 2945)539 (375, 774) 7F11629 (9054, 14938)268 (165, 436) 19A1024 (774, 1355)29 (19, 44) N = range in the number of subjects with a determinate antibody titer to the given serotype. GMT ratio: PCV13 to PCV7 reference.

67. 67 Study 004: IgG Seroresponse Rates ≥ 0.35 µg/mL for the 7 Common Serotypes, 1 Month Post-dose 3 Prevnar 13 (N=251-252) Prevnar (N=250-252) Difference (95% CI) [PCV13 – PCV7] Serotype% (95% CI) 494.4 (90.9, 96.9)98.0 (95.4, 99.4)-3.6 (-7.3, -0.1) 6B87.3 (82.5, 91.1)92.8 (88.9, 95.7)-5.5 (-10.9, -0.1) 9V90.5 (86.2, 93.8)98.4 (96.0, 99.6)-7.9 (-12.4, -4.0) 1497.6 (94.9, 99.1)97.2 (94.4, 98.9)0.4 (-2.7, 3.5) 18C96.8 (93.8, 98.6)98.4 (96.0, 99.6)-1.6 (-4.7, 1.2) 19F98.0 (95.4, 99.4)97.6 (94.9, 99.1)0.4 (-2.4, 3.4) 23F90.5 (86.2, 93.8)94.0 (90.4, 96.6)-3.6 (-8.5, 1.2) N = number of subjects with a determinate IgG antibody concentration to the given serotype. Difference in proportions (PCV13 – PCV7 reference value) expressed as percentage.

68. 68 Study 004: IgG Seroresponse Rates ≥ 0.35 µg/mL for the 6 Additional Serotypes, 1 month Post-dose 3 Prevnar 13 (N=249-252) Prevnar Reference (Serotype 6B) (N=250) Difference (95% CI) [PCV13 – PCV7] Serotype% (95% CI) 195.6 (92.3, 97.8)92.8 (88.9, 95.7)2.8 (-1.3, 7.2) 363.5 (57.1, 69.4)92.8 (88.9, 95.7)-29.3 (-36.2, 22.4) 589.7 (85.2, 93.1)92.8 (88.9, 95.7)-3.1 (-8.3, 1.9) 6A96.0 (92.8, 98.1)92.8 (88.9, 95.7)3.2 (-0.8, 7.6) 7F98.4 (96.0, 99.6)92.8 (88.9, 95.7)5.6 (1.9, 9.7) 19A98.4 (96.0, 99.6)92.8 (88.9, 95.7)5.6 (1.9, 9.7) N = number of subjects with a determinate IgG antibody concentration to the given serotype. Difference in proportions (PCV13 – PCV7 reference value) expressed as percentage. For additional serotypes, the reference value is serotype 6B from the PCV7 group.

69. 69 Study 004: IgG GMC (µg/mL) for the 7 Common Serotypes, 1 month Post-dose 4 Prevnar 13 (N=234-236) Prevnar (N=222-223) GMC Ratio (95% CI) [PCV13 / PCV7] SerotypeGMC (95% CI) 43.7 (3.3, 4.2)5.5 (4.9, 6.1)0.68 (0.57, 0.80) 6B11.5 (10.0, 13.3)15.6 (13.8, 17.7)0.74 (0.61, 0.89) 9V2.6 (2.3, 2.9)3.6 (3.3, 4.1)0.72 (0.62, 0.85) 149.1 (8.0, 10.5)12.7 (11.2, 14.4)0.72 (0.60, 0.86) 18C3.2 (2.8, 3.6)4.7 (4.2, 5.3)0.68 (0.57, 0.81) 19F6.6 (5.9, 7.4)5.6 (4.9, 6.4)1.18 (0.98, 1.41) 23F5.1 (4.4, 5.8)7.8 (6.9, 8.9)0.65 (0.54, 0.78) N = number of subjects with a determinate IgG antibody concentration to the given serotype. GMC ratio: PCV13 to PCV7 reference. For the additional serotypes, the reference value is serotype 9V from the PCV7 group.

70. 70 Study 004: IgG GMC (µg/mL) for the 6 Additional Serotypes, 1 month Post-dose 4 Prevnar 13 (N=232-236) Prevnar Reference (Serotype 9V) (N=223) GMC Ratio (95% CI) [PCV13 / PCV7] SerotypeGMC (95% CI) 15.1 (4.4, 5.8)3.6 (3.3, 4.1)1.40 (1.17, 1.66) 30.9 (0.8, 1.1)3.6 (3.3, 4.1)0.26 (0.22, 0.30) 53.7 (3.3, 4.2)3.6 (3.3, 4.1)1.03 (0.87, 1.20) 6A8.2 (7.3, 9.2)3.6 (3.3, 4.1)2.26 (1.93, 2.65) 7F5.7 (5.0. 6.4)3.6 (3.3, 4.1)1.56 (1.32, 1.85) 19A8.6 (7.6, 9.6)3.6 (3.3, 4.1)2.36 (2.01, 2.76) N = number of subjects with a determinate IgG antibody concentration to the given serotype. GMC ratio: PCV13 to PCV7 reference. For the additional serotypes, the reference value is serotype 9V from the PCV7 group.

71. 71 7 Common Serotypes: IgG GMC (µg/mL) 1 month post-dose 3 Prevnar 13 (N=251-252) Prevnar (N=250-252) GMC Ratio (95% CI) [PCV13 / PCV7] SerotypeGMC (95% CI) GMC Ratio (95% CI) 41.31 (1.19, 1.45)1.93 (1.75, 2.13)0.68 (0.59, 0.78) 6B2.10 (1.77, 2.49)3.14 (2.64, 3.74)0.67 (0.52, 0.85) 9V0.98 (0.89, 1.08)1.40 (1.27, 1.55)0.70 (0.61, 0.80) 144.74 (4.18, 5.39)5.67 (5.02, 6.40)0.84 (0.70, 1.00) 18C1.37 (1.24, 1.52)1.79 (1.63, 1.96)0.77 (0.67, 0.88) 19F1.85 (1.69, 2.04)2.24 (2.01, 2.50)0.83 (0.72, 0.96) 23F1.33 (1.17, 1.51)1.90 (1.68, 2.15)0.70 (0.59, 0.84) N = number of subjects with a determinate IgG antibody concentration to the given serotype. GMC ratio: PCV13 to PCV7 reference. For the additional serotypes, the reference value is serotype 9V from the PCV7 group.

72. 72 6 Additional Serotypes: IgG GMC (µg/mL) 1 month post-dose 3 Prevnar 13 (N=249-252) Prevnar (N=252) GMC Ratio (95% CI) [PCV13 / PCV7] SerotypeGMC (95% CI) GMC Ratio (95% CI) 12.03 (1.78, 2.32)1.40 (1.27, 1.55)1.45 (1.23, 1.71) 30.49 (0.43, 0.55)1.40 (1.27, 1.55)0.35 (0.30, 0.41) 51.33 (1.18, 1.50)1.40 (1.27, 1.55)0.95 (0.81, 1.11) 6A2.19 (1.93, 2.48)1.40 (1.27, 1.55)1.56 (1.33, 0.83) 7F2.57 (2.28, 2.89)1.40 (1.27, 1.55)1.83 (1.57, 2.13) 19A2.07 (1.87, 2.30)1.40 (1.27, 1.55)1.48 (1.28, 1.71) N = number of subjects with a determinate IgG antibody concentration to the given serotype. GMC ratio: PCV13 to PCV7 reference. For the additional serotypes, the reference value is serotype 9V from the PCV7 group.

73. 73 Vaccine Exposure and Study Completion 6096A1-0036096A1-0046096A1-3005Total PCV13PCV7PCV13PCV7PCV13PCV7PCV13PCV7 N=122N=127N=334N=332N=1466N=246N=1922N=705 Dose 112112633233114552441908701 Doses 1, 2, and 311011829429012902181694626 Doses 1, 2, 3, and 486109264252--350361 Completed study8098259252--339350 Completed 6m follow up8299282270--364369

74. 74 Serotype 6B Exploratory Endpoints N = Number of subjects with a determinate antibody titer for the specified serotype. Ratio of GMTs; PCV13 to PCV7 reference. Difference in seroresponse rates ≥ 1:8: PCV13 – PCV7. Prevnar 13Prevnar Ratio or Difference (95% CI) Post-dose 3N=94 OPA GMT 1054 (817.34, 1360.87) 1513.66 (1206.64, 1898.81) 0.70 (0.50, 0.98) % with ≥ 1:8 OPA titer 98.9 (94.2, 100.0) 100.0 (96.2, 100.0) -1.1 (-5.8, 2.8) Post-dose 4N=92N=95 OPA GMT 3099.51 (2337.02, 4110.79) 4066.22 (3243.42, 5097.76) 0.76 (0.53, 1.09) % with ≥ 1:8 OPA titer 98.9 (94.1, 100.0) 100.0 (96.2, 100.0) -1.1 (-5.9, 2.8)

75. 75 Serotype 9V Exploratory Endpoints N = Number of subjects with a determinate antibody titer for the specified serotype. Ratio of GMTs; PCV13 to PCV7 reference. Difference in seroresponse rates ≥ 1:8: PCV13 – PCV7. Prevnar 13Prevnar Ratio or Difference (95% CI) Post-dose 3N=93N=94 OPA GMT 4035.40 (2932.68, 5552.75) 3259.01 (2288.43, 4641.25) 1.24 (0.77, 1.99) % with ≥ 1:8 OPA titer 100.0 (96.1, 100.0) 98.9 (94.2, 100.0) 1.1 (-2.9, 5.8) Post-dose 4N=90N=94 OPA GMT 11856.03 (8809.85, 15955.49) 18032.33 (14124.99, 23020.53) 0.66 (0.45, 0.96) % with ≥ 1:8 OPA titer 98.9 (94.0, 100.0) 100.0 (96.2, 100.0) -1.1 (-6.1, 2.9)

76. 76 Serotype 3 Exploratory Endpoints N = Number of subjects with a determinate antibody titer for the specified serotype. Ratio of GMTs; PCV13 to PCV7 reference. Difference in seroresponse rates ≥ 1:8: PCV13 – PCV7. Prevnar 13Prevnar Ratio or Difference (95% CI) Post-dose 3N=94 OPA GMT 120.67 (92.38, 157.62) 6.7 (5.27, 8.52) 18.00 (12.60, 25.72) % with ≥ 1:8 OPA titer 96.8 (91.0, 99.3) 21.3 (13.5, 30.9) 75.5 (65.3, 83.9) Post-dose 4N=91N=96 OPA GMT 380.41 (300.19, 482.08) 11.81 (8.68, 16.08) 32.2 (21.82, 47.52) % with ≥ 1:8 OPA titer 97.8 (92.3, 99.7) 43.8 (33.6, 54.3) 54.1 (43.2, 64.4)

77. 77 Study 004 Empirical Reverse Cumulative Distribution Curves (RCDCs)  For each serotype, the Applicant provided graphical presentations of the distribution of subjects in each study group achieving all possible anti-pneumococcal IgG antibody concentrations and OPA titers.  Separate figures provided for post-dose 3 and post-dose 4 immune response measurements.  The RCDCs are descriptive and can not be used for statistical comparisons.

78. 78 RCDC Curves: Distribution of Pneumococcal Serotype 6B IgG Antibody Concentrations Figure 1: Reverse Cumulative Distribution Curves (RCDC) for Pneumococcal Serotype 6B, IgG Antibody Concentrations in the Evaluable Infant Immunogenicity Population – After the Infant Series. The RCDCs are separated, with the PCV13 vaccine curve being lower than the PCV7 curve at concentrations at or above the 0.35 µg/mL comparison level. The 2 curves approach one another at about the 1.0 µg/mL concentration, with the PCV13 vaccine curve still lower than the PCV7 curve. The curves then separate and the PCV7 curve remains clearly higher compared to the PCV13 vaccine curve at all remaining concentrations greater than 1.0 µg/mL. The 0.35 µg/mL comparison level is close to the top of both curves. Figure 2: RCDCs for Pneumococcal Serotype 6B, IgG Antibody Concentrations in the Evaluable Toddler Immunogenicity Population – Posttoddler Dose. The RCDCs are separated, with the PCV13 vaccine curve being lower than the PCV7 curve throughout the curve. The two curves approach one another at about the 25µg/mL comparison level; however the PCV13 vaccine curve continues to remain lower than the PCV7 curve. Figure 1: One Month After Dose 3Figure 2: One Month After Dose 4

79. 79 RCDC Curves: Distribution of Pneumococcal Serotype 6B OPA Antibody Titers Figure 1: RCDCs for Pneumococcal Serotype 6B, OPA Titers in the Evaluable Infant Immunogenicity Population – After Infant Series. The RCDCs are separated with the PCV13 vaccine curve being lower than the PCV7 curve. Figure 2: RCDCs for Pneumococcal Serotype 6B, OPA Titers in the Evaluable Toddler Immunogenicity Population – Posttoddler Dose. The RCDCs are separated at the top of the curve and along the mid-to lower slope of the curve. The curves lie close together at the upper portion of the slope of the curve. Figure 1: One Month After Dose 3Figure 2: One Month After Dose 4

80. 80 RCDC Curves: Distribution of Pneumococcal Serotype 9V IgG Antibody Concentrations Figure 1: Figure 9-2: Reverse Cumulative Distribution Curves, Pneumococcal Serotype 9V, IgG Antibody Concentrations in the Evaluable Infant Immunogenicity Population – After the Infant Series. The RCDCs are separated, with the PCV13 vaccine curve being lower than the PCV7 curve at all concentrations at or above the 0.35 µg/mL comparison level. The 0.35 µg/mL comparison level is close to the top of both curves. Figure 2:Figure 16.17: Pneumococcal Serotype 9V, IgG Antibody Concentrations in the Evaluable Toddler Immunogenicity Population – Posttoddler Dose. The RCDCs are separated with the PCV13 vaccine curve being lower than the PCV7 curve at concentrations greater than 0.35 µg/mL. The two curves approach one another at approximately the 0.35 µg/mL and 10.0 µg/mL comparison levels. Figure 1: One Month After Dose 3Figure 2: One Month After Dose 4

81. 81 RCDC Curves: Distribution of Pneumococcal Serotype 9V OPA Antibody Titers Figure 1: Reverse Cumulative Distribution Curves (RCDCs) for Pneumococcal Serotype 9V, OPA Titers in the Evaluable Infant Immunogenicity Population – After Infant Series. The RCDCs are separated with the PCV13 vaccine curve being higher than the PCV7 curve at antibody titers ≤ approximately 1:100. The curves lie close together along the downward slope of the curve. Figure 2: RCDCs for Pneumococcal Serotype 9V, OPA Titers in the Evaluable Toddler Immunogenicity Population – Posttoddler Dose. The RCDCs lie close together at the top of the curve and are separated along the majority of the downward slope of the curve. The PCV13 vaccine curve is lower than the PCV7 curve along the entire curve. Figure 1: One Month After Dose 3Figure 2: One Month After Dose 4

82. 82 RCDCs: Distribution of Pneumococcal Serotype 3 IgG Antibody Concentrations Figure 1: Reverse Cumulative Distribution Curves ( RCDCs) for Pneumococcal Serotype 3, IgG Antibody Concentrations in the Evaluable Infant Immunogenicity Population – After the Toddler Dose. The RCDCs are separated to a large extent, with the PCV13 vaccine lying much higher than the PCV7 curve. Figure 2: RCDCs for Pneumococcal Serotype 3, IgG Antibody Concentrations in the Evaluable Infant Immunogenicity Population – After the Toddler Dose. The RCDCs are separated to a large extent, with the PCV13 vaccine lying much higher than the PCV7 curve. Figure 2: One Month After Dose 4Figure 1: One Month After Dose 3

83. 83 RCDC Curves: Distribution of Pneumococcal Serotype 3 OPA Antibody Titers Figure 1: Reverse Cumulative Distribution Curves (RCDCs) fo Pneumococcal Serotype 3, OPA Titers in the Evaluable Infant Immunogenicity Population – After Infant Series. The RCDCs are separated to a large extent, with the PCV13 vaccine curve lying much higher than the PCV7 curve along the entire curve. Figure 2: RCDCs for Pneumococcal Serotype 3, OPA Titers in the Evaluable Toddler Immunogenicity Population – Posttoddler Dose. The RCDCs are separated, with the PCV13 vaccine curve lying much higher than the PCV7 curve along the entire curve. Figure 1: One Month After Dose 3Figure 2: One Month After Dose 4

84. 84 Proposed Catch-Up Schedule For Pneumococcal Vaccine Naïve Children 7 Months through 5 Years of Age Age at 1 st Dose Total Number of 0.5 mL Doses 7-11 months of age3* 12-23 months of age2** ≥ 24 months through 5 years of age1 *2 doses ≥ 4 weeks apart; 3 rd dose after 1-year birthday, separated from 2 nd dose by ≥ 2 months. **2 doses ≥ 2 months apart.

85. 85 Catch-up Study 3002 Previously Unvaccinated Children 7 Months Through 5 Years of Age

86. 86 Catch-up Study 3002 Design  Open-label, multicenter, descriptive study conducted in Poland.  354 pneumococcal vaccine naïve infants 7 months to < 72 months of age enrolled into 3 groups  No control group Study Groups Age Number of PCV13 doses Dose intervals Group 1 (N=90) 7 to < 12 mo3 doses Dose 1 and 2: 4 wks apart Dose 3: 2 mo after dose 2 Group 2 (N=112) 12 to < 24 mo2 doses2 months apart Group 3 (N=154) 24 to < 72 mo1 dose- Study 3002: Three Catch-up Schedules Evaluated

87. 87 Study 3002 Demographics  Approximately 49% males.  100% White, Non-hispanic and non-Latino

88. 88 Study 3002 Immunogenicity

89. 89 Study 3002: IgG Seroresponse Rates ≥ 0.35 µg/mL for the 7 Common Serotypes, 1 Month After Last Prevnar 13 Vaccination Group 1: 7 to < 12 months Post-dose 3 N=83-84 Group 2: 12 to < 24 months Post-dose 2 N=104-110 Group 3: 24 to < 72 months Post-dose 1 N=135-151 Serotype% (95% CI) 4100.0 (95.7, 100.0)100.0 (96.7, 100.0)99.3 (96.4, 100.0) 6B98.8 (93.5, 100.0)100.0 (96.7, 100.0)99.3 (96.3, 100.0) 9V98.8 (93.5, 100.0)99.0 (94.8, 100.0)98.6 (95.2, 99.8) 14100.0 (95.7, 100.0)100.0 (96.6, 100.0)88.1 (81.5, 93.1) 18C100.0 (95.7, 100.0)100.0 (96.7, 100.0)98.7 (95.3, 99.8) 19F97.6 (91.7, 99.7)100.0 (96.7, 100.0)98.0 (94.2, 99.6) 23F98.8 (93.5, 100.0)92.7 (86.2, 96.8)93.4 (88.2, 96.8)

90. 90 Study 3002: IgG Seroresponse Rates ≥ 0.35 µg/mL for the 6 Additional Serotypes, 1 month After the Last Prevnar 13 Vaccination Group 1: 7 to < 12 months Post-dose 3 N=83-84 Group 2: 12 to < 24 months Post-dose 2 N=107-110 Group 3: 24 to < 72 months Post-dose 1 N=142-152 Serotype% (95% CI) 1100.0 (95.7, 100.0)100.0 (96.6, 100.0)96.6 (92.3, 98.9) 398.8 (93.5, 100.0)100.0 (96.6, 100.0)97.3 (93.3, 99.3) 597.6 (91.7, 99.7)99.1 (94.9, 100.0)98.7 (95.3, 99.8) 6A100.0 (95.7, 100.0)98.2 (93.6, 99.8)100.0 (97.6, 100.0) 7F100.0 (95.7, 100.0)100.0 (96.6, 100.0)99.3 (96.1, 100.0) 19A100.0 (95.7, 100.0)100.0 (96.7, 100.0)100.0 (97.6, 100.0)

91. 91 Study 3002: IgG GMCs for the 7 Common Serotypes, 1 Month After Last Prevnar 13 Vaccination Group 1: 7 to < 12 months Post-dose 3 N=83-84 Group 2: 12 to < 24 months Post-dose 2 N=104-110 Group 3: 24 to < 72 months Post-dose 1 N=135-151 SerotypeGMC (95% CI) 43.63 (3.11, 4.23)4.28 (3.78, 4.86)3.37 (2.95, 3.85) 6B4.77 (3.90, 5.84)3.38 (2.81, 4.06)3.41 (2.80, 4.16) 9V2.56 (2.21, 2.96)3.08 (2.69, 3.53)2.67 (2.32, 3.07) 148.04 (6.95, 9.30)6.45 (5.48, 7.59)2.24 (1.71, 2.93) 18C2.77 (2.39, 3.23)3.71 (3.29, 4.19)2.56 (2.17, 3.03) 19F2.88 (2.35, 3.54)3.07 (2.68, 3.51)2.53 (2.14, 2.99) 23F2.16 (1.82, 2.55)1.98 (1.64, 2.39)1.55 (1.31, 1.85)

92. 92 Study 3002: IgG GMCs for the 6 Additional Serotypes, 1 month After the Last Prevnar 13 Vaccination Group 1: 7 to < 12 months Post-dose 3 N=83-84 Group 2: 12 to < 24 months Post-dose 2 N=107-110 Group 3: 24 to < 72 months Post-dose 1 N=142-152 SerotypeGMC (95% CI) 12.88 (2.44, 3.39)2.74 (2.37, 3.16)1.78 (1.52, 2.08) 31.94 (1.68, 2.24)1.86 (1.60, 2.15)1.42 (1.23, 1.64) 52.85 (2.34, 3.46)2.16 (1.89, 2.47)2.33 (2.05, 2.64) 6A3.72 (3.12, 4.45)2.62(2.25, 3.06)2.96 (2.52, 3.47) 7F5.30 (4.54, 6.18)5.99 (5.40, 6.65)4.92 (4.26, 5.68) 19A4.77 (4.28, 5.33)4.94 (4.31, 5.65)6.03 (5.22, 6.97)

93. 93 Study 3002 Safety

94. 94 Study 3002 Serious Adverse Events  Overall 9 (2.5%) subjects across all study groups experienced 12 serious adverse events.  No subjects died during this study.  No subjects were withdrawn early in this study due to an adverse event.

95. 95 Study 3002: Rates (%) of Solicited Local Reactions on Days 1-4 After Each Prevnar 13 Vaccination Group 1Group 2Group 3 Dose 1 N=86 Dose 2 N=86-87 Dose 3 N=78-82 Dose 1 N=108-110 Dose 2 N=98-106 Dose 1 N=147-149 Erythema Any 0.5 to 2.0 cm > 2.0 to 7.0 cm > 7.0 cm 48.8 41.9 16.3 0.0 46.0 40.2 9.3 0.0 37.8 31.3 12.5 0.0 70.0 55.5 38.2 0.0 54.7 44.7 25.5 0.0 50.0 37.4 25.7 0.0 Induration Any 0.5 to 2.0 cm > 2.0 to 7.0 cm > 7.0 cm 36.0 32.6 11.6 0.0 32.2 28.7 14.0 0.0 25.0 20.5 11.3 0.0 44.5 36.7 24.8 0.0 41.0 36.2 12.1 0.0 36.9 28.2 20.3 0.0 Tenderness Any Severe* 15.1 1.2 15.1 3.5 15.2 6.4 33.3 0.0 43.7 4.1 42.3 4.1 *Interferes with limb movement

96. 96 Study 3002: Rates (%) of Fever on Days 1-4 After Each Prevnar 13 Vaccination Group 1Group 2Group 3 Fever Dose 1 N=86-87 Dose 2 N=86 Dose 3 N=78-79 Dose 1 N=108 Dose 2 N=98 Dose 1 N=147 ≥ 38.0 o C and ≤ 39.0 o C 3.48.15.13.45.10.7 > 39.0 o C and ≤ 40.0 o C 1.22.31.31.20.00.7 > 40.0 o C 0.0 * Statistically significant difference between the two study groups (Fisher exact test, 2-sided).

97. 97 Study 3002: Rates (%) of Solicited Systemic AEs, Days 1-4 After Each Prevnar 13 Vaccination Group 1Group 2Group 3 Dose 1 N=87 Dose 2 N=86-87 Dose 3 N=78-81 Dose 1 N=108 Dose 2 N=98-100 Dose 1 N=147-148 Decreased appetite 19.517.217.519.525.516.3 Irritability 24.134.524.724.134.014.3 Decreased sleep 24.118.415.024.120.46.8 Increased sleep 9.29.32.69.210.111.6