1. 1 Prevnar 13 for Adult Use (Age >50 Years) (Pneumococcal 13-valent Conjugate Vaccine (Diphtheria CRM 197 Protein) Applicant: Wyeth Pharmaceuticals, Inc. Rosemary Tiernan, MD, MPH Division of Vaccines and Related Products Applications CBER/FDA Vaccines and Related Biological Products Advisory Committee Meeting November 16, 2011

2. 2 Overview of Safety Presentation Studies Supporting Safety in Adults Age > 50 yrs Safety Population Safety Monitoring and Data Collection Adverse Reactions Summary/Conclusions

3. 3 Six Phase 3 Studies Supported Safety of PCV13 in Adults StudySite Age (Yrs ) Schedule and ( # Vaccinated) 004 Naive USA 60-64 50-59 Initial Study: Extension (3-4.5yrs): Cohort 1 PCV13 (417) PCV13/PCV13 (108) PCV13/23vPS (108) Cohort 1 23vPS (414) 23vPS/23vPS (189) Cohort 2 PCV13 (404) PCV13/PCV13 (214) 3000 >1 dose 23vPS > 3 yrs prior USA, GER Sweden > 68 1 dose of PCV13 (1049) 3001 Naive USA50-59 Group 1 PCV13 + TIV / Placebo (551-538) Group 2 Placebo + TIV / PCV13 (560-543) 3005 1 dose 23vPS > 5 yrs prior USA, Sweden > 70 Group 1 PCV13 (463) Year 0 Group 2 23vPS (473) Group 1.1 PCV13 / PCV13 (391) Year 1 Group 2.1 23vPS / PCV13 (404) 3008 Naive GER, NETH BELG, HUNG > 65 Group 1 PCV13 + TIV / Placebo (577-560) Group 2 Placebo + TIV / PCV13 (575-558) 3010 Naive USA60-64 Group 1 PCV13 (478 ) Year 0 Group 2 23vPS (237) Group 1.1 PCV 13 / PCV 13 (161) Year 1 Group 1.2 PCV13 / 23vPS (266) Group 2.1 23vPS/ PCV13 (223)

4. 4 Six Phase 3 Studies Supported Safety of PCV13 in Adults Description of the Six Phase 3 Studies that Supported the Safety of Prevnar13 in Adults: –History of Prior PNEUMOVAX23 Vaccination –Study Site –Subject Age –Vaccine Schedule and –Number Vaccinated

5. 5 Safety Population

6. 6 Demographics Demographic Factors (N = 6198)PCV13 (N = 5667) Age (Years)50 - 93 50-64 2616 (46.2) 65-69 646 (11.4) 70-74 1139 (20.1) 75-79 760 (13.4) > 80 506 (8.9) Gender Female50.2 - 61.8%* Race/Ethnicity White> 91% Black or African American0.2 - 7.5% Hispanic or Latino0.6 - 4.8% Asian0.0 - 1.7% Native Hawaiian or other Pacific Islander <1% American Indian<1% Alaskan Native<1% Other<1.4% *Study 3005 Males (50.3-52.3%)

7. 7 Demographics Demographics of Subjects (Across 6 Studies) and Specific Age Strata for Prevnar13 Recipients

8. 8 Study Populations Pre-existing underlying diseases included if condition was “stable”: Disease not requiring significant change in therapy or hospitalization for worsening disease for 12 weeks before receipt of study vaccine Change to new therapy allowed if not caused by worsening disease Change in dose or therapy within category allowed Key Exclusion Criteria included: Receipt of diphtheria-tetanus toxoid containing vaccines within 6 months of study vaccine Streptococcus pneumoniae infection documented w/in past 5 years Impairment of immunological function: –Immunoglobulin deficiencies, hematological malignancies, known HIV infection, collagen vascular disorders and subjects receiving immunosuppressive therapy –If systemic corticosteroids administered short term for treatment of acute illness, subjects excluded from vaccination until corticosteroid therapy had been discontinued for at least 30 days. Serious chronic disorders: –Metastatic malignancy, severe chronic obstructive pulmonary disease, end-stage renal disease, clinically unstable cardiac disease, or any other disorder that in investigator’s opinion precluded subject from participating in study.

9. 9 Underlying Medical Conditions in PCV13 Recipients (at 1 st Dose) Medical Conditions Vaccine NaïvePre-immunized Study 3001 0043010300830003005 Age (Yrs) 50-59 60-64 > 65> 68>70 N=1094 % N=403 % N=417 % N=478 % N=1134 % N=1049 % N=463 % Cardiac2.72.24.35.916.121.218.4 Pulmonary8.08.78.99.422.226.213.0 Diabetes8.48.28.415.316.219.715.3 Renal0.30.00.2 1.25.05.2 Liver0.70.00.20.4 0.80.9 Asthma6.07.25.56.58.812.66.3

10. 10 Underlying Medical Conditions in PCV13 Recipients (at 1 st Dose) Underlying Medical Conditions in Prevnar13 Recipients at Initial Dose Evaluated by –Pneumococcal Vaccine Naïve and –Pre-immunized Status and by –Study

11. 11 Safety Data Collection and Monitoring

12. 12 Solicited Adverse Events Local and systemic reactions monitored daily for 14 days: –Electronic diary cards used to record information –Local events included Redness, swelling, pain, limitation of motion (LOM) –Systemic events included: Fever measured using oral digital thermometer daily (at bedtime and whenever fever suspected) Fatigue, headache, chills, rash, vomiting, decreased appetite, new generalized muscle pain, aggravated generalized muscle pain, new generalized joint pain and aggravated generalized joint pain –Data regarding medications to treat pain and fever collected in all studies, except study 004.

13. 13 Analysis of Adverse Events (AEs) Solicited Local and Systemic AEs –Vaccine Naïve –Pre-immunized Unsolicited Adverse Events Deaths Discontinuations due to Adverse Event Serious Adverse Events (SAES)

14. 14 Vaccine Naïve Subjects Studies 004 and 3010 Solicited Local Adverse Reactions Solicited Systemic Adverse Reactions

15. 15 Local Reactogenicity Within 14 Days of PCV13 or 23vPS (Naïve) Local Reactions STUDY 004STUDY 3010 PCV13 23vPSPCV1323vPS 50-59 yrs60-64 yrs N=136-322 % N=178-193 % N=179-301 % N=258-370 % N=127-134 % Redness Any15.820.214.212.211.2 Severe0.71.701.20.8 Swelling Any21.719.313.11010.4 Severe00.61.100 Pain Any8980.173.469.258.3 Severe3.61.78.62.30.8 Limitation of Motion Any40.728.530.823.528.2 Severe2.91.74.31.12.3

16. 16 Local Reactogenicity Within 14 Days of PCV13 or 23vPS (Naïve) Local Reactogenicity within 14 days of Vaccination in a Pneumococcal Vaccine Naïve Population (Study 004 and Study 3010) with –Prevnar13 or –PNEUMOVAX23

17. 17 Systemic Reactogenicity Within 14 Days of PCV13 or 23vPS (Naïve) Systemic Reactions STUDY 004STUDY 3010 PCV13 23vPSPCV1323vPS 50-59 yrs60-64 yrs N=144-248 % N=180-277 % N=185-273 % N=261-328 % N=127-173 % Any Fever (>38C) 1.57.75.94.21.6 Fatigue 63.363.261.550.549.1 Headache 65.954.054.449.746.1 Chills 19.623.524.119.926.9 Rash 14.216.513.08.613.4 Vomiting 6.93.95.43.1 Decreased Appetite 25.321.321.714.723.0 New Myalgia 61.856.257.846.951.5 Aggravated Myalgia 39.932.637.322.032.5 New Joint Pain 31.524.430.115.523.8 Aggravated Joint Pain 25.624.921.414.021.1 Pain Meds N/A 31.332.7 Fever Meds N/A 8.617.5

18. 18 Systemic Reactogenicity Within 14 Days of PCV13 or 23vPS (Naïve) Systemic Reactogenicity within 14 days of Vaccination in a Pneumococcal Vaccine Naïve Population (Study 004 and Study 3010) with –Prevnar13 or –PNEUMOVAX23

19. 19 Summary on Reactogenicity in Naïve Subjects Local Reactogenicity –Study 004 PCV 13 >23vPS for “any” redness/swelling/pain 23vPS >PCV13 for “severe” pain (8.6% > 1.7-3.6%) –Study 3010 PCV13 >23vPS for “any” pain (69.2 % vs 58.3%) Systemic Reactogenicity –Study 004 PCV13 vs 23vPS similar incidences of systemic reactions –Study 3010 23vPS>PCV13 for decreased appetite, aggravated muscle pain, new joint pain, use of medication to treat fever

20. 20 Pre-Immunized Subjects Studies 3000 and 3005 Solicited Local Reactions Solicited Systemic Reactions

21. 21 Local Reactogenicity Within 14 days of PCV13 or 23vPS (Pre-Immunized) Local Reactions Study 3000 ( > 68 yrs. )Study 3005 ( > 70 yrs) > 1 dose 23vPS > 3 yrs prior1 dose 23vPS > 5 yrs prior PCV13 23vPS N=634-777 % N=297-362 % N=306-383 % Redness Any14.310.822.2 Severe 1.11.74.8 Swelling Any12.810.423.1 Severe 0.60.04.8 Pain Any51.051.758.5 Severe 0.2 1.32.3 Limitation of Motion Any16.210.527.6 Severe1.60.73.0

22. 22 Local Reactogenicity Within 14 days of PCV13 or 23vPS (Pre-Immunized) Local Reactogenicity within 14 days of Vaccination in a Pre-Immunized Population (Prior receipt of PNEUMOVAX23) with –Prevnar13 or –PNEUMOVAX23

23. 23 Systemic Reactogenicity Within 14 days of PCV13 or 23vPS (Pre-Immunized) Systemic Reactions Study 3000 ( > 68 yrs. ) > 1 dose 23vPS > 3 yrs prior Study 3005 ( > 70 yrs) 1 dose of 23vPS > 5 yrs prior PCV13 23vPS N= 638-733 % N=297-350 % N=301-367 % Any Fever(>38C) 2.01.02.3 >40C0.90.00 Fatigue34.434.043.3 Headache26.123.726.0 Chills7.57.911.2 Rash8.47.316.4 Vomiting0.91.71.3 Appetite Decreased 11.210.411.5 New Myalgia 25.336.844.7 Aggravated Myalgia 12.320.627.5 New Joint Pain 12.812.614.9 Aggravated Joint Pain 9.711.616.5 Pain Meds17.022.026.6 Fever Meds6.43.06.2

24. 24 Systemic Reactogenicity Within 14 days of PCV13 or 23vPS (Pre-Immunized) Systemic Reactogenicity within 14 days of Vaccination in a Pre-Immunized Population (Prior receipt of PNEUMOVAX23) with Prevnar13 or PNEUMOVAX23

25. 25 Summary of Reactogenicity: Pre-Immunized Subjects Local Reactogenicity –Study 3005 23vPS > PCV13 for all local reactions Systemic Reactogenicity –Study 3005 23vPS >PCV13 for fatigue, rash, new muscle pain (myalgia), aggravated muscle pain

26. 26 Reactogenicity of Sequential Vaccine Administration (Studies 004 and 3010) Single dose 23vPS (naïve) compared to: –PCV13 /23vPS 1 year interval (study 3010) 3-4 year interval (extension study 004) –23vPS / 23vPS administered at 3-4 year interval (extension study 004)

27. 27 Local Reactogenicity within 14 days Post Dose Local Reactions 60-64 Yrs STUDY 004STUDY 3010 Year 0Year 3.5 - 4Year lYear 0 23vPS*PCV13 / 23vPS23vPS/ 23vPSPCV13 / 23vPS23vPS* N=185-301 % N=41-87 % N=82-164 % N=131-231 % N=127-175 % Redness Any14.227.535.827.811.2 Severe02.410.66.90.8 Swelling Any13.120.435.625.810.4 Severe1.12.47.36.10 Pain Any73.483.984.885.758.3 Severe8.69.111.612.90.8 Limitation of Motion Any30.842.148.253.428.2 Severe4.44.99.58.12.3 23vPS* administered at Year 0 was 3-4.5 years prior in Study 004 and was 1 year prior in Study 3010.

28. 28 Local Reactogenicity within 14 days Post Dose Local Reactogenicity within 14 days of a Single Dose of PNEUMOVAX23 at Year 0 compared to a Subsequent Dose of PNEUMOVAX23 using a Dosing Interval of 1 Year and 3.5 - 4 Years

29. 29 Systemic Reactogenicity within 14 days Post Dose Systemic Reactions Age 60-64 Yrs STUDY 004STUDY 3010 Year 0Year 3.5-4Year 1Year 0 23vPS*PCV13 / 23vPS23vPS/ 23vPSPCV13 / 23vPS23vPS* N=85-273 (%) N=43-68 (%) N=79-136 (%) N=129-196 (%) N=127-173 (%) Any Fever(>38C) 5.94.72.53.11.6 Fatigue61.563.257.651.949.1 Headache54.450.054.249.746.1 Chills24.133.934.329.026.9 Rash13.018.432.624.013.4 Vomiting5.44.71.34.63.1 Decreased Appetite 21.731.523.717.023.0 New Myalgia57.865.267.661.251.5 Aggravated Myalgia 37.341.439.641.532.5 New Joint Pain 30.124.523.125.523.8 Aggravated Joint Pain 21.422.417.617.521.1 Pain MedsN/A 46.232.7 Fever MedsN/A 17.417.5 23vPS* administered at Year 0 was 3-4.5 years prior for Study 004 and was 1 year prior for Study 3010.

30. 30 Systemic Reactogenicity within 14 days Post Dose Systemic Reactogenicity within 14 days of a Single Dose of PNEUMOVAX23 at Year 0 compared to a Subsequent Dose of PNEUMOVAX23 using a Dosing Interval of 1 Year and 3.5 - 4 Years

31. 31 Summary on Reactogenicity: Sequential Doses Solicited Local –Using a dosing interval of 3-4 yrs (extension study 004): 23vPS/23vPS is more reactogenic than PCV13/23vPS for redness, swelling and limitation of motion –Using a dosing interval of 1 year (study 3010): PCV13/23vPS is more reactogenic than 23vPS alone Solicited Systemic –Using a dosing interval of 3-4 yrs, 23vPS/23vPS is more reactogenic for rash when compared to 23vPS alone –Using a dosing interval of 1 yr, PCV13/23vPS is more reactogenic for rash and use of pain medications when compared to 23vPS alone

32. 32 Reactogenicity of Concomitant Administration of PCV13 with Trivalent Influenza Vaccine (TIV) Studies 3001 and 3008 Solicited Adverse Reactions for PCV13 + TIV compared to PCV13: –Local –Systemic Reactogenicity of Concomitant Administration of PCV13 with Trivalent Influenza Vaccine (TIV) in a Pneumococcal Vaccine Naïve Population: Design for Studies 3001 and 3008 Study ArmsConcomitant Dose 1Dose 2 (1 month later) Group 1PCV13 + TIVPlacebo Group 2Placebo + TIVPCV13

33. 33 Local Reactogenicity (PCV13+TIV vs PCV13) within 14 Days (Naïve) Study 3001 (age 50-59 yrs)Study 3008 ( age > 65 yrs) Local Reactions PCV13 +TIV / Placebo Concomitant Dose 1 Placebo +TIV / PCV13 Dose 2 PCV13 +TIV/ Placebo Concomitant Dose 1 Placebo +TIV/ PCV13 Dose 2 N=266-317 % N=241-453 % N=429-480 % N=420-470 % Redness Any16.312.116.612.3 Severe0.41.20.71.0 Swelling Any18.414.713.810.2 Severe0.4 0.20 Pain Any86.884.540.043.4 Severe4.14.81.42.6 Limitation of Motion Any35.642.513.914.8 Severe3.42.91.91.4

34. 34 Local Reactogenicity (PCV13+TIV vs PCV13) within 14 Days (Naïve) Local Reactogenicity within 14 days of PCV13 Administered Concomitantly with TIV compared to PCV13 alone in a Pneumococcal Vaccine Naïve Population

35. 35 Systemic Reactogenicity (PCV13 + TIV vs PCV13) within 14 Days (Naive) Systemic Reactions Study 3001 (Age 50-59 yrs) Study 3008 (Age > 65 yrs) PCV13 +TIV /Placebo Concomitant Dose 1 Placebo +TIV /PCV13 Dose 2 PCV13 +TIV /Placebo Concomitant Dose 1 Placebo +TIV /PCV13 Dose 2 N =266-399 % N=247-350 % N=432-476 % N=428-456 % Any Fever(>38C) 3.42.55.84.7 Fatigue 58.151.837.428.5 Headache 65.950.932.624.7 Chills 31.424.613.89.1 Rash 12.69.56.96.8 Vomiting 5.36.13.01.7 Appetite Decreased 30.225.816.911.3 New Myalgia 65.559.126.923.4 Aggravated Myalgia 34.736.718.715.0 New Joint Pain 33.027.416.211.5 Aggravated Joint Pain 21.223.815.78.6 Pain Meds 39.332.8N/A Fever Meds 22.818.8N/A

36. 36 Systemic Reactogenicity (PCV13 + TIV vs PCV13) within 14 Days (Naive) Systemic Reactogenicity within 14 days of PCV13 Administered Concomitantly with TIV compared to PCV13 alone in a Pneumococcal Vaccine Naïve Population

37. 37 Reactogenicity of Concomitant Administration of PCV13 with Trivalent Influenza Vaccine (TIV) Studies 3001 and 3008 (Naïve) Solicited Adverse Reactions for PCV13 + TIV compared to Placebo +TIV: –Local –Systemic Reactogenicity of Concomitant Administration of PCV13 with Trivalent Influenza Vaccine (TIV) in a Pneumococcal Vaccine Naïve Population: Design for Studies 3001 and 3008 Study ArmsConcomitant Dose 1Dose 2 (1 month later) Group 1PCV13 + TIVPlacebo Group 2Placebo + TIVPCV13

38. 38 Local Reactogenicity (PCV13+TIV vs TIV+ Placebo) within 14 Days (Naïve) Local Reactions Study 3001 (Age 50-59 yrs) Study 3008 (Age > 65 yrs) PCV13 +TIV / Placebo Concomitant Dose 1 Placebo +TIV / PCV13 Concomitant Dose 1 PCV13 +TIV /Placebo Concomitant Dose 1 Placebo +TIV / PCV13 Concomitant Dose 1 N=262-324 % N=257-325 % N=429-480 % N=420-470 % Redness Any16.33.016.612.3 Severe0.40.00.71.0 Swelling Any18.43.013.810.2 Severe0.40.00.20.0 Pain Any86.837.140.043.4 Severe4.10.41.12.6 Limitation of Motion Any35.68.913.914.8 Severe3.40.81.91.4

39. 39 Local Reactogenicity (PCV13+TIV vs TIV+ Placebo) within 14 Days (Naïve) Local Reactogenicity within 14 days of PCV13 Administered Concomitantly with TIV compared to PCV13 alone in a Pneumococcal Vaccine Naïve Population

40. 40 Systemic Reactogenicity (PCV13 + TIV vs TIV+ Placebo) within 14 Days (Naive) Systemic Reactions Study 3001 (Age 50-59 yrs) Study 3008 (Age > 65 yrs) PCV13 +TIV /Placebo Concomitant Dose 1 Placebo +TIV /PCV13 Concomitant Dose 1 PCV13 +TIV /Placebo Concomitant Dose 1 Placebo +TIV /PCV13 Concomitant Dose 1 N =261-389 % N=257-382 % N=-428-476 % N=420-456 % Any Fever(>38C) 3.41.25.84.7 Fatigue 58.152.437.431.9 Headache 65.956.532.629.7 Chills 31.421.013.89.1 Rash 12.64.96.93.4 Vomiting 5.33.43.03.4 Appetite Decreased 30.222.616.914.6 New Myalgia 65.537.726.916.7 Aggravated Myalgia 34.724.118.714.0 New Joint Pain 33.024.716.213.1 Aggravated Joint Pain 21.218.015.713.0 Pain Meds 39.324.510.710.5 Fever Meds 22.813.94.85.0

41. 41 Systemic Reactogenicity (PCV13 + TIV vs TIV+ Placebo) within 14 Days (Naive) Systemic Reatogenicity within 14 days of PCV13 administered concomitantly with TIV compared to TIV given with Placebo in a Pneumococcal Vaccine Naïve Population

42. 42 Summary of Reactogenicity for Concomitant Administration of PCV13 +TIV compared to PCV13 and TIV+ Placebo: Studies 3001 and 3008 (Naïve) Solicited Local Reactogenicity –Study 3001 (age 50-59 yrs) PCV13 (42%) > PCV13+TIV (35.6%) for “any” limitation of motion PCV13 +TIV > TIV for all local reactions Solicited Systemic Reactogenicity –Incidence of “any” fever (>38C) not increased with concomitant administration of PCV13+TIV compared to PCV13 or TIV + placebo in studies 3001 and 3008. –In study 3001 and 3008, when compared to PCV 13 or TIV+ placebo, PCV13+ TIV study arm had a higher incidence of these AEs: Fatigue Headache Chills Rash Decreased appetite New and aggravated muscle pain New joint pain Aggravated joint pain

43. 43 Unsolicited Adverse Events within 1 Month Incidence across 6 studies for PCV13 was 11.4 -19.2% Similar incidence in naïve and pre-immunized subjects Similar incidence for initial dose of PCV13 when compared to 23vPS in naïve and pre-immunized subjects: –Naïve subjects Study 004 (60-64 yrs) –PCV 13 (17.0%) vs 23vPS (16.7 %) Study 3010 (60-64 yrs) –PCV 13 (19.2%) vs 23vPS (20.7 %) –Pre-immunized subjects Study 3005 –PCV13 (14.9 % ) vs 23vPS (18.6%) Most frequent AEs reported for PCV13: –Infections and Infestations (4.1-8.6%) –Musculoskeletal (1.6-4.1%) –Gastrointestinal (1.2-2.6%) –General disorders and administration site conditions (0.6-3.1%)

44. 44 Summary of 16 Deaths Across 6 Studies StudyVaccine AdministeredLast Dose Days Post-Dose Age at Death (Yrs) MedDRA Term 3008PCV13 +TIV / Placebo2372Cardiac Failure 3008Placebo +TIV / PCV1322069Peritonitis 3001PCV13 +TIV / Placebo27155Hemoptysis 300523vPS17285 Post-Procedure Pulmonary Embolus 3005PCV13 / PCV1328584 Atherosclerotic coronary artery disease 3005PCV13110471Myocardial Infarction 3005PCV13113587Cardiac Arrest 300523vPS114175Cardiac Failure Congestive 3000PCV13114669Metastatic Neoplasm 3000PCV13118679Septic Shock 3000PCV13119271Lung Neoplasm Malignant 3005PCV13120079Colon Cancer 004PCV13122463 Hepatic neoplasm Malignant, Pancreatic carcinoma, Thrombosis 300523vPS125677Acute Myocardial Infarction 300523VPS126286Cardiac Arrest 3005PCV13130981 Atherosclerotic coronary artery disease

45. 45 Summary of 16 Deaths Across 6 Studies Summay of 16 Deaths (Across 6 Studies) by: –Study –Vaccine Administered –Dose Number –Days Post-Dose –Age at Death –Cause of Death (MedDRA)

46. 46 Deaths (Across 6 Studies) 16 subjects died: 2/16 deaths occurred within 30 days of vaccination –Cardiac Failure at 3 days after PCV13+TIV / Placebo –Peritonitis at 20 days after Placebo+TIV / PCV13 9/16 in study 3005 –Subjects ≥70 years of age 12/5667 (0.21%) received PCV13 or PCV13+TIV 4/1391 (0.29%) subjects received 23vPS

47. 47 Summary of 16 Adverse Events leading to Discontinuation (6 Studies) StudyVaccine Administered Last Dose Days Post-Dose SeverityMedDRA Term 3001Placebo +TIV11ModerateFatigue and Headache 3005PCV13 / PCV1329SevereWorsening of COPD 3008PCC13 +TIV/ Placebo 210Life-threateningAngina pectoris, ECG ST segment elevation 300523vPS123SevereProstate cancer 301023vPS128SevereUnstable Angina 301023vPS139Life-threateningMalignant Melanoma 300523vPS1135ModerateHyperthyroidism, Mental Status Changes 300523vPS1154SevereProstate cancer 3005PCV131174SevereMetastatic prostate cancer/bone 300523vPS1235ModeratePolymyalgia 3005PCV131274Life-threateningCerebral Infarction 300523vPS1284/297Severe / Moderate Atrial Flutter, Congestive Heart Failure / Pneumonia and Pericardial/pleural effusion status post drainage 00423vPS1290SevereLung cancer metastatic 3005PCV131323ModerateAbdominal Pain Upper 3005PCV131329ModerateBladder Neoplasm 300523vPS1365SevereAdenocarcinoma

48. 48 Summary of 16 Adverse Events leading to Discontinuation (6 Studies) Summary of 16 Adverse Events Leading to Discontinuation (Across 6 Studies) by: –Study –Vaccine Administered –Dose Number –Days Post-Dose –Severity and Cause (MedDRA)

49. 49 Adverse Events leading to Discontinuation (Across 6 Studies) 16 subjects discontinued due to adverse events –7 of 16 subjects discontinued due to cancer 6 of 16 subjects received PCV13 9 of 16 subjects received 23vPS 1 of 16 subjects received TIV +placebo

50. 50 Incidence of Serious Adverse Events after Initial Dose (6 Studies) Subjects with SAEsWithin 1 month n (%)Within 6 months n (%) Naïve Subjects: Study 004 Initial Dose PCV13 ( N= 417) (60-64 yrs)1 (0.2)12 (2.9) 23vPS (N= 414) 2 (0.5)10 (2.4) PCV13 (N= 403) (50-59yrs)2 (0.5)5 (1.2) Study 3010 (60-64 yrs) Initial Dose PCV13 (N= 478)2 (0.4)15 (3.1) 23vPS (N= 237)1 (0.4)6 (2.5) Study 3001 (50-59 yrs) PCV13+TIV / Placebo (N=551 / 538)4 (0.7) / 3 (0.6)18 (3.3) Placebo+TIV / PCV13 (N= 560 / 543)5 (0.9) / 6 (1.1)10 (1.8) Study 3008 (>65 yrs) PCV13+TIV / Placebo (N= 576) 4 (0.7) / 5 (0.9)No 6 month follow-up Placebo+TIV / PCV13 (N=575)0 (0) / 8 (1.4)No 6 month follow-up Pre-Immunized Subjects: Study 3000 ( > 68 yrs) PCV13 (N = 1049)10 (1.0)41 (3.9) Study 3005 ( >70 yrs) (Initial Dose) PCV13 (N= 463)3 (0.6)27 (5.8) 23vPS (N= 473)8 (1.7)26 (5.5)

51. 51 Incidence of Serious Adverse Events after Initial Dose (6 Studies) Incidence of Serious Adverse Events after Initial Dose (Across 6 Studies) Within 1 Month and Within 6 Months by –Pneumococcal vaccine naïve status –Pre-immunized status –Study –Treatment arm

52. 52 Serious Adverse Events (Initial Dose, 6 Studies) SAE range within 1 month of vaccination: –0.2% to 1.4% of PCV13 recipients –0.4% to 1.7% of 23vPS recipients. SAE range within 6 months of vaccination: –1.2% to 5.8% of PCV13 recipients –2.4% to 5.5% of 23vPS recipients Categories of SAE: –Age > 65 years Cardiac disorders, cerebrovascular events, neoplasms, respiratory disorders and injuries occurred more frequently than in younger subjects

53. 53 Incidence of Serious Adverse Events after Subsequent Dose (3 Studies) Subjects with SAEsWithin 1 month n (%)Within 6 months n (%) Naïve Subjects: Study 004 Extension Study (Year 3-4) PCV13/ PCV13 (N =108) (60-64 yrs) 1(.01)*N/A PCV13/ 23vPS (N=108)1(.01)N/A 23vPS/ 23vPS (N=189) 0 (0)N/A PCV13 / PCV13 (N=214 ) (50-59yrs) 0 (0)N/A Study 3010 (Year 1) PCV13/ PCV13 (161) (60-64 yrs)0 (0)5 (3.1) PCV13/ 23vPS (266)2 (0.7)6 (2.2) 23vPS / PCV13 (223)1 (0.4)3 (1.3) Pre-Immunized Subjects: Study 3005 (Year 1) PCV13/ PCV13 (N= 391) (>70 yrs)4 (1.0)17 (4.3) 23vPS/ PCV13 (N= 404)7(1.7)21 (5.2) *Erythema multiforme at day 34.

54. 54 Incidence of Serious Adverse Events after Subsequent Dose (3 Studies) Incidence of Serious Adverse Events after Subsequent Dose (Across 3 Studies: 004, 3010 and 3005) Within 1 Month and Within 6 Months by: Pneumococcal vaccine naïve status Pre-immunized status Study Vaccine schedule

55. 55 Conclusions Regarding Safety In 6 clinical studies, which included vaccine naïve and adult subjects with prior receipt of PNEUMOVAX23, no imbalances in deaths or serious adverse events were detected in subjects who received Prevnar13 when compared to PNEUMOVAX23. No safety issues were identified for administration of Prevnar13, as a single dose, to vaccine naïve or pre-immunized adults aged > 50 years –the safety database is not large enough to detect rare events that could occur at a frequency lower than 0.1%. When Prevnar13 was concomitantly administered with TIV, systemic reactogenicity was increased in subjects aged 50-59 yrs and subjects > 65 yrs when compared to administration of TIV or Prevnar13 alone. No data available for concomitant administration of Prevnar13 with adult vaccines other than TIV. No data available for use of Prevnar13 in immunocompromised adults. Safety data will be submitted from the randomized, placebo-controlled CAPITA trial of PCV13 for the prevention of vaccine type pneumococcal pneumonia conducted in 85,000 subjects aged > 65 years in the Netherlands. Safety data will include: –SAEs in the 28 days post-vaccination for subjects not in the immunogenicity cohort –SAEs for 6 months post-vaccination for the 2000 subjects in the immunogenicity cohort –Incidence rates of local, systemic and adverse events for all subjects in the immunogenicity cohort.