1. By Ahmed Khaled Vaccine team Pfizer KSA Ahmed.khaled@pfizer.com

2. In the Year 2000,Prevenar was the first PCV to be licensed for the prevention of PD in children. For more than 9 years Prevenar had significantly reduced the incidence of PD in children and adult through direct and Indirect Effect. In 2009,Prevenar 13 was licensed to provide the broadest coverage of any PCV.

3. Why children need Broadest coverage

4. Global IPD serotype distribution among children <5 years – before pneumococcal conjugate vaccination *Weighted by regional disease burden Serotype Serotyped isolates (%) Cumulative distribution (%) Serotypes by rank order and cumulative serotype distribution Pneumococcal Global Serotype Project (version 2), 30 November 2008. Prepared by GAVI’s PneumoADIP Serotypes covered by Prevenar(PCV7)

5. Global IPD serotype distribution among children <5 years *Weighted by regional disease burden Serotype Serotyped isolates (%) Cumulative distribution (%) Serotypes by rank order and cumulative serotype distribution Pneumococcal Global Serotype Project (version 2), 30 November 2008. Prepared by GAVI’s PneumoADIP Important serotypes not covered by Prevenar (PCV7)

6. Global IPD serotype distribution among children <5 years – before pneumococcal conjugate vaccination *Weighted by regional disease burden Serotype Serotyped isolates (%) Cumulative distribution (%) Serotypes by rank order and cumulative serotype distribution Pneumococcal Global Serotype Project (version 2), 30 November 2008. Prepared by GAVI’s PneumoADIP Prevenar 13 contains the 13 serotype causing most of IPD in children < 5 years.

7. 7 Rationale for inclusion of additional serotypes in PCV13 Serotype 1 Important cause of pneumococcal disease in many regions Cause of epidemic disease Important cause of pneumococcal pneumonia, predominant serotype in empyema in children Serotype 5 Cause epidemic disease Among the leading serotypes in Africa and South America Serotype 7F Important cause of pneumococcal disease globally, increasing in many European countries Higher case fatality reported from Germany Serotype 3 Important cause of pneumococcal disease including pneumonia and AOM Increasingly reported in IPD in Europe Among the leading serotypes in CAP and IPD in adults Serotype 6A Commonly found in carriage and frequently antibiotic resistant Important cause of pneumococcal disease, particularly AOM Decrease in 6A pediatric IPD following use of PCV7, remaining disease may be mostly 6C Serotype 19A Commonly found in carriage and frequently antibiotic resistant Significantly increased in IPD globally Commonly found in AOM 19F antibodies from PCV7 vaccination do not cross-protect for 19A infection Dagan et al. J Infect Dis 2008;197(8):1094-102. Dagan et al. Clin Infect Dis 2000;30(2):319-21. Brueggemann et al. Journal of Clinical Microbiology 2003;41(11):4966-70, Gratten Med J Aust 1993;158(5):340-2, Nunes et al. Clin Microbiol Infect 2008;14(1):82-4, Romney et al. Clin Infect Dis 2008;47(6):768-74, Ruckinger et al. Pediatr Infect Dis J 2009;28(2):118-22, Whitney et al. Lancet 2006;368(9546):1495-502, Dagan & Klugman Lancet Infect Dis, 8(12), 785-795 (2008), Byington et al. Pediatr Infect Dis J, 25(3), 250-254 (2006), Fletcher et al. Pediatr Infect Dis J, 25(6), 559-560 (2006), Cohen et al. Vaccine, (2009) in press, Hausdorff WP, Vaccine, 25(13), 2406-2412 (2007), Imohl et alClin Microbiol Infect, (2009), in press)

8. Summary for the 6 additional serotypes 1,5,7F3,6A,19A Age group Above 2 YearsBelow 2 Years IPD/NIPDMainly IPDBoth IPD/NIPD ColonizationRarely colonizedCommonly Colonized AB resistanceAB resistance is lowAB resistance is high

9. Serotype 19A :in USA Hicks LA, Harrison LH, Flannery B, et al; for the Active Bacterial Core Surveillance Program of the Emerging Infections Program Network. Incidence of pneumococcal disease due to non–pneumococcal conjugate vaccine (PCV7) serotypes in the United States during the era of widespread PCV7 vaccination, 1998–2004. J Infect Dis. 2007;196:1346-1354

10. 8. Lepoutre A, Varon E, Georges S,et al. Impact of infant pneumococcal vaccination on invasive pneumococcal diseases in France, 2001-2006. Euro Surveill. 2008;13:1-6. 9. Aguiar SI, Serrano I, Pinto FR, et al; on behalf of Portuguese SurveillanceGroup for the Study of Respiratory Pathogens. Changes in Streptococcus pneumoniae serotypes causing invasive disease with non-universal vaccination coverage of the seven-valent conjugate vaccine. Clin Microbiol Infect. 2008;14:835-843. 10. Barricarte A, Castilla J, Gil-Setas A, et al. Effectiveness of the 7-valent pneumococcal conjugate vaccine: a population-based case-control study. Clin Infect Dis. 2007;44:1436-1441. 11. Centers for Disease Control and Prevention. Invasive pneumococcal disease in children 5 years after conjugate vaccine introduction—eight states, 1998–2005. MMWR. 2008;57:144-148. 12. Bekri H, Cohen R, Varon E, et al. Streptococcus pneumoniae serotypes involved in children with pleural empyemas in France. Arch Pediatr. 2007;14:239-243. 13. Cliff D, Spencer DA, Paton JY, et al. The first year of enhanced surveillance of pneumococcal empyema in UK children. Poster presented at: 26th Annual Meeting of ESPID; May 13-17, 2008; Graz, Austria.

11. 9. Dagan R, Givon-Lavi N, Leibovitz E, et al. Introduction and expansion of multidrug-resistant Streptococcus pneumoniae serotype 19A clones causing acute otitis media in an unvaccinated population. J Infect Dis. In press.

12. Distribution of serotypes in KSA 2000-2004 Shibl AM. Clin Microbiol Infect 2008; 14 (9): 876-879

13. Antibiotic resistance in children <5 years 2000-2004 Shibl AM. Clin Microbiol Infect 2008; 14 (9): 876-879

14. PCV746B9V1418C19F23F PCV7 13 46B9V1418C19F23F 1356A7F19A With six additional serotypes PCV7 13 offers the broadest serotype coverage against pneumococcal disease PCV13 contains the same carrier protein – CRM 197, a carrier protein used in bacterial conjugate vaccines for more than 20 years

16. Why selecting CRM197 as a carrier for Prevenar 13

17. Experience with Carrier Protein – CRM 197 Carrier Protein - CRM197 Non-toxic variant of diphtheria toxin Over 300M doses delivered in conjugate vaccines for past 20 years Used in HibTITER, Meningitec, and Prevenar Over 75 clinical studies of vaccines containing CRM197 Can be administered concomitantly with other routine pediatric vaccines. More Immunogenic than Protein D carrier used in PCV10

18. 18 Total levels of antibodies (GMC values)elicited - post primary series (2, 3, 4 mos)* Prevenar (CRM 197 based) elicited significantly higher levels of antibodies (ELISA GMCs) for all 7 common serotypes GMC (µg/mL) *only 7 common serotypes shown, † n indicates number of subjects with available results for at least one serotype † † Vesikari T et al. Pediatr Infect Dis J 2009;28(4):S66-76

19. 19 Total levels of antibodies (GMC values) - post booster* (2, 3, 4 & 12-18 mos), 4 doses of either PCV10 or PCV7 **Prevenar elicited significantly higher GMCs for 5(conjugated to Protein D) of 7 common serotypes ^PCV10 elicited significantly higher ELISA GMCs for serotype 19F ** ^ GMC (µg/mL) *only 7 common serotypes shown, † n indicates number of subjects with available results for at least one serotype †† Vesikari T et al. Pediatr Infect Dis J 2009;28(4):S66-76

20. Total levels of antibodies (GMC Levels )Post Booster* (2, 3, 4 & 12-18 mos)- 4 doses of either PCV10 or PCV7 Vesikari T et al. Pediatr Infect Dis J 2009;28(4):S66-76 GMC (µg/mL) Protein D is a less immunogenic carrier than CRM 197 *only 7 common serotypes shown, † n indicates number of subjects with available results for at least one serotype ††

21. Prevenar 13

22. Therapeutic indications –Active immunization for the prevention of invasive disease, pneumonia and acute otitis media caused by Streptococcus pneumoniae in infants and children from 6 weeks to 5 years of age.

23. Prevenar 13 is Indicated for Active immunisation for the prevention of invasive disease, pneumonia & acute otitis media caused by Streptococcus pneumoniae in infants & children from 6 weeks to 5 years of age (SMPC Section 4.1) Prevenar 13 SmPC 2009 and adapted from Bogaert D, et al. The Lancet Infectious Diseases. 2004;4(3):144-154.

24. Pneumonia is the Leading Killer of Children Worldwide WHO, Pneumonia: The Forgotten Killer of Children, 2006

25. Pneumonia is the Leading Killer of Children Worldwide WHO, Pneumonia: The Forgotten Killer of Children, 2006

26. Prevenar 13 has the Broadest Serotype Coverage of any PCV Based on serotype surveillance in Europe performed before the introduction of Prevenar, Prevenar 13 is estimated to cover 73-100 % (depending on the country) of serotypes causing invasive pneumococcal disease (IPD) in children less than 5 years of age. (SMPC Section 5.1) In this age group, serotypes 1, 3, 5, 6A, 7F, and 19A account for 15.6 % to 59.7 % of invasive disease, depending on the country the time period studied, and the use of Prevenar1. (SMPC Section 5.1) 1 Prevenar 13 SmPC 2009

27. Prevenar 13 Dosing

28. Prevenar 13 vaccine schedule for infants and children previously vaccinated with Prevenar (7-valent) Transition from Prevenar to Prevenar 13 at any point during the schedule Dose 1Dose 2Dose 3Booster Child 1 PREVENAR Prevenar 13 (1 or 2 doses)* Child 2 PREVENAR Prevenar 13 (1 or 2 doses)* Child 3 PREVENAR Prevenar 13 Child 4 Prevenar 13

29. ACIP recommendation for Children completely vaccinated with PCV7

30. ACIP recommendation for High risk children >24 months NB:Prevenar 13 is approved in EMEA only up to 5 years

31. It is recommended that infants who receive a first dose of Prevenar 13 complete the vaccination coursewith Prevenar 13.

32. Method of administration The vaccine should be given by intramuscular injection. The preferred sites are the anterolateral aspect of the thigh (vastus lateralis muscle) in infants or the deltoid muscle of the upper arm in young children.

33. Contraindications Hypersensitivity to the active substances, to any of the excipients (see section 6.1), or to diphtheriatoxoid. As with other vaccines, the administration of Prevenar 13 should be postponed in subjects suffering from acute, severe febrile illness. However, the presence of a minor infection, such as a cold, should not result in the deferral of vaccination.

34. Special precautions for storage Store in a refrigerator (2°C–8°C). Do not freeze.

35. Concomitant vaccine conclusions PCV13 can be given with any of the following vaccine antigens, either as monovalent or combination vaccines: –Diphtheria –Tetanus –Acellular or whole cell pertussis –Haemophilus influenzae type b –Inactivated poliomyelitis –Hepatitis B –Meningococcal serogroup C –Measles, mumps, rubella and varicella –Rotavirus vaccine (safety evaluation) –Hepatitis A (safety evaluation)

36. Safety Conclusions The safety profile of PCV13 is comparable to that of PCV7 The most commonly reported adverse reactions were –Injection-site reactions –Fever –Irritability –Decreased appetite –Increased and/or decreased sleep

37. Scientific foundation of Prevenar 13

39. StudySample SizeEfficacy in ITT, %, (95% CI) United States 1 (1995-1998, PCV7, 4 doses) 37,868 94% (80-99) United States (American Indians) 2 (1997-2000, PCV7, 4 doses) 8,29283% (21-96) South Africa (1998-2001 3, PCV9*, 3 doses) 39,836 HIV-negative 83% (39-97) HIV-positive 65% (24-86) The Gambia (2000-2004 4, PCV9, 3 doses) 17,43771% (46-86) Efficacy of Prevenar (PCV7) Clinical Studies of PCV in IPD: Summary 1. Black S, et al. Pediatr Infect Dis J. 2000;19:187-195.3. Klugman KP, et al. N Engl J Med. 2003;349:1341-1348. 2. O’Brien KL, et al. Lancet. 2003;362:355-361.4. Cutts FT, et al. Lancet. 2005;365:1139-1146. *Investigational vaccine, not available commercially † IPD included culture-confirmed pneumonia, meningitis, or bacteremia Evaluation of Efficacy of PCV in Infants Against IPD 1-4 Efficacy studies have demonstrated PCV7 and investigational PCV9 decreases incidence of vaccine serotype-specific IPD 1-4†

40. Efficacy of Prevenar (PCV7) Clinical Studies of PCV in CXR-positive Pneumonia 1.Black SB, et al. Pediatr Infect Dis J. 2002;21:810-815. 2.Hansen J, et al. Pediatr Infect Dis J. 2006;25:779-781. StudyEfficacy (95% CI) [CXR-positive Pneumonia † (ITT)] PCV7 United States—NCKP 1 18% (5-29) Re-analysis of NCKP (WHO criteria) 2 26% (7-41) Investigational PCV9* South Africa 3 Total population 17% (4-28) HIV-negative 20% (2-35) HIV-positive 13% (-7-29) The Gambia 4 36% (27-43) *Investigational 9-valent pneumococcal conjugate vaccine † All-cause hospitalization and mortality reduced by 15% and 16%, respectively CXR=chest x-ray; NCKP=Northern California Kaiser Permanente 3.Klugman KP, et al. New Engl J Med. 2003;349:1341-1348. 4.Cutts F, et al. Lancet. 2005;365:1139-1146. Efficacy of PCV7 and PCV9* in Radiologically Confirmed Pneumonia 1-4 PCV decreases radiologically documented alveolar pneumonia 1-4

41. Efficacy of Prevenar (PCV7) Clinical Study of PCV in AOM/OM (Finland, U.S.) Finnish Trial, Follow- up 1,2 n=1,662 Age <2 yrs NCKP Trial, Follow-up 3,4 n=37,868 Age <2 yrs All AOM/OM episodes6%7% OM visits--9% Recurrent OM episodesRange, 16%-18%Range, 9%-26% Tympanostomy tube placement*39% 2 24% 4 All pneumococcal AOM episodes34%-- All vaccine-serotype AOM episodes57%-- 1.Eskola J, et al. N Engl J Med. 2001;344:403-409. 2.Palmu AA, et al. Pediatr Infect Dis J. 2004;23:732-738. 3.Black S, et al. Pediatr Infect Dis J. 2000:19:187-195. 4.Fireman B, et al, Pediatr Infect Dis J. 2003; 22:10-16. PCV7 Efficacy Results for OM Outcomes—Per-Protocol Analysis PCV7 significantly decreases otitis media and associated outcomes at follow-up *Tympanostomy tube placement is a marker of more severe AOM

42. What is the safety profile of the vaccine shown in clinical trials and real world use? What is the ability of the vaccine to reduce the incidence of disease shown in real world use? What is the ability of the vaccine to reduce the incidence of disease shown in clinical trials? Is the vaccine able to produce the protective level of antibodies? What is the Percentage of IPD cases in certain population that is caused by the vaccine serotypes? Criteria for evaluating PCVs: Epidemiology Immunogenicity Efficacy Effectiveness Safety

43. S. pneumoniae Disease Burden in Children Otitis media Pneumonia Bacteremia Meningitis Disease severity For each case of pneumococcal meningitis in a year: X 1000 to 10,000 X 100 to 1000 X 10 Prevalence Invasive Non-invasive Adapted from: American Academy of Pediatrics. Pediatrics. 2000;106:367-376 & MMWR. 1997;46:1-24

44. Effectivness of Prevenar (PCV7) PCV Effectiveness AOM Antibiotic resistance Herd immunity Pneumonia IPD

45. Effectivness of PCV PCV Effectivness AOM Antibiotic resistance Herd immunity Pneumonia IPD

46. Adapted from Hicks LA, et al. J Infect Dis. 2007;196:1346-1354. Effectiveness of PREVENAR * IPD (U.S.) PREVENAR introduced baseline Cases/100,000 population Design: U.S. study in children <5 years of age. Latest published data from U.S. CDC’s Active Bacterial Core surveillance Rates of IPD Among Children <5 Years of Age Year Because PREVENAR was first studied and licensed in the U.S., much effectiveness data come from there IPD significantly declined in the U.S. since the introduction of PREVENAR in 2000 *Trademark

47. Effectiveness of PREVENAR * IPD (Canada) Cases of infection/100,000 Adapted from Kellner JD, et al. CMAJ. 2005;173:1149-1151. Year 81.6% decrease in IPD (all serotypes) (p=0.02) 93.4% decrease in IPD (PREVENAR and related serotypes) (p<0.001) Cases of Pneumococcal Infection per 100,000 in Children <2 Years of Age PREVENAR introduced In Canada, rates of pneumococcal infection in children aged ≤23 months declined 81.6% *Trademark

48. Effectiveness of PREVENAR * IPD (Australia) 1. Roche PW, et al. Commun Dis Intell. 2006;30:80-92. 2. Roche PW, et al. Commun Dis Intell. 2008;32:18-30. Rate/100,000 population PREVENAR recommended for all indigenous children Universal PREVENAR vaccination Year Rate of IPD Following Vaccination of Indigenous Children Beginning in 2001, Universal Vaccination Beginning in 2004 (Children <2 Years of Age) 1,2 As more regions study the effects of routine PREVENAR vaccination, similar outcomes to the U.S. studies are being realized The rate of IPD caused by vaccine serotypes in Australia decreased by 74% between 2001 and 2004 1 *Trademark

49. Adapted from Dubos F, et al. Arch Dis Child. 2007;92:1009-1012. Effectiveness of PREVENAR * Pneumococcal Meningitis (France) As PREVENAR vaccine use increased, pneumococcal meningitis cases decreased Estimated pneumococcal meningitis cases (all serotypes) Vaccine doses sold Year Relationship Between Number of Meningitis Cases † (Children <18 Years of Age) and Distributed Vaccine Doses † Estimated cases of pneumococcal meningitis *Trademark

50. PREVENAR introduced PREVENAR introduced Adapted from Tsai CJ, et al. Clin Infect Dis. 2008;46:1664-1672. Effectiveness of PREVENAR * Pneumococcal Meningitis (U.S.) Trends in Hospitalizations for Pneumococcal Meningitis (All Ages) and Mortality Rates in the U.S., 1994 to 2004 Bars represent 95% CIs Hospitalization rate/100,000 Year Mortality rate/100,000 Year HospitalizationsIn-hospital deaths After the introduction of PREVENAR, annual rates for pneumococcal meningitis hospitalizations and mortality decreased and then remained relatively stable during following years 33% decrease *Trademark

51. PREVENAR introduced PREVENAR introduced Adapted from Tsai CJ, et al. Clin Infect Dis. 2008;46:1664-1672. Effectiveness of PREVENAR * Pneumococcal Meningitis (U.S.) Trends in Hospitalizations for Pneumococcal Meningitis (All Ages) and Mortality Rates in the U.S., 1994 to 2004 Bars represent 95% CIs Hospitalization rate/100,000 Year Mortality rate/100,000 Year HospitalizationsIn-hospital deaths After the introduction of PREVENAR, annual rates for pneumococcal meningitis hospitalizations and mortality decreased and then remained relatively stable during following years 33% decrease *Trademark

52. Effectivness of PCV PCV Effectiveness AOM Antibiotic resistance Herd immunity Pneumonia IPD

54. PREVENAR introduced into routine vaccination schedules in the U.S. Zhou F, et al. Arch Pediatr Adolesc Med. 2007;161:1162-1168. Effectiveness of PREVENAR * Pneumococcal Pneumonia-related Health Care Utilization Hospitalization rates for pneumococcal pneumonia declined 57.6% Hospitalizations (Cases per 1,000 Person-years) for Pneumococcal Pneumonia (Children <2 Years of Age) Year Hospitalizations ↓ 57.6% (p<0.001) † † p-values for 2004 vs 1997 Hospitalizations/1,000 person-years *Trademark

56. Effectiveness of PREVENAR * Pneumonia (U.S.) Grijalva CG, et al. Lancet. 2007;369:1179-1186. † Design: Interrupted time-series analysis comparing admission rates for 2001 to 2004 (years following PREVENAR introduction) to expected rates calculated for 1997 to 1999 ‡ p<0.0001 Estimated % Reduction in U.S. Admission Rates for All-cause and Pneumococcal Pneumonia, 2004 † Age (yrs)All-cause Pneumonia Reduction (CI) Pneumococcal Pneumonia Reduction (CI) <2 39% ‡ (22-52) 65% ‡ (47-77) *Trademark After the introduction of PREVENAR, there was a 39% annual decline in all-cause pneumonia admissions—representing ~41,000 fewer pneumonia admissions in 2004 in children <2 years of age

57. Effectivness of PCV PCV Effectivness AOM Antibiotic resistance Herd immunity Pneumonia IPD

59. Effectivness of PCV PCV Effectivness AOM Antibiotic resistance Herd immunity Pneumonia IPD

60. Effectiveness of PREVENAR * Indirect Effect—IPD (U.S.) † Active Bacterial Core surveillance, United States, 1998 to 2003 ‡ p<0.05, 2003 vs 1998-1999 Rate of Vaccine-type (VT) IPD Before and After Introduction of PREVENAR, by Age Group and Year † 94% reduction 65% reduction Routine childhood immunization programs Unvaccinated population Adapted from CDC. Morb Mortal Wkly Rep. 2005;54:893-897. PREVENAR vaccination was associated with a reduction in IPD in vaccinated and unvaccinated populations ‡ Rate/100,000 Age group (y) *Trademark ‡

61. Effectiveness of PREVENAR * Indirect Effect (U.S.) The CDC Surveillance System has reported an increased incidence of IPD due to nonvaccine serotypes in children <5 and in adults ≥40 years of age. It is unknown whether these effects would be observed in other populations. † Direct VT IPD cases prevented in 2003 = 1998/1999 average number of VT IPD cases in children <5 years of age x 2003 PREVENAR coverage with 3 doses (68.1%) x PREVENAR effectiveness for VT IPD (93.9%) ‡ Indirect VT IPD cases prevented in 2003 = (1998/1999 average number of VT IPD cases across all ages – 2003 number of VT IPD cases across all ages) – 2003 direct VT IPD cases prevented Note: Calculation of indirect cases prevented does not account for replacement disease Adapted from CDC. MMWR. 2005;54:893-897. Estimated Vaccine-type Cases Averted by Direct † and Indirect Effects ‡ of PREVENAR: U.S., 2003 Estimated cases prevented (no.) 25,000 20,000 15,000 10,000 5,000 0 *Trademark

63. Effectivness of PCV PCV Effectivness AOM Antibiotic resistance Herd immunity Pneumonia IPD