1. Basis for Developing a Pneumococcal Conjugate Vaccine for Adults George R. Siber, MD Executive Vice President and Chief Scientific Officer Wyeth Vaccines Research VRBPAC, November 17, 2005

2. 2 Summary 1. Need for another pneumococcal vaccine for adults 2. Advantages of the conjugate pneumococcal vaccine 3. Potential public health impact of adult pneumococcal conjugate 4. Proposed regulatory basis for licensing pneumococcal conjugate vaccine for adults 5. Feasibility of efficacy trials for community acquired pneumonia or invasive pneumococcal disease (IPD)

3. 3 Question # 1 Why do we need another Pneumococcal Vaccine for Adults?

4. 4 Because there are limitations of 23vPs vaccine Antibody titers and efficacy appear to wane after 5 years (Shapiro, et al, NEJM, 1991) Effectiveness is very low in immunocompromised patients 23vPs induces hyporesponsiveness to either another dose of 23vPs (Torling, et al Vaccine, 2003) or to a dose of conjugate (deRoux, et al IDSA, 2005) Re-vaccinations cause more severe adverse events (Jackson, et al JAMA, 1999, Vaccine, 2005) Therefore, 23vPs is generally given only once, which provides only a narrow window of protection during a prolonged period of risk (ACIP recommendation: MMWR, 1997)

5. 5 Cases Cases per 100,000 Deaths Age Group Years Estimated # of deaths Age Group Years And because there remains a substantial invasive pneumococcal disease burden in the US (2004 rates with 60% uptake of 23vPs Vaccine) CDC, ABC Surveillance 2004 (provisional)

6. 6 Question #2 What are the advantages of a pneumococcal conjugate vaccine for adults?

7. 7 Pneumococcal Conjugate Offers Additional Benefits over Ps Vaccine Conjugate antibody responses are significantly better or non-inferior to 23vPs  By both ELISA and OPA Conjugate does not induce hyporesponsiveness to subsequent 23vPs or a 2 nd dose of conjugate Conjugate can therefore be used to extend the age range of protection against pneumococcal disease (i.e.,50-64yo) and to provide long-term protection by repeat dosing, if needed

8. 8 Randomized Trial in Naïve Elderly 70+ years of age (Germany) PnC Ps PnC (PnC/PnC) (PnC/Ps) (Ps/PnC) Year 1 Year 2 N = 110 N = 109 Bleeds for IgG, OPA pre and 1 month post year 1 and year 2 dose N=43 N=38 N=78

9. 9 7vPnC N = 110; 23vPs N = 104-107 * statistically significant * * * * * Immunogenicity of Prevnar vs 23vPs after Dose 1 – ELISA Antibody * GMC (µg/ml)

10. 10 Immunogenicity of Prevnar vs 23vPs after Dose 1 – OPA * * * OPA GMT 7vPnC N = 110; 23vPs N = 104-107 * statistically significant *

11. 11 Randomized Trial in Naïve Elderly Does Prior Ps affect the response to PnC? PnC PsPnC(Ps/PnC) Year 1 Year 2 N = 61 Ps N = 62

12. 12 Prior 23vPs Blunts the Response to Subsequent Prevnar (Hyporesponsiveness) 7vPnC (N=61); 23vPs/7vPnC (N=62) * Statistically significant ELISA GMC (  g/mL) * * * * * *

13. 13 Prior Prevnar Does Not Blunt the Response to a 2 nd Dose of Prevnar 7vPnC (N=61); 7vPnC/7vPnC (N=31) ELISA GMC (  g/mL)

14. 14 PnC Ps PnC Randomized Trial in Naïve Elderly Does prior PnC affect the response to Ps? Year 1Year 2 N=62 PnC (PnC/Ps) N = 30

15. 15 Prior Prevnar Does Not Blunt the Response to Subsequent 23vPs – ELISA Antibody 23vPS (N=62); 7vPnC/23vPs (N=30) ELISA GMC (  g/mL)

16. 16 Would Ps induced hyporesponsiveness improve with longer interval? ELISA GMC µg/ml Seattle Study: > 5 year interval Wyeth Study: 1 year interval Lisa Jackson, unpublished, by permission Ps/PnC 1 yr (Wyeth) (n=62) Ps/PnC >5yr (Seattle) (n=44) Ps/Ps 5yr (Seattle) (n=44)

17. 17 23vPS reduces the response to subsequent doses of 23vPS (Torling, Vaccine 2003) Combined geometric mean pneumococcal antibody concentration (GMC) to six antigens prior to and 4 weeks after primary vaccination and revaccination, respectively, for serotypes 1, 4, 7F, 14, 18C, and 19F. Note that the Y-axis scale for serotype 14 differs from the other serotypes. A: before vaccination; B: 4 weeks after vaccination; C: 1 year after vaccination; D: revaccination after 4–7 years; E: 4 weeks after revaccination.. (Torling, Vaccine 2003)

18. 18 Prevnar Immunogenicity in the Elderly support the following Prevnar conjugate can be used repeatedly without inducing hyporesponsiveness 23vPS can be given after pneumococcal conjugate vaccine without hyporesponsiveness If both vaccine are used to maximize coverage conjugate should be used first

19. 19 Question # 3 What is the potential public health impact of pneumococcal conjugate vaccine for adults?

20. 20 Estimated Impact on Invasive Pneumococcal Disease-Simplifying Assumptions: 23vPs13v ConjugateReference Serotype coverage 75%56%ABC surv. 2003 IPD rates See briefing package. Rates adjusted upward for effect of 23vPs (per Fry et al) ABC, 2004 US census Efficacy (immuno- competent) 88% for 5 years, declining to 0% by 15 years 88% Maintained over at-risk period Shapiro, NEJM 1991 (PS) Efficacy (immuno- compromised) 0% Shapiro, NEJM 1991 (PS) Vaccine uptake 60% in >65 y/o 43% in high risk <65 y/o 0% in healthy <65 y/o 60% in > 50 y/oNHIS, 2004/MMWR, 2004

21. 21 Impact of Extending The Age Range of Protection 50 yr65 yr70 yr IPD Cases (Deaths) Preventable/yr 2979 (489) 23vPs alone

22. 22 Impact of Extending The Age Range of Protection 50 yr65 yr70 yr IPD Cases (Deaths) Preventable/yr 2979 (489) 23vPs alone 13vPnC alone 5544 (895) 86% more than 23vPs

23. 23 13vPnC + 23vPs566 (93) 5544 (895) 6110 (988) Impact of Extending The Age Range of Protection 50 yr65 yr70 yr IPD Cases (Deaths) Preventable/yr 2979 (489) 23vPs alone Conjugate with re-vaccination 13vPnC alone 5544 (895) 86% more than 23vPs

24. 24 This is Conservative Estimate of Public Health Impact of PnC 1. Does not assume higher IPD efficacy, despite higher ELISA and OPA antibody responses 2. Does not assume protection of immunocompromised, although HIV (+) patients and other high risk groups respond better to PnC than Ps 3. Assumes no efficacy against pneumonia, although OPA antibody after PnC in elderly is similar to OPA post 3 doses of PnC in infants.

25. 25 Question #4 Are serologic studies adequate to demonstrate efficacy of adult pneumococcal conjugate?

26. 26 Historically 2 Approaches Used for Licensure of Polysaccharide-based Vaccines 1. When there is no vaccine to prevent the disease in a particular age group, an efficacy trial is required, if feasible  14vPneumococcal Ps  Group A and C Meningococcal Ps  Hib Ps in toddlers  Hib conjugate in infants  Pneumococcal conjugate in infants 2. When there is already a licensed vaccine to prevent the disease in a particular age group, immunogenicity comparison has been acceptable to extend coverage or to improve immunogenicity.  23vPneumococcal Ps after 14vPs in adults  4vMeningococcal Ps after 2vPs in adults  Hib conjugate after Hib Ps in toddlers  4vMening conjugate after 4vPs in adolescents

27. 27 Proposal Licensing Criteria for Adult Pneumococcal Conjugate # 1. Based on regulatory precedents the efficacy of Pneumococcal conjugate vaccine for adults can be proven by showing serologic non-inferiority to the shared serotypes in the licensed 23vPs vaccine based on OPA # 2. Lack of hyporesponsiveness to 2 nd dose of conjugate (which enables using repeated doses, if needed, to maintain protection) # 3. Lack of hyporesponsiveness to 23vPs given subsequently, (which enables extending serotype coverage in high risk groups, if desired)

28. 28 Scientific Basis for Proving Efficacy Based on Serologic Studies 1. The efficacy/effectiveness of 23vPs is established. The capsular Ps is the protective antigen 2. Antibody is the protective mechanism against IPD (passive immunization) 3. Opsonophagocytosis is the functional mechanism whereby antibody protects 4. Induction of opsonophagocytic activity (OPA) is believed to correlate with clinical efficacy and is proposed as the primary basis for comparing adult vaccines 5. Antibody binding assays (e.g., ELISA) can be used as a surrogate when they correlate highly with OPA (e.g., in infants after conjugate vaccine.)

29. 29 Efficacy of 23v Ps Vaccine for IPD has been established StudyPopulationVaccineEfficacy vs IPD Austrian, 1976S. African Miners6, 13 valent82% * Riley, 1977Papua New Guinea14 valent86%** StudyPopulationVaccineEfficacy vs IPD Shapiro, 1991Elderly/high risk14, 23 Overall56% (42, 67) Immunocompetent61% (47, 72) Immunocompromised21% (-55,60) Butler, 1993Elderly/high risk Overall Immunocompetent 14, 23 valent 57% (45, 66) 75% (57, 85) Effectiveness Efficacy * By blood culture ** By blood culture or lung tap

30. 30 Rationale for OPA as a Surrogate for Clinical Efficacy in Adults OPA in infants is high and so is efficacy, i.e., high OPA correlates with high efficacy Type 19F has lower OPA in infants than the other 6 types in Prevnar Although efficacy of Prevnar is high for 19F IPD, it is low for otitis media and inhibition of colonization

31. 31 ELISA and OPA of Infants (140-1) after 3 Doses of Prevnar (7 mos) Serotype ELISA GMC (µg/ml) OPA GMT 6B5.181887.6 9V1.883551.3 18C2.881558.6 19F4.17203.2 23F2.164845.5 N=33-34

32. 32 Efficacy of Prevnar in Infants by Serotype Serotype IPD Efficacy Kaiser 1 IPD Effectiveness (ABC) 2 Otitis (Finland) 3 Colonization (Israel) 4 4-87 (39, 97)49 (-176, 91)- 6B86 (-11,100)88 (65, 96)84 (62, 93)88 (46, 91) 9V100 (-42, 100)100 (79, 100)54 (-48, 86)61 (17, 82) 14100 (60, 100)94 (80, 98)69 (20, 88)49 (4, 73) 18C100 (49, 100)96 (82, 99)58 (-4, 83)- 19F85 (32, 98)81 (52, 93)25 (-14, 51)21 (-17, 46) 23F100 (15, 100)96 (70, 99)59 (35, 75)47 (12, 67) All VT97 (83, 100)92 (86, 95)57 (44, 78)50 (34, 62) 1.Black S., et al PIDJ 2000 2.Whitney C., personal communication 3.Eskola J., NEJM 2001 4.Dagan R., JID 2002

33. 33 Low OPA explains why elderly are at risk of IPD Despite Good ELISA Antibody The conundrum: Elderly adults have similar ELISA antibody levels, even prior to immunization, as infants after Prevnar. Yet they are at high risk of IPD. The explanation: Pneumococcal Ab in the elderly have lower opsonic function relative to infant Ab

34. 34 Pneumococcal Antibody Levels in Unimmunized Elderly vs Infants after Prevnar Infants – Post 3 doses 7vPnC Elderly - Unimmunized ELISA 6B5.181.04 9V1.880.87 18C2.881.15 19F4.171.17 23F2.160.95 Infants: N=33-34; Elderly: N=209-218 (7vPnC & 23vPS Combined)

35. 35 Infants – Post 3 doses 7vPnC Elderly - Unimmunized ELISAOPAELISAOPA 6B5.1818901.0458.1 9V1.8835500.87129 18C2.8815601.1546.9 19F4.172031.1713.6 23F2.1648500.9542.4 Pneumococcal Antibody Levels in Unimmunized Elderly vs Infants after Prevnar Infants: N=33-34; Elderly: N=209-218 (7vPnC & 23vPS Combined)

36. 36 After a single dose of Prevnar, the elderly increase OPA antibody titers to levels similar to infants after 3 doses

37. 37 OPA and ELISA Responses to Pneumococcal Conjugate Vaccine in Elderly vs Infants Infants (140-1) (post 3 doses PnC) Elderly (166-508) (post 1 dose PnC) TypeELISAOPAELISAOPA 6B5.188.02 9V1.889.82 18C2.8812.97 19F4.175.5 23F2.1612.4 Infants: N=33-34; Elderly: N=104-107 (23vPs), 110 (7vPnC)

38. 38 OPA and ELISA Responses to Pneumococcal Conjugate Vaccine in Elderly vs Infants Infants (140-1) (post 3 doses PnC) Elderly (166-508) (post 1 dose PnC) TypeELISAOPAELISAOPA 6B5.1818888.021351.2 9V1.8835519.822914.6 18C2.88155912.971317.5 19F4.172035.5182.2 23F2.16484512.41309.3 Infants: N=33-34; Elderly: N=104-107 (23vPs), 110 (7vPnC)

39. 39 Proposed Licensing Criteria for Adult Pneumococcal Conjugate Demonstrate non-inferiority of the immune response of the shared serotypes in the 13 valent conjugate and 23vPs vaccines  Primary comparison is based on OPA Demonstrate no hyporesponsiveness to 2 nd dose of 13vPnC  To support repeat dosing with 13vPnC for long term protection, if needed Demonstrate no hyporesponsiveness to subsequent dose of 23vPs  To support extending serotype coverage with 23vPnC in high-risk groups, if desired

40. 40 Question #5 Is an Efficacy Trial Feasible for Invasive Pneumococcal Disease or Community Acquired Pneumonia?

41. 41 Constraints on Performing Pneumococcal Conjugate Vaccine Efficacy Trials in Adults for CAP or IPD Placebo-controlled trial is necessary to assess efficacy of 13vPnC Placebo is not possible in high risk adults who are currently recommended to receive 23vPs  > 65 year olds  < 65 year olds with high risk conditions Therefore, only healthy <65 y/o can be studied  In this age-group 72% of all invasive disease occurs in high-risk groups (2004 ABC Surveillance).  Therefore, IPD rates in healthy <65 y/o are much lower than the published rates for this age group overall

42. 42 Pneumococcal Conjugate Vaccine Efficacy Trials Studies of IPD or CAP in healthy 100,000/limb) for adequate power Alternative designs (e.g., sequential 13vPnC/23vPs vs 23vPs alone in high risk groups) cannot demonstrate the efficacy of 13vPnC alone and would be even larger than placebo controlled trials Post-marketing effectiveness studies are the only feasible way to assess impact of 13vPnC on IPD and CAP

43. 43 What is the Sample Size to Show IPD Efficacy Trial in 50-64 y/o Healthy Adults? Assumptions: Incidence rate of 25 per 100,000 (high), 15 per 100,000 (intermediate) or 7.5 per 100,000 (low) Note: CDC estimates pre Prevnar (’99-’00) are 9.9/100,000 in healthy 50-64 y/o. (Kyaw et al. JID 2005) 56% of IPD covered by 13vPnC True V E of 70%, 80% or 90% for vaccine type IPD 90% power Lower 95% confidence interval of > 30% Trial length of 3 yrs: 1 yr enrollment, 2 yrs follow-up

44. 44 Invasive Disease Efficacy Trial in 50-64 y/o Sample Size Calculations

45. 45 Demonstration of Efficacy against CAP is Risky and/or Impractical Can ethically study only < 65 y/o without underlying conditions   low CAP risk  very large sample sizes Proportion of all CAP due to pneumococcus is not known, making required trial size uncertain   risk Etiologic diagnosis of pneumonia would enable smaller trial size, but no validated techniques exist (sensitivity and specificity unknown)   risk: Lack of validated outcome is “show-stopper” for VT- specific CAP efficacy trial Ability to enroll large numbers of healthy, low risk adults and to ascertain outcomes by non-routine methods is uncertain   risk

46. 46 Conclusions The 13v pneumococcal conjugate vaccine has the potential for a significant public health impact because it can extend the duration of protection throughout the high risk period The 23vPs vaccine may be given after the 13vPnC to expand serotype protection in high-risk patients Efficacy of a conjugate vaccine in adults can be proven by showing non-inferiority of the immune response to the licensed polysaccharide vaccine for the serotypes in the conjugate vaccine Placebo controlled efficacy studies in the adult population are not feasible due to ethical considerations and size Effectiveness against IPD can be confirmed by post marketing studies

47. 47 BACK-UPS

48. 48 HIV+ Study: PS can be given after PnC if desired Conducted under the auspices of the Agence National de Recherches sur le SIDA (ANRS) PnC/23vPS at least as good as or better than 23vPS alone P<0.05 for all serotypes except 6B GMCs after PS 1 month interval between vaccines

49. 49 OPA and ELISA Responses to Pneumococcal Conjugate Vaccine in Elderly vs Infants Infants (140-1) (post 3 doses PnC) Elderly (166-508) (post 1 dose PnC) Elderly (166-508) (post 1 dose 23vPs) TypeELISAOPA OPA/ ELISAELISAOPA OPA/ ELISAELISAOPA OPA/ ELISA 6B5.181888364.68.021351.2168.54.56809.2177.3 9V1.8835511884.49.822914.6296.73.63984.6271.6 18C2.881559540.912.971317.5101.66.82464.668.1 19F4.1720348.75.5182.233.14.43202.745.8 23F2.1648452243.112.41309.3105.73.97302.476.3 Infants: N=33-34; Elderly: N=104-107 (23vPs), 110 (7vPnC)

50. 50 Pneumococcal Antibody Levels in Unimmunized Elderly vs Infants after Prevnar Infants – Post 3 dosesElderly - Pre ELISAOPAOPA/ELISAELISAOPAOPA/ELISA 6B5.1818903651.0458.155.7 9V1.88355018800.87129147 18C2.8815605411.1546.940.7 19F4.1720348.71.1713.611.7 23F2.16485022400.9542.444.4 Infants: N=33-34; Elderly: N=209-218 (7vPnC & 23vPS Combined)

51. 51 What is the sample size estimate for a CAP efficacy trial?

52. 52 Community Acquired Pneumonia Efficacy Trial in 50-64 y/o Healthy Adults Assumptions for sample size calculations:  Event rate for CAP of 350 per 100,000 person-years  30% of CAP is pneumococcal  56% of pneumococcal CAP is vaccine-type (13vPnC)  Vaccine efficacy of 70% for CAP due to vaccine serotypes  90% power  Lower 95% confidence limit > 0% (and > 30% for VTCAP)  Trial length of 3 yrs: 1yr enrollment, 2yrs mean follow- up

53. 53 Community Acquired Pneumonia Efficacy Trial: Sample Size Calculation (50-64 y/o) With these assumptions  Event rate for CAP due to vaccine types is 58.8 / 100,000 (350 x 0.3 x 0.56)  Effectiveness against all CAP is 11.8% (.70 x.30 x.56) Sample size per group for average 2 years of follow-up No. of cases in placebo gp. No. of subjects per gp. All CAP (LCI 95 > 0)2,676199,123 VT CAP (LCI 95 > 0) (LCI 95 > 30) 35 69 20,420 41,691 (assuming 100% specificity and 100% sensitive assay)

54. 54 REACTOGENICITY OF Prevnar vs 23vPs in elderly adults

55. 55 Local Reactions* within 7 Days of Prevnar or 23vPs Swelling at injection sitePain at injection siteRedness at injection site * More severe reactions in red

56. 56 Systemic Reactions* within 7 Days of Prevnar or 23vPs 0 10 20 30 40 50 60 70 7vPnC23vPs 7vPnC -23vPs 23vPs -7vPnC 7vPnC -7vPnC % Subjects Dose 1Dose 2 * NS * Fever > 38°C, fatigue, headache, chills, rash, vomiting, decreased appetite, muscle and/or joint pain. Marks significant differences compared to group following hyphen (-).

57. 57 Seattle Study: PnC and Ps as a second dose after Ps > 5 years previous Redness Arm Mvt Limited PainSwelling Jackson, L., Neuzil, K., Whitney, C. et al Vaccine 2005 Local Reactions within 7 Days

58. 58 23vPS reduces the response to subsequent doses of 23vPS Combined geometric mean pneumococcal antibody concentration (GMC) to six antigens prior to and 4 weeks after primary vaccination and revaccination, respectively, and 1 year after primary vaccination, in 61 middle age and elderly persons (Torling, Vaccine 2003)

59. 59 23vPS reduces the response to subsequent doses of 23vPS Combined geometric mean pneumococcal antibody concentration (GMC) to six antigens prior to and 4 weeks after primary vaccination and revaccination, respectively, and 1 and 3 years after primary vaccination, in 20 middle age and elderly persons. (Torling, Vaccine 2003)

60. 60 23vPS reduces the response to subsequent doses of 23vPS Combined geometric mean pneumococcal antibody concentration (GMC) to six antigens prior to and 4 weeks after primary vaccination and revaccination, respectively, in relation to age at primary vaccination. Circles: 50–68 years; squares: ≥69 years. (Torling, Vaccine 2003) O = 50 – 68 years  = > 69 years

61. 61 23vPS reduces the response to subsequent doses of 23vPS Geometric mean antibody fold increase to six pneumococcal capsular polysaccharide antigen, and all types combined, after primary vaccination and revaccination with 23-valent pneumococcal vaccine in 61 patients. (Torling, Vaccine 2003)

62. 62 23vPS reduces the response to subsequent doses of 23vPS Geometric mean antibody fold increase after primary vaccination and revaccination, respectively. (Torling, Vaccine 2003)